Medical Microbiology

Section 4 Clinical manifestation and diagnosis of infections by body system

29 Fever of unknown origin

Introduction

Fever is an abnormal increase in body temperature and may be continuous or intermittent

The homeostatic mechanisms of the body maintain a constant body temperature with daily fluctuations (circadian temperature rhythm) not exceeding ±    1–1.5°C. Although 37°C (98.6°F) is taken as ‘normal’, individuals vary in their body temperature; in some it may be as low as 36°C, in others as high as 38°C. Fever is defined as an abnormal increase in body temperature – an oral temperature higher than 37.6°C (100.4°F) or a rectal temperature higher than 38°C (101°F) – and may be continuous or intermittent:

• In continuous fever the body temperature is elevated over the whole 24-h period and swings less than 1°C; this is characteristic of, for example, typhoid and typhus fever.

• In an intermittent fever the temperature is above normal throughout the 24-h period, but swings more than 1°C during that time. A swinging fever is typical of pyogenic infections, abscesses and tuberculosis.

Fever may be produced in response to:

• exogenous pyrogen such as endotoxin in Gram-negative cell walls

• endogenous pyrogen such as interleukin 1 (IL-1) released from phagocytic cells.

It is thought that fever may be a protective response by the host (Fig. 29.1).

Figure 29.1 Mechanisms of fever. Fever may be induced either by exogenous pyrogens such as microbes or their toxins or by endogenous pyrogens released in the host, and may have a protective effect. IL-, interleukin; PG, prostaglandin; TNF, tumour necrosis factor.

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 abortusB. 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 rickettsiiRickettsia 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:

• seriously ill neonates

• the elderly

• patients with uraemia

• patients receiving corticosteroids

• those taking antipyretic drugs continuously.

In these people, other signs and symptoms of infection have to be sought. This chapter deals only with patients whose presenting complaint is fever.

Investigation of classic FUO

Steps in the investigative procedure

Because of the many possible infectious and non-infectious causes of FUO, it is clearly not practical to attempt specific investigations for each at the outset. However, an example of the minimum diagnostic evaluation necessary to categorize a presenting case as FUO is shown in Box 29.1. In addition, the diagnostic pathway can be divided into a series of stages, each stage attempting to focus the investigation on the likely causes (Fig. 29.3).

Box 29.1 Example of Minimum Diagnostic Evaluation Necessary to Categorize a Case as Classical Fever of Unknown Origin

• Comprehensive history (including travel history, risk for venereal diseases, hobbies, contact with pet animals and birds, etc.)

• Comprehensive physical examination (including temporal arteries, rectal digital examination, etc.)

• Routine blood tests (complete blood count including differential, ESR or CRP, electrolytes, renal and hepatic tests, creatine phosphokinase and lactate dehydrogenase)

• Microscopic urinalysis

• Cultures of blood, urine (and other normally sterile compartments if clinically indicated, e.g. joints, pleura, cerebrospinal fluid)

• Chest radiograph

• Abdominal (including pelvic) ultrasonography

• Antinuclear and antineutrophilic cytoplasmic antibodies, rheumatoid factor

• Tuberculin skin test

• Serological tests directed by local epidemiologic data

• Further evaluation directed by abnormalities detected by above test, e.g.:

    • HIV antibodies depending on detailed history

    • CMV-IgM and EBV serology in case of abnormal differential WBC count

    • Abdominal or chest helical CT scan

    • Echocardiography in case of cardiac murmur

(Adapted from, Knockaeert, D. C., Vanderschuern, S., Blockmans, D. (2003) Fever of unknown origin in adults: 40    years on. From the Department of General Internal Medicine, Gasthuisberg University Hospital, Leuven, Belgium. J Intern Med 253:263–275.)

Figure 29.3 Computerized tomography (CT) scans help in the demonstration of abscesses. The patient in (A) has a tuberculoma of the brain, but the CT appearance is not sufficiently characteristic to distinguish this from a pyogenic abscess or a meningioma. (Courtesy of J. Ambrose.) The chest radiograph in (B) shows a patient with sarcoidosis. The differential diagnosis between infective and non-infective causes of granulomas is important, and can be difficult in the early stages of the investigation.

(Courtesy of M. Turner-Warwick.)

Stage 1 comprises careful history-taking, physical examination and screening tests

Careful history-taking is essential and should include questions about travel, occupation, hobbies, exposure to animals and known infectious hazards, antibiotic therapy within the previous 2    months, substance misuse and other habits. Some of the infections listed in Table 29.2 are zoonoses (e.g. leptospirosis, spotted fevers), whereas others are vector-borne (e.g. malaria, trypanosomiasis) and/or of limited geographic distribution (e.g. histoplasmosis), hence the importance of a travel history.

In the light of the history and the differential diagnosis, a complete physical examination of the patient with FUO is essential, in particular:

• the skin, eyes, lymph nodes and abdomen should be examined

• the heart should be auscultated.

It is also important to confirm that the patient does have a fever. In some series, as many as 25% of patients whose presenting complaint was an FUO did not have a fever, but had a naturally exaggerated circadian temperature rhythm. The possibility of a factitious fever must also be considered.

Routine investigations such as chest radiography and blood tests should be performed at this stage.

Stage 2 involves reviewing the history, repeating the physical examination, specific diagnostic tests and non-invasive investigations

A review of the patient’s history, particularly after discussion with colleagues and perhaps carried out by a second physician, is valuable to check for omissions such as exposure to particular risk factors in the recent or more distant past. The physical examination should also be repeated because rashes and other signs of infection can be transient.

Clues to the diagnosis elicited by careful history-taking should direct specific investigations. As the most common cause of unexplained fever is infection, collection and careful examination of appropriate specimens are essential. Skin tests may also be appropriate at this stage. The most important specimens include:

• blood for culture

• blood for examination of antibodies. A sample of serum collected when the patient presents should also be stored for comparison with later samples to detect rising antibody titres even if the patient is some weeks into the infection. Serologic tests are helpful, particularly in the diagnosis of cytomegalovirus (CMV) and Epstein–Barr virus (EBV) infection, toxoplasmosis, psittacosis and rickettsial infections. Positive results in syphilis serology should be viewed with caution as other infections can cause biologic false-positives (see Ch. 21)

• direct examination of blood to diagnose malaria, trypanosomiasis and relapsing fever.

Repeated sampling of blood, urine and other body fluids is often required, and the laboratory should be alerted to search for unusual and fastidious organisms (e.g. nutritionally variant streptococci as a cause of endocarditis; see below). If possible, serial cultures should be collected before antimicrobial therapy is commenced.

Technical advances in diagnostic imaging techniques have provided the physician with a wide range of non-invasive investigative methods (e.g. ultrasound, CT scan, MRI, etc.). Some radiologic procedures such as chest radiographs are routine in the work-up of patients with FUO (Fig. 29.4), while others such as gallium or technetium scans may be applied depending on the likely diagnosis (Table 29.3).

Figure 29.4 Gallium concentrates in many inflammatory and neoplastic tissues and is a useful non-invasive technique in the investigation of a patient with fever of unknown origin. (A) Retroperitoneal lymphadenopathy of Hodgkin’s disease highlighted by a gallium scan. (Courtesy of H Tubbs.) (B) Intra-abdominal abscess shown by a gallium scan. A, abscess; G, gallium in colon.

(Courtesy of W.E. Farrar.)

Table 29.3 Representative infective causes of fever of unknown origin (FUO) in specific patient groups

Category of FUO

Infection

Usual cause

Nosocomial

Vascular-line related

Staphylococci

 

Other device related

Staphylococci, Candida

 

Transfusion-related

Cytomegalovirus

 

Cholecystitis and pancreatitis

Gram-negative rods

 

Pneumonia (related to assisted ventilation)

Gram-negative rods, including Pseudomonas

 

Postoperative abscesses, e.g. intra-abdominal

Gram-negative rods and anaerobes

 

Post-gastric surgery

Systemic candidiasis

Neutropenic

Vascular-line related

Staphylococci

 

Oral infection

Candida, herpes simplex virus

 

Pneumonia

Gram-negative rods, CandidaAspergillus, CMV

 

Soft tissue, e.g. perianal abscesses

Mixed aerobes and anaerobes

HIV-associated

Respiratory tract

Cytomegalovirus, PneumocystisMycobacterium tuberculosisM. avium-intracellulare

 

Central nervous system

Toxoplasma

 

Gastrointestinal tract

SalmonellaCampylobacterShigella

 

Genital tract or disseminated

Treponema pallidumNeisseria gonorrhoeae

Patients who contract their FUO in hospital are most likely to be infected with ‘hospital pathogens’, either from their own normal flora or from the hospital environment. This also applies to neutropenic patients if they are hospitalized, but some are treated as outpatients and may therefore be exposed to a wider range of pathogens. People with AIDS commonly become infected with opportunistic pathogens, though an increasing range of organisms is now implicated. It is important to take a detailed history, as latent infections can become florid as the patient’s immune status deteriorates. CMV, cytomegalovirus.

Stage 3 comprises invasive tests

Biopsy of liver and bone marrow should always be considered in the investigation of classic cases of FUO, but other tissues such as skin, lymph nodes and kidney may also be sampled. It is undesirable or impossible to repeat biopsies, and therefore it is important to organize the laboratory examination of material carefully to maximize the information obtained.

Stage 4 involves therapeutic trials

Trials of corticosteroids (e.g. prednisone, dexamethasone) or prostaglandin inhibitors (e.g. aspirin, indometacin) may be indicated if a non-infectious cause is suspected. There are few indications for empiric antimicrobial or cytotoxic chemotherapy in the management of classic FUO. However, a trial of antituberculosis drugs may be advocated in patients with a history of tuberculosis in the absence of supporting microbiologic evidence. Infections can progress very rapidly in people who are neutropenic or have AIDS, and ‘blind’ therapy is warranted (see below).

Treatment of FUO

The investigation and management of a patient with FUO requires persistence and an informed and open mind in order to reach the correct diagnosis. As the range of infective causes of FUO is enormous, the correct diagnosis is an essential prelude to the choice of appropriate treatment. As soon as the cause has been identified, specific therapy, if available, should be given.

FUO in specific patient groups

The main difference between FUO in these groups and classic FUO is the time course

As mentioned above, an increasing number of people are surviving with severe underlying disease that predisposes them to infection or are receiving treatment, such as cytotoxic drugs, that compromises their defences against infection. These groups of patients are discussed in more detail inChapter 30, but are included here because, in addition to classic FUO, other classifications of FUO (see Table 29.1) define:

• nosocomial FUO

• neutropenic FUO

• HIV-associated FUO.

Classically, a FUO may exist for weeks or months before a diagnosis is made, whereas for hospital-acquired (nosocomial) FUO and in neutropenic patients the time course is hours to days. The more common infective causes of FUO in these groups are shown in Table 29.4.

Table 29.4 Causative agents of endocarditis in different groups of patients (in general order of decreasing importance)

Patient group

Major etiologic agents of infective endocarditis

Native valve

Oral streptococci and enterococci
Staph. aureus
Coagulase-negative staphylococci
Gram-negative (enteric) rods
Fungi (mainly Candida)

Intravenous drug misuser

Staph. aureus
Oral streptococci and enterococci
Gram-negative (enteric) rods
Fungi (mainly Candida)
Coagulase-negative staphylococci

Prosthetic valve (early)

Coagulase-negative staphylococci
Staph. aureus
Gram-negative (enteric) rods
Oral streptococci and enterococci
Fungi (mainly Candida)

Prosthetic valve (late)

Oral streptococci and enterococci
Coagulase-negative staphylococci
Staph. aureus
Gram-negative (enteric) rods
Fungi (mainly Candida)

Although almost any organism can cause endocarditis, the majority of cases are caused by a relatively small range of species. The relative importance of these species varies depending upon whether the patient has his/her own heart valves or a prosthetic valve.

Investigation should proceed in the stages listed above, but with the particular emphasis depending upon the patient. In hospital patients the emphasis will depend upon:

• the type of operative procedures performed; fever is a common complaint in patients who have received transplants and may indicate graft-versus-host disease rather than infection

• the presence of foreign bodies, especially intravascular devices

• drug therapy, as drug fevers are a common non-infective cause of FUO

• the underlying disease and stage of chemotherapy in neutropenic patients

• the presence of known risk factors such as intravenous drug misuse, travel and contact with infected individuals in patients with HIV. Although the major opportunist infections in people with AIDS are well described (see Ch. 30), common infections can present atypically and new infections continue to emerge.

Infective endocarditis

Infective endocarditis is an uncommon disease that often presents as an FUO and is fatal if untreated. The infection involves the endothelial lining of the heart, usually including the heart valves. It may occur as an acute, rapidly progressive disease or in a subacute form. The majority of these patients have a pre-existing heart defect, either congenital or acquired (e.g. as a result of rheumatic fever), or a prosthetic heart valve in situ. However, the patient may be unaware of any defect before the infection.

Almost any organism can cause endocarditis, but native valves are usually infected by oral streptococci and staphylococci

Infection of native valves is most commonly caused by species of oral streptococci (viridans group) such as Streptococcus sanguisStrep. oralis and Strep. mitis and by Staphylococcus aureus. Intravenous drug misusers have the added complication of infection due to organisms they inject into themselves. Coagulase-negative staphylococci are common causes of early prosthetic valve endocarditis and are probably acquired at the time of surgery. The species causing late infections – more than 3    months after cardiac surgery – are somewhat more like those causing native valve endocarditis (Fig. 29.5).

Figure 29.5 Bacteria circulating in the bloodstream adhere to, and establish themselves on, the heart valves. Multiplication of the microbes is associated with destruction of valve tissue and the formation of vegetations, which interfere with, and may severely compromise, the normal function of the valve. These histologic sections show the virtual destruction of the leaflet at the mitral valve by staphylococci. (A) Gram stain. (B) Eosin–Van Gieson stain. LA, left atrium; LV, left ventricle; MV, remnant of mitral valve; TV, thrombotic vegetation.

(Courtesy of R.H. Anderson.)

Endocarditis is an endogenous infection acquired when organisms entering the bloodstream establish themselves on the heart valves. Therefore, any bacteraemia can potentially result in endocarditis. Most commonly, streptococci from the oral flora enter the bloodstream, for example, during dental procedures or vigorous teeth cleaning or flossing, and adhere to damaged heart valves. It is thought that fibrin-platelet vegetations are present on damaged valves before the organisms implant, and that adherence is probably associated with the ability of the organisms to produce dextran as well as adhesins and fibronectin-binding proteins. Having attached themselves to the heart valve, the organisms multiply and attract further fibrin and platelet deposition. In this position, they are protected from the host defences, and vegetations can grow to several centimetres in size. This is probably quite a slow process and correspondingly the time period between the initial bacteraemia and the onset of symptoms averages around 5    weeks (Fig. 29.6).

Figure 29.6 Outward signs of endocarditis may be helpful in suggesting the diagnosis. These result from the host’s response to infection in the form of immune complex-mediated vasculitis, focal platelet aggregation and vascular permeability. (A and B, different views.) Splinter haemorrhages in the nailbed and petechial lesions in the skin. (C) Osler’s nodes. These are tender nodular lesions that tend to affect the palms and fingertips.

(Courtesy of H. Tubbs.)

A patient with infective endocarditis almost always has a fever and a heart murmur

The signs and symptoms of infective endocarditis are very varied, but relate essentially to four ongoing processes:

• the infectious process on the valve and local intracardiac complications

• septic embolization to virtually any organ

• bacteraemia, often with metastatic foci of infection

• circulating immune complexes and other factors.

The patient almost always has a fever and a heart murmur and may also complain of non-specific symptoms such as anorexia, weight loss, malaise, chills, nausea, vomiting and night sweats, symptoms that are common to many of the causes of FUO listed in Table 29.2. Peripheral manifestations may also be evident in the form of splinter haemorrhages and Osler’s nodes (Fig. 29.6). Microscopic haematuria resulting from immune complex deposition in the kidney is characteristic (see Ch. 17).

Blood culture is the most important test for diagnosing infective endocarditis

Microbiologic and cardiologic investigations are of critical importance. The blood culture is the single most important laboratory test. Ideally, three separate samples of blood should be collected within a 24-h period and before antimicrobial therapy is administered. Isolation of the causative organism is essential so that antibiotic susceptibility tests can be performed and optimum therapy prescribed. Nutritionally variant strains of oral streptococci are known to cause infective endocarditis. These may fail to grow in blood culture media unless pyridoxal is added. Alternatively, they grow as satellite colonies around Staph. aureus colonies on blood agar.

The mortality of infective endocarditis is 20–50% despite treatment with antibiotics

In the past, most organisms causing infective endocarditis have been susceptible to a range of antimicrobials. However, antibiotic resistance has become an increasing issue (see Ch. 33). Even with appropriate treatment, complete eradication takes several weeks to achieve, and relapse is not uncommon. This is probably due to factors such as:

• relative inaccessibility of the organisms within the vegetations both to antibiotics and to host defences

• the organism’s high population density and relatively slow rate of multiplication.

Before the advent of antibiotics infective endocarditis had a mortality of 100%, and even today, despite treatment with appropriate antibiotics, the mortality remains at 20–50%.

The antibiotic treatment regimen for infective endocarditis depends upon the susceptibility of the infecting organism

For prosthetic valve endocarditis with penicillin-susceptible streptococci, high-dose penicillin is the treatment of choice. Patients with a good history of penicillin allergy can be treated with ceftriaxone or vancomycin. MIC (minimum inhibitory concentration) and MBC (minimum bactericidal concentration) tests (see Ch. 33) should be performed to detect organisms that are less susceptible or tolerant to penicillin (inhibited, but not killed; e.g. MBC        =       32    ×    MIC). Organisms less susceptible to penicillin and enterococci, which are always more resistant to penicillin, are treated with a combination of a beta-lactam antibiotic and an aminoglycoside. Combinations such as this act synergistically against streptococci and enterococci (see Ch. 33). However, vancomycin-resistant enterococci (VRE; usually E. faecium) pose a therapeutic challenge and require linezolid or daptomycin.

Staphylococcal endocarditis, particularly in prosthetic valve endocarditis when the organisms may be hospital-acquired and consequently often resistant to many antibiotics, often presents a more difficult therapeutic challenge. The increasing incidence of methicillin-resistant staphylococci requires a combination approach (vancomycin plus rifampin and gentamicin). A number of sources exist for detailed treatment regimens including the American Heart Association and the British Society for Antimicrobial Chemotherapy.

People with heart defects need prophylactic antibiotics during invasive procedures

People with known heart defects should be given prophylactic antibiotics to protect them during dental surgery and any other invasive procedure that is likely to cause a transient bacteraemia.

Most people with an FUO have a treatable disease presenting in an unusual manner

The clinical investigation needs to be individualized, but this chapter outlines the essential stages in the investigation of every patient and draws attention to the important infective causes of FUO.

Although classically a patient with FUO presents with a long history (weeks or months of fever), patients also present with fevers that are not immediately diagnosed by routine laboratory investigations. Definitions of FUO have also been proposed for these groups (nosocomial, neutropenic and HIV-associated). The list of pathogens causing fever in these patients is growing.

The clinician’s aim in the investigation of every patient with FUO should be to discover the cause, i.e. to change a FUO to a fever of known origin, and to initiate appropriate treatment.

Key Facts

• Fever is the body’s response to exogenous and endogenous pyrogens. It is a common symptom and may have a protective effect.

• The term fever of unknown origin (FUO) is used when the cause of fever is not obvious, has classically exceeded 3    weeks’ duration, and is not revealed by routine clinical and laboratory investigations.

• Increased numbers of immunocompromised patients have prompted the definition of FUO groups other than classical (i.e. nosocomial, neutropenic and HIV-associated FUO).

• Among the causes of FUO, infection is the most common, but neoplasms and autoimmune diseases are also significant. Cases of FUO often remain undiagnosed.

• The list of infective causes is long; therefore the first stage of investigation (i.e. the patient’s history and results of physical examination and screening tests) is a critical pointer to subsequent specific diagnostic tests.

• Therapeutic trials may be indicated if a diagnosis has not been achieved, but may confuse the results of further tests.

• The correct diagnosis is paramount to direct appropriate specific therapy.

• Infective endocarditis is an uncommon, but classic, example of an FUO. It is usually caused by Gram-positive cocci, the species depending upon the patient’s underlying predisposition, and is fatal unless treated.