Definition

Petersdorf and Beeson defined pyrexia of unknown origin (PUO) in 1961.^[1] It is defined as:

• A temperature greater than 38.3°C on several occasions.
• Accompanied by more than 3 weeks of illness.
• Failure to reach a diagnosis after 1 week of inpatient investigation.

This timing allowed exclusion of patients with protracted, but self-limited viral illnesses giving time for studies to be completed. This has now been modified to include patients who are diagnosed after 2 outpatient visits or 3 days in hospital.

Additional categories have now been added including:

• Nosocomial PUO in hospital patients with fever of 38.3°C on several occasions caused by a process not present or incubating on admission where initial cultures are negative and diagnosis unknown after 3 days' investigation.
• Neutropenic PUO includes patients with fever as above with <1 x 10⁹ neutrophils with initial negative cultures and diagnosis uncertain after 3 days.^[2]
• HIV-associated PUO includes HIV-positive patients with fever as above for 4 weeks as outpatients or 3 days as inpatients, with an uncertain diagnosis after 3 days' investigation where at least 2 days have been allowed for cultures to incubate.

Common causes of pyrexia of unknown origin^[3]

Most cases are unusual presentations of common diseases, eg tuberculosis, endocarditis, gallbladder disease and HIV infection, rather than rare or exotic diseases.^[4]

• In adults: infections and cancer (25-40% of cases each) account for most pyrexias of unknown origin (PUOs).^[5] Autoimmune disorders account for 10-20% of cases.^[6]
• Children: 30-50% of cases are due to infections, 5-10% to cancer, and autoimmune disorders 10-20%.

Bacterial

• Abscesses
  • There may be no localising symptoms.
  • Previous abdominal or pelvic surgery, trauma or history of diverticulosis or peritonitis increase the likelihood of an occult intra-abdominal abscess.
  • They are most commonly in the subphrenic space, liver, right lower quadrant, retroperitoneal space or the pelvis in women.
• Tuberculosis
  • When dissemination has occurred, eg in patients who are immunocompromised, the initial presentation is more likely to consist of constitutional symptoms than localising signs. Chest X-ray may be normal.
• Urinary tract infections (UTIs) are rare causes. Perinephric abscesses occasionally fail to communicate with the urinary system, resulting in a normal urinalysis.
• Endocarditis is a rare cause of PUO:
  • Culture-negative endocarditis is reported in 5-10% of endocarditis cases.
  • The HACEK group is responsible for 5-10% of cases of infective endocarditis and is the most common cause of Gram-negative endocarditis among people who do not abuse intravenous drugs.
  • This is a group of Gram-negative bacilli - H aemophilus spp., (H. parainfluenzae, H. aphrophilus, and H. paraphrophilus), A ctinobacillus actinomycetemcomitans, C ardiobacterium hominis, E ikenella corrodens, and K ingella spp.
  • They are part of the normal oropharyngeal flora, are slow growers and prefer a carbon dioxide-enriched atmosphere.
  • Because of their fastidious growth requirements, they have been a frequent cause of culture-negative endocarditis.
  • Previous antibiotic therapy is the most frequent reason for negative blood cultures.
• Hepatobiliary infections, eg cholangitis, can occur without local signs and with only mildly elevated or normal liver function tests, especially in the elderly.
• Osteomyelitis usually causes localised pain or discomfort at least sporadically.
• Brucellosis should be considered in patients with persistent fever and a history of contact with cattle, swine, goats or sheep, or patients who consume raw milk products.
• Borrelia recurrentis is transmitted by ticks. It is responsible for causing relapsing fever.
• Other spirochetal diseases that can cause PUO include Spirillum minor (rat-bite fever), Borrelia burgdorferi (Lyme disease), and Treponema pallidum (syphilis).

Viral

• Herpes viruses, such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV), can cause prolonged febrile illnesses with constitutional symptoms and no prominent organ manifestations, particularly in the elderly.
• HIV:
  • Prolonged febrile episodes are frequent in patients with advanced HIV infection.
  • Approximately 75% of the cases are infectious in nature, about 20-25% are due to lymphomas and a small fraction (0-5%) are due to HIV itself.
  • Over 80% of patients with AIDS and lymphomas have involvement of extranodal sites - usually the brain.

Fungi

• Immunosuppression, the use of broad-spectrum antibiotics, the presence of intravascular devices and total parenteral nutrition all predispose people to disseminated fungal infections.

Parasites

• Toxoplasmosis. This should be considered in patients who are febrile with lymph node enlargement.
• Trypanosoma, leishmania and amoeba species may rarely cause PUO.

Rickettsial organisms

• Coxiella burnetii may cause chronic infections, chronic Q fever or Q fever endocarditis may be identified in patients with a PUO.

Psittacosis

• Infection by the causative organism, Chlamydophila should be considered in a patient with PUO who has a history of contact with birds.

Lymphogranuloma venereum

• This should also be considered, but is rare.

Neoplasms

• Hodgkin's lymphoma and non-Hodgkin's lymphoma may cause PUO.
• Leukaemias may also be responsible.
• Among solid tumours, renal cell carcinoma is most commonly associated with PUO.
• Solid tumours such as adenocarcinomas of the breast, liver, colon or pancreas and liver metastases from any primary site may present with fever.
• Malignant histiocytosis is a rare, rapidly progressive malignant disease.

Drug fever

A wide variety of drugs can cause drug fever:

• The most common are beta-lactam antibiotics, procainamide (now discontinued) and isoniazid. Stopping the drug generally leads to recovery within 2 days.
• It is usually accompanied by a rash.

Collagen vascular and autoimmune diseases

• Systemic-onset juvenile rheumatoid arthritis. High-spiking fevers, nonpruritic rashes, arthralgias and myalgias, pharyngitis and lymphadenopathy typically are present.
• Polyarteritis nodosa (PAN), rheumatoid arthritis and mixed connective-tissue diseases should be considered.

Granulomatous diseases

• Sarcoidosis.
• Crohn's disease (the most common gastrointestinal cause).
• Granulomatous hepatitis.

Vasculitides

• Giant cell arteritis and also the related polymyalgia rheumatica.^[7]
• Polyarteritis nodosa.
• Behçet's disease has also been reported.^[8]

Peripheral pulmonary emboli

Peripheral pulmonary emboli and occult thrombophlebitis can cause PUO.

Inherited diseases

Familial Mediterranean fever.

Hyperthyroidism and subacute thyroiditis

• These are the most common endocrine causes of PUO.
• Adrenal insufficiency is a rare, but potentially fatal cause of PUO.

Kikuchi's disease

Kikuchi's disease is a self-limiting necrotising lymphadenitis. It has been reported as a cause of PUO.^[9]

Undiagnosed

10-15% of patients remain undiagnosed despite extensive investigations and, in 75% of these, the fever resolves spontaneously. In the remainder, other signs and symptoms make the diagnosis clear.

Epidemiology

Incidence

This is a common problem.

• In patients older than 50 years more than 30% of cases are related to connective-tissue disorders and vasculitic disorders.
• Giant cell arteritis and polymyalgia rheumatica account for 50% of the cases.

Diagnosis

The first step is to confirm temperature by taking it yourself.^[10] Look for signs usually accompanying fever, eg tachycardia, chills. It is very important to take a thorough history:^[11]

• Inquire about symptoms from all major systems. Include general complaints,.g. fever, weight loss, night sweats, headaches and rashes.
• Record all complaints, even if not currently present. Previous illnesses, including surgery and psychiatric problems, are important.
• Discuss nutrition, including consumption of dairy products and the source of these products.
• Drug history should be recorded, to include over-the-counter medications, prescription medications and any illicit substances.
• Immunisation status should be documented.
• Enquire about family history of illness.
• Occupational history should include exposure to chemicals/animals.
• Take a history of travel and recreational habits - including possible exposure to ticks and other vectors.
• Sexual history should be recorded.

Examination of the patient should include:

• Documentation of fever and exclusion of factitious fever (may be up to 10% of cases), which are essential early steps in the physical examination.
• Measuring the fever more than once and in the presence of another. Electronic thermometers give access to rapid and unequivocal documentation of fever.
• Diseases such as brucellosis, borreliosis and Hodgkin disease tend to cause recurrent episodes of fever.
• Physical examination should be repeated daily while the patient is in hospital. Particularly, watch for:
  • Rashes.
  • Lymph node enlargement.
  • Signs of arthritis.
  • New/changing cardiac murmurs.
  • Abdominal tenderness or rigidity.
  • Fundoscopic changes and neurological deficits.
• The pattern of fever is usually of little help in the diagnosis. Correlation between fever patterns and specific diseases is weak. The exception is in tertian and quartan malaria, where the diagnosis is usually made within 3 weeks.

Investigations

• FBC, erythrocyte sedimentation rate (ESR), U&Es, C-reactive protein (CRP), liver function tests (LFTs), antinuclear antibody (ANA), Rh factor and thyroid function tests (TFTs) should be taken.
• Labelled white cell scan; in this investigation white cells are labelled extracorporeally and then reinjected into the patient. It is used to identify areas of sepsis. If the patient is neutropenic then donor white cells may be used.
  False-positive scans may occur with haematomas and inflammatory disease. False-negatives may occur in chronic sepsis.
• Blood cultures (preferably having been off antibiotics for several days) should be taken at differing times and from different sites. Culture for 2 weeks to detect slow-growing organisms and on special media if necessary.
• Culture urine, sputum, stool, CSF and morning gastric aspirates (if tuberculosis is suspected).
• Chest X-ray, abdominal CT scan, and echocardiography (if endocarditis or atrial myxoma is suspected) should be considered.
• CT, intravenous pyelogram (IVP), MRI^[12] and PET scanning^[13] all have a place in diagnosis
• Invasive procedures for abnormal findings:
  • Lumbar puncture for headache.
  • Skin biopsy for rash.
  • Lymph aspiration or biopsy for lymphadenopathy.
  • In an HIV-positive patient - bone marrow aspiration or biopsy.
  • Abnormal LFTs should prompt a liver biopsy (even if normal size).
  • In deteriorating patients, consider laparotomy or laparoscopy.^[14]
• Therapeutic trials if diagnosis is strongly suspected, eg tuberculosis, brucellosis.

Management

This will depend on diagnosis. Empirical treatment has never been advocated in cases of PUO. There are, however, three important exceptions:^[15]

• Cases that meet criteria for culture-negative endocarditis.
• Cases suggestive of cryptic disseminated tuberculosis (or other granulomatous infections).
• Cases in which temporal arteritis (with vision loss) is suspected.

In an immunocompromised host

Any course of management should include consideration of risk-benefit for the patient. The patient may be clinically well, apart from fever, but broad-spectrum treatment may bring debilitating side-effects.

The disease course can be rapid, progressive and life-threatening:^[16]

• In neutropenic patients, fever may be the first and only sign of bacteraemia:
  • Gram-negative organisms were mainly responsible in the past, but now Gram-positive ones are most common isolates in many units, especially coagulase-negative staphylococci. However, 50-60% of cultures will be negative despite rigorous investigations, and empirical treatment is required.
  • In high swinging fever without any obvious focus or positive cultures, deep fungal infection is likely and, in fever persisting for >72 hours, amphotericin B should be added. This preparation has high levels of toxicity and alternatives have been trialled and found equivalent in efficacy, but with reduced toxic side-effects.^[17] In cancer patients with neutropenia, amphotericin B is the only antifungal for which there is evidence suggesting that it might reduce mortality.^[18]
• Take cultures and institute immediate antibiotic therapy before waiting for results:
  • Commonly used regimens include antipseudomonal penicillin plus aminoglycoside, eg piperacillin/gentamicin; 3rd-generation cephalosporin, eg ceftazidime or meropenem.
  • These are very effective against common Gram-negative organisms, but less so against Gram-positive ones which are now a more common problem. Reliably effective antibiotics against these are glycopeptides, eg vancomycin. These are not generally added to empirical treatment because of their toxicity, cost and the fact that coagulase-negative staphylococci rarely cause death.
  • Generally, vancomycin should be used only when blood culture results are known. 4th-generation cephalosporins, eg cefepime, which include Gram-positive bacteria in their spectrum are under investigation.
• If a patient responds to initial treatment, continue for at least 7 days and ideally until the neutrophil count reaches >0.5 x 10⁹/L. If not, the therapy should be changed.

In non-neutropenic immunosuppressed patients, the situation is rarely immediately life-threatening and the diagnosis should be pursued as above.