Fever of Unknown Origin

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CME: CLINICAL PRACTICE AND ITS BASIS

uted to infection, neoplasm, collagen vascular disease and miscellaneous Infectious diseases causes. Arnow and Flaherty have suggested a minimum set of investigations to be performed prior to so defining a Edited by Andrew Freedman MD FRCP, patient (Table 1).5 Adoption of these Senior Lecturer in Infectious Diseases and Honorary Consultant Physician, criteria is recommended to attempt to Cardiff University School of Medicine establish greater comparability between future publications on FUO. It has been suggested that FUO can be subclassified into four different types: Fever of unknown origin • classic FUO • nosocomial FUO • immune-deficient FUO John Williams MRCP DTMH, Infectious ness of at least three weeks’ duration, with HIV-related FUO. Diseases Specialist Registrar repeated temperature measurements of • Richard Bellamy MRCP DPhil MSc MMedEd, 38.3°C or higher, that defies diagnosis Only the definition of classic FUO Infectious Diseases Consultant after one week of hospital inpatient evalu- specifies that the patient must have had 4 6 Department of Infection and Travel Medicine, ation. This has subsequently been modi- fevers for at least three weeks. This may James Cook University Hospital, fied to remove the requirement that potentially cause confusion; it is prob- Middlesbrough investigations are performed in the inpa- ably preferable to restrict the term FUO tient setting because most patients can be to those cases where FUO has been pre- Clin Med 2008;8:526–30 evaluated as outpatients. sent for at least three weeks and to One problem with the definition of exclude HIV and immune deficiency. FUO is that it does not specify which Unfortunately, many clinicians use the Definitions investigations should have been per- term loosely to include any fever for formed prior to stating that a patient ful- which a cause has not been found. This Fever fils the definition. This is probably should be strongly discouraged because responsible for many of the reported dif- The definition of fever is: the most likely causes of short-term ferences in the frequency of FUO attrib- fevers which have not been thoroughly a state of elevated core temperature often, but not necessarily, part of the defensive resistance of multicellular organisms Table 1. Minimum investigations which should have been performed (host) to the invasion of live (microorgan- without a diagnosis being established prior to qualifying as fever of isms) or inanimate matter recognised as unknown origin.5 Reproduced from the Lancet with permission from pathogenic or alien by the host.1 Elsevier. The term ‘pyrexia’ is often used synony- • Comprehensive history mously with fever in the UK. Fever should • Repeated physical examination be distinguished from hyperthermia, • Full blood count which is an unregulated rise in body tem- • Routine biochemical profile perature due to a failure of temperature • Urinalysis and microscopic examination homeostasis.2 Over 100 years ago • Chest X-ray Wunderlich recorded multiple tempera- • Erythrocyte sedimentation rate (and/or C-reactive protein) ture measurements on around 25,000 • Antinuclear antibodies people. He defined normal body temper- • Rheumatoid factor ature as 37°C and suggested that the • Angiotensin-converting enzyme upper limit of the normal range should be • Routine blood cultures (three sets) while not receiving antibiotics regarded as 38°C.3 This has formed the • Cytomegalovirus IgM antibodies or virus detection in blood basis for subsequent definitions of fever. • Heterophile antibody test in children and young adults • Mantoux skin test • CT scan of abdomen (or radionuclide scan) Fever of unknown origin • HIV antibody test • Further evaluation of any abnormalities detected by the above tests Petersdorf and Beeson provided the classic definition of ‘fever of unknown CT = computed tomography; Ig = immunoglobulin. origin’ (FUO) as a prolonged febrile ill-

526 Clinical Medicine Vol 8 No 5 October 2008 © Royal College of Physicians, 2008. All rights reserved. CME Infectious diseases investigated are very different from those the thoroughness of the investigations under 18 years with FUO compared with of FUO. performed prior to classifying a patient less than 5% for adults over 65 years.9 as having FUO and the diagnostic tests However, joint disease in children with Causes of fever of unknown subsequently available to investigate it. FUO suggests a serious underlying dis- origin For example, the availability of highly order such as connective tissue disease sensitive blood culture techniques and (CTD), endocarditis or leukaemia.10 The causes of FUO in Europe and the high quality echocardiography means Still’s disease, an important cause of USA, reviewed by Armstrong and that bacterial endocarditis is now a less FUO in children, can also affect young Kazanjian7 in 14 papers published since common cause of FUO because the con- adults and is a condition often neglected 1930 (Table 2), were found to be: dition can be diagnosed relatively easily during the search for a cause. Malig- • infection: 30% of cases and is therefore unlikely to meet the nancy is a relatively uncommon cause in • neoplasms: 18% FUO criteria. children8 and young adults,11 but lym- collagen vascular diseases: 12% phoma is a potential diagnosis which is • important to exclude because delay in miscellaneous causes: 14% Children and young adults • diagnosis may adversely affect prognosis. • undiagnosed: 26%. The relative likelihood of FUO being due There is substantial variation between to specific causes is related to the age of The elderly the different series. In particular, col- the patient. In children, infections are the lagen vascular diseases were less frequent most common cause. Jacobs and Schutze Haematologic malignancies and solid causes of FUO in earlier case series than found that 64 of 164 children with FUO tumours are more common causes of presently. In resource poor countries had infections including Epstein-Barr FUO in elderly patients than in younger FUO is more frequently due to infections virus infection, osteomyelitis, bartonel- adults.11,12 Infections and CTDs are also than in established market economies.6 losis and urinary tract infections.8 Many frequent causes in the elderly. Temporal This may partly represent differences in children with FUO recover without a arteritis and polymyalgia rheumatica are the geographic and temporal distribu- diagnosis ever being established. A cause particularly common in this age group. tion of diseases, but is also explained by is not found in over 40% of children Symptoms of temporal arteritis may be

Key Points

Table 2. Causes of fever of unknown origin in Europe and the USA and their relative The term ‘fever of unknown origin’ frequency reported in the literature (1930–97). Adapted from Reference 7. (FUO) should be used only if the patient has had a febrile illness for Patients with attributed diagnosis (%) more than three weeks and a thorough history, examination and Collagen appropriate investigations have Country and year vascular failed to elucidate the cause of publication Infection Neoplasm disease Miscellaneous Undiagnosed

Careful history taking and repeated, USA 1930 24 11 0 2 63 thorough physical examinations are more likely to establish the USA 1936 59 22 0 0 19 diagnosis than a ‘scatter-gun USA 1939 64 24 0 12 0 approach’ to performing complex Sweden 1953 24 16 6 6 49 investigations USA 1959 21 30 0 29 20 FUO can be caused by a wide range of USA 1961* 36 19 15 23 7 conditions including infections, Finland 1962 19 6 6 0 69 connective tissue diseases and USA 1963 20 18 13 10 38 malignancies Sweden 1966 13 32 3 7 45 The older the patient the more likely USA 1973 40 20 15 17 8 malignancy is to be the cause of USA 1982 30 31 9 17 12 FUO Belgium 1992 23 7 21 24 26 A therapeutic trial of empirical USA 1992 33 24 21 13 9 antibiotics is usually inappropriate Netherlands 1997 26 13 20 12 30 Total 30 18 12 14 26 KEY WORDS: antipyretic drugs, body temperature, fever, fever of unknown * The classic paper of Petersdorf and Beeson.4 origin, pyrexia

Table 3. Clues to the cause of a fever of unknown origin suggested by the history. Adapted from Reference 13.

Medication or exposure Drug fever Recent history of stroke Culture-negative endocarditis to toxic substances Fume fever Takayasu arteritis Polyarteritis nodosa History of tick bite Relapsing fever Cough with sputum Tuberculosis Lyme disease production Coxiella infection Psittacosis Typhoid Lung cancer Acute rheumatic fever Contact with animals Psittacosis Visual disturbance or Temporal arteritis or birds Leptospirosis eye pain Culture-negative endocarditis Brucellosis Brain abscess Toxoplasmosis Takayasu arteritis Bartonellosis Coxiella infection Rat-bite fever Complaint of myalgia Trichinosis Complaint of fatigue Carcinoma Culture-negative endocarditis Lymphoma Polyarteritis nodosa Cytomegalovirus infection Rheumatoid arthritis Typhoid Familial Mediterranean fever Systemic lupus erythematosus Polymyositis Rheumatoid arthritis Toxoplasmosis Complaint of headache Relapsing fever Abdominal pain Polyarteritis nodosa Rat-bite fever Familial Mediterranean fever Chronic meningoencephalitis Relapsing fever Malaria Brucellosis CNS malignancy Cognitive function Sarcoid meningitis Complaint of back pain Brucellosis slowing/confusion Tuberculous meningitis Culture-negative endocarditis Vertebral osteomyelitis Complaint of neck pain Subacute thyroiditis Cryptococcal meningitis Adult Still’s disease Carcinomatous meningitis Temporal arteritis (angle of jaw) CNS malignancy Mastoiditis Brucellosis Septic jugular phlebitis Typhoid HIV infection

CNS = central nervous system.

non-specific, such as lethargy and gen- repeated physical examinations. Table 3 performing unnecessary tests. Table 4 eral malaise, which may result in diag- lists clues to the cause of an FUO sug- indicates clues to the cause of an FUO nostic delay and risk of blindness from gested by information identified from which may be elicited by physical exami- retinal artery occlusion. the history.13 nation (this list is not exhaustive). Repeated, careful and targeted physical Approach to diagnosis examination may reveal physical signs Treatment missed on previous examinations. It is Disease-modifying treatment The investigations to be performed prior worth documenting a careful examina- to defining a patient as having FUO are tion of the sinuses for tenderness, the In considering treatment of FUO, the listed in Table 1. There are many poten- oropharynx, fundi, skin and nails, thy- concern is essentially with symptomatic tial causes of FUO so it is not possible to roid gland, lymph nodes, external geni- treatment because, by definition, the list a standard battery of tests which talia and rectum. All too frequently these underlying disease is unknown. Specific should be performed to investigate every are omitted from the physical examina- disease-modifying treatment can usually case. It is preferable to tailor the investi- tion or performed in a cursory way and be commenced only once the diagnosis gations according to clues which may important signs omitted. This can result has been established. The exception is have been suggested by the history and in diagnostic delay and wasted resources when empirical drug therapy is used to

Table 4. Clinical findings which may suggest specific diagnoses in patients with fever useful in the individual patient (except of unknown origin. Adapted from Reference 6. perhaps in malaria). Antipyretic drugs Finding on clinical examination Suggested diagnosis are unlikely to affect the prognosis of conditions causing FUO, so it is not Tenderness of facial sinuses or mastoid Sinusitis unreasonable to give them to patients Temporal artery tenderness or nodularity Temporal arteritis with FUO if they are suffering discom- Tenderness of a tooth Periapical dental abscess fort, particularly if they are being investi- Choroidal tubercle on fundoscopy Tuberculosis, sarcoidosis or syphilis gated as outpatients. Roth’s spots on fundoscopy Endocarditis Enlarged tender thyroid and/or bruit Thyroiditis Steroids. If corticosteroids are used as a Cardiac murmur Endocarditis therapeutic trial, they may mask symp- Splenomegaly Lymphoma, endocarditis, leishmaniasis toms (eg rashes and fever). If the patient has an underlying haematological malig- Lymphadenopathy Lymphoma, tuberculosis, HIV nancy, steroids may potentially adversely Perirectal tenderness and fluctuance Perirectal abscess affect future treatment response. Thus, if a Prostatic tenderness on rectal examination Prostatitis or prostate abscess therapeutic trial of steroids is being con- Testicular nodule on genital examination Polyarteritis nodosa sidered for a suspected CTD such as tem- Epididymal nodule on genital examination Tuberculosis, sarcoidosis poral arteritis or polymyalgia rheumatica, Tenderness over calf muscles Deep vein thrombosis the clinician needs to be certain that the Petechiae, splinter haemorrhages, Infected pressure sore and/or underlying patient does not have an occult lymphoma subcutaneous nodules or clubbing osteomyelitis or other malignancy. Ulceration over pressure areas or affecting toes Endocarditis or vasculitis

Summary There are many potential causes of FUO. Most cases are due to unusual presenta- attempt to confirm or refute a suspected 1 Will the symptomatic treatment tions of common diseases rather than rare diagnosis. Giving empirical antibiotic mask the clinical signs and thus or exotic diseases. The key to establishing therapy for a patient with an FUO is usu- hinder diagnosis? the diagnosis is a careful history and ally not appropriate. If the fever responds 2 Could the symptomatic treatment careful repeated examinations followed without a specific diagnosis being estab- affect the prognosis of any of the by targeted investigations. lished, there is a risk that an important potential differential diagnoses? condition such as endocarditis may be missed. This may result in a potentially Antipyretic agents. Antipyretic drugs are References adverse outcome in that the endocarditis frequently overprescribed in patients 1 Glossary of terms for thermal physiology, is suppressed but not cured and the with fevers, particularly among in- 2nd edn. Revised by The Commission for patient subsequently relapses. patients with recent onset of fever. The Thermal Physiology of the International Empirical therapy with antitubercu- masking of temperature by paracetamol Union of Physiological Sciences (IUPS Thermal Commission). Pflugers Arch 1987; losis drugs can be used as a therapeutic and non-steroidal drugs can lead to the trial if extrapulmonary tuberculosis (TB) 410:567–87. erroneous conclusion that a patient is 2 Mackowiak PA. Temperature regulation appears likely, but there is little potential recovering. Therefore, fever in hospi- and the pathogenesis of fever. In: Mandell for obtaining a positive mycobacterial talised patients should usually be treated GL, Bennett JE, Dolin R (eds), Principles culture. However, if rifampicin is only if it poses a threat to the patient or is and practice of infectious diseases, 5th edn. Philadelphia: Churchill Livingstone, 2000: included among the empirical anti-TB causing substantial discomfort. Treat- drugs it must be remembered that this 604–22. ment of fever is less likely to obscure the 3 Mackowiak PA, Worden G. Carl Reinhold antibiotic could suppress fever in many diagnosis in patients with an established August Wunderlich and the evolution of other conditions including brucellosis FUO than in hospital inpatients with clinical thermometry. Clin Infect Dis 1994; and osteomyelitis. Therefore, many clini- recent symptoms. This is both because 18:458–67. 4 Petersdorf RG, Beeson PB. Fever of cians omit rifampicin from therapeutic the established fever is unlikely to sub- trials of anti-TB drugs. unexplained origin: report on 100 cases. side completely and because the longer Medicine (Baltimore) 1961;40:1–30. duration of symptoms means that 5 Arnow PM, Flaherty JP. Fever of unknown origin. Lancet 1997;350:575–80. Symptomatic treatment apparent short-term resolution of fever should be interpreted with caution. 6 Mackowiak PA, Durack DT. Fever of unknown origin. In: Mandell GL, Bennett There are two important issues to take Historically, the pattern of fever has JE, Dolin R (eds), Principles and practice of into account when considering sympto- been said to correlate with specific con- infectious diseases, 5th edn. Philadelphia: matic treatment: ditions, but this is rarely diagnostically Churchill Livingstone, 2000:622–33.

7 Armstrong W, Kazanjian P. Fever of Philadelphia: Lippincott-Raven, 1997: 13 Cunha BA. Fever of unknown origin. In: unknown origin in the general population 237–49. Gorbach SL, Bartlett JG, Blacklow NR and in HIV-infected persons. In: Cohen J, 10 Chantada G, Casak S, Plata JD, Pociecha J, (eds), Infectious diseases, 2nd edn. Powderly WG (eds), Infectious diseases, 2nd Bologna R. Children with fever of unknown Philadelphia: Saunders, 1998:1678–89. edn. London: Mosby, 2004:871–80. origin in Argentina: an analysis of 113 cases. 8 Jacobs RF, Schutze GE. Bartonella henselae Pediatr Infect Dis J 1994;13:260–3. as a cause of prolonged fever and fever of 11 Iikuni Y, Okada J, Kondo H, Kashiwazaki S. unknown origin in children. Clin Infect Dis Current fever of unknown origin 1998;26:80–4. 1982–1992. Intern Med 1994;33:67–73. 9 Durack DT. Fever of unknown origin. In: 12 Knockaert DC, Vanneste LJ, Bobbaers HJ. Mackowiak PA (ed), Fever basic Fever of unknown origin in elderly patients. mechanisms and management, 2nd edn. J Am Geriatr Soc 1993;41:1187–92.