Bacterial diseases

pyrexia of unknown origin

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 origin³

Most cases are unusual presentations of common diseases, e.g. 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, e.g. 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 - Haemophilus spp., (H. parainfluenzae, H. aphrophilus, and H. paraphrophilus), Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella 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, e.g. 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.