Fever of unknown origin (FUO) -Causes of FUO

Fever of unknown origin (FUO)

 refers to a prolonged febrile illness that persists without diagnosis after careful initial assessment. Although over 200 causes have been described, including rare diseases, most cases are due to familiar entities presenting in an atypical fashion.

Causes of FUO—The 'big three' are 

(1) infections—including tuberculosis, endocarditis, abdominal and hepatobiliary infections and abscesses, complicated genitourinary tract infections, pleuropulmonary infections, bone and joint infections, salmonellosis, cytomegalovirus, Epstein-Barr virus and HIV; 

(2) tumours—including lymphoma; 

(3) multisystem inflammatory conditions—including connective tissue diseases, vasculitic syndromes and granulomatous disorders. A miscellaneous category including factitious fever, habitual hyperthermia, and drug fever deserves consideration early in a patient's workup, since timely recognition may avert invasive and expensive procedures.

Clinical approach to the patient with FUO—The clinician must rely on a very careful and thorough clinical history and examination that does not neglect any part of the body, followed by appropriately targeted investigations directed by knowledge of the broad spectrum of diseases and local epidemiology. 

Definition

Original definition

Most fevers are readily explained or resolve rapidly. Fever with unclear cause or source at first sight should not be labelled fever (or pyrexia) of unknown (or undetermined) origin (FUO). Defined properly, true FUO is uncommon and is encountered once or twice a month at most teaching hospitals. A strict definition, which should not be changed too rapidly, is necessary for comparison of literature data and to guide clinicians faced with this rather rare clinical problem. The three criteria initially proposed by Petersdorf and Beeson in 1961 are: 

(1) an illness of at least 3 weeks' duration, 

(2) a fever (temperature more than 38.3°C on at least three occasions),  

(3) no established diagnosis after 1 week of hospital investigation. 

The first criterion eliminates acute, self-limiting, frequently viral diseases and the second eliminates habitual hyperthermia, an entity commonly diagnosed at that time.

Update of the initial definition

In 1991, Durack and Street suggested modification of the third criterion to an uncertain diagnosis after at least three outpatient visits or at least 3 days in hospital. This revision reflected trends in medical practice, including a shift towards outpatient management, advances in diagnostic techniques, and an accelerated pace of investigation. They also divided FUO into four groups: classic FUO, nosocomial FUO, neutropenic FUO, and HIV-associated FUO. In the last three groups the case mixture differs from that of classic FUO, and the predominance of nosocomial and opportunistic infections in these often frail patients frequently justifies early empirical antimicrobial therapy. This article  focuses on classic FUO in adults.

Modern definition of classic FUO

•Illness of more than 3 weeks duration

• Temperature of at least 38.3°C, or lower temperature with laboratory signs of inflammation, on at least three occasions

• No diagnosis or reasonable (eventually confirmed) diagnostic hypothesis after an initial diagnostic investigation

• Exclusion of nosocomial fevers and severe immunocompromise

The causes are conveniently classified into five categories: 

(1) infections, 

(2) malignancies, 

(3) noninfectious inflammatory diseases, 

(4) miscellaneous causes,

(5) undiagnosed cases

 Common causes of classic fever of unknown origin in adults

1.Infections

• Tuberculosis

• Endocarditis

• Abdominal and hepatobiliary infections and abscesses

• Complicated genitourinary tract infections

• Pleuropulmonary infections

• Bone and joint infections

• Salmonellosis (including typhoid fever)

• Cytomegalovirus, Epstein-Barr virus, HIV

2.Neoplasms

- Haematological

• Non-Hodgkin's lymphoma

• Hodgkin's disease

• Leukaemia

- Solid

• Adenocarcinoma (e.g. colon, kidney)

3.Noninfectious inflammatory diseases

- Connective tissue diseases

• Adult-onset Still's disease

• Polymyalgia rheumatica

• Rheumatoid arthritis

• Sjogren's syndrome

• Systemic lupus erythematosus

- Vasculitis syndromes

• Giant cell arteritis

• Polyarteritis nodosa

• Wegener's granulomatosis

- Granulomatous disorders

• Inflammatory bowel disease

• Sarcoidosis

4.Miscellaneous

• Drug fever

• Habitual hyperthermia

• Factitious fever

• Subacute thyroiditis

• Venous thromboembolism

• Haematoma

Rare causes of fever of unknown origin in adults

Infections

• Bartonellosis (including Bartonella henselae, B. quintana), brucellosis, campylobacter, gonococcaemia, melioidosis, meningococcemia, listeriosis, tularaemia, yersiniosis

• Chlamydial infections (including psittacosis), ehrlichioses, rickettsioses (including Q fever)

• Atypical mycobacterioses, leprosy

• Febris recurrens, leptospirosis, Lyme disease, rat-bite fever, syphilis

• Actinomycosis, nocardiosis, Whipple's disease

• Human herpesvirus type 8, parvovirus B19

• Aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, mucormycosis, pneumocystosis, sporotrichosis

• Amoebiasis, babesiosis, echinococcosis, fascioliasis, malaria, leishmaniasis, schistosomiasis, toxocariasis, toxoplasmosis, trichinosis, trypanosomiasis

• Malakoplakia, xanthogranulomatous pyelonephritis

• Central nervous system infection, dental infection, upper respiratory tract infection, wound infection

• Intravenous catheter infection, infected vascular graft, mycotic aneurysm

Neoplasms and related conditions

- Haematological

• Angioimmunoblastic T-cell lymphoma

• Intravascular lymphoma

• Amyloidosis

• Hypereosinophilic syndrome

• Multiple myeloma

• Myelodysplastic syndromes

• Myelofibrosis

- Solid

• Atrial myxoma

• Hepatoma

• Renal cell carcinoma

• Other (more than 30 reported), with or without necrosis, with or without metastases

Noninfectious inflammatory diseases

- Connective tissue diseases

• Acute rheumatic fever

• Crystal-induced arthropathy

• Eosinophilic fasciitis

• Felty's syndrome

• Mixed connective tissue disease

• Polymyositis, dermatomyositis

• Reactive arthritis, including Reiter's syndrome

• Relapsing polychondritis

• Seronegative spondylarthropathy

- Vasculitis syndromes

• Behcet's disease

• Henoch-Schonlein purpura

• Mixed cryoglobulinaemia

• Takayasu's arteritis

• Urticarial vasculitis

- Granulomatous disorders

• Granulomatous hepatitis

-Miscellaneous

• Addison's disease, hyperparathyroidism, hyperthyroidism, hypothalamic hypopituitarism, phaeochromocytoma

• Erythema multiforme, erythema nodosum, linear IgA dermatosis, Sweet's disease

• Castleman's disease, inflammatory pseudotumour of lymph nodes, Kikuchi's disease

• Vogt-Koyanagi-Harada syndrome

• Giant haemangioma

• Dissecting aneurysm

• Retroperitoneal fibrosis

• Thrombophlebitis

• Cholesterol embolism, PTFE (Teflon) embolism, silicone embolism

• Antiphospholipid syndrome

• Cyclic neutropenia, haemolytic anaemia, haemoglobinopathies, macrophage activation (haemophagocytic) syndrome, vitamin B12 deficiency

• Schnitzler's syndrome

• Dressler's syndrome (postmyocardial infarction syndrome)

• Cerebrovascular accident, epilepsy

• Alcoholic hepatitis, autoimmune hepatitis, cirrhosis (with active necrosis), primary sclerosing cholangitis

• Extrinsic allergic alveolitis, hypersensitivity pneumonitis, interstitial pneumonia

Common diseases prevail

Although the possible aetiologies of FUO are myriad, a limited list of disorders  accounted for the great majority of diagnoses in published series. Most patients do not have esoteric diseases, unfamiliar to the clinician, but rather are exhibiting atypical manifestations of common illnesses. A few examples may illustrate this point. The forms of tuberculosis that give rise to FUO are often disseminated disease, yet without the characteristic miliary pattern on chest radiograph, or extrapulmonary disease without clear localizing features; tuberculin skin tests and sputum smears are often negative. 

The forms of endocarditis that enter the FUO spectrum are frequently culture-negative or are caused by fastidious organisms; a new regurgitant murmur or signs of peripheral emboli are frequently absent. 

Leukaemia presents as an FUO characteristically in the aleukaemic phase. 

Giant cell arteritis may manifest with constitutional symptoms only (anorexia, weight loss, fever), without polymyalgia or arteritic signs and symptoms, and without a strikingly elevated ESR. 

Likewise, in subacute thyroiditis, localizing symptoms and signs may be subtle or nonexistent.