Fever is an increase in body temperature above the normal range of 98.2 +/- 0.7°F. It is a beneficial response to a noxious stimulus that may be infectious or non-infectious. The body temperature in humans is controlled by a part of the brain called the anterior hypothalamus. Normally, there is a variation between the morning and evening body temperature, which is called the diurnal variation. Any increase above this normal variation of temperature is called a fever. Fever is often accompanied by other complaints like headache, feeling of cold (chills), pain in the muscles (myalgia) and joints (arthralgia).

Pyrexia, the scientific name for fever, may be divided into two types - short duration fever lasting less than 2 weeks and long duration fever which lasts for more than 2 weeks. The majority of short duration fevers are due to infectious causes, like viral infections, malaria, bacterial infections of the lungs, intestines or urinary tract. Rarely, short duration pyrexia can be due to a non-infectious cause like drug allergy or gout.

When fever has been present for more than 3 weeks, the temperature is higher than 101°F and despite thorough clinical evaluation and intelligently carried out investigations, the cause cannot be ascertained, such cases are called fevers of uncertain origin (FUO).

There are many causes of FUO These include various chronic infections, cancers (solid tumours and haematological malignancies including leukaemia) and collagen vascular diseases among others.

Even among long duration pyrexias, infection is the most common cause. In India, tuberculosis is the commonest cause. Other causes include infections of the heart (infective endocarditis), pus collections in the abdomen, infections of bone (osteomyelitis), pus collections in the liver and HIV infection.

The second group of causes are cancers. The commonest cancers causing FUO are cancers of the lymph nodes (lymphoma) and blood cancer (leukaemia). Among the solid cancers, the common ones are cancers of the liver (hepatoma), pancreas and kidney.

The third group of FUO is associated with collagen vascular diseases. In this category, fever is due to the immune response in which antibodies are produced against normal body cells. Conditions like systemic lupus erythematosus (SLE), polyarteritis nodosa and Wegener’s granulomatosis are included in this group. Usually more than two body organs are involved. The disease affects the skin, joints, kidneys and central nervous system. There are special investigations available to diagnose these conditions.

Among the miscellaneous causes of FUO are drug-induced fever, habitual hyperthermia, subacute thyroiditis and factitious fever (malingering). Habitual hyperthermia is a condition in which fever is of a low grade, no cause is found and the patient remains in good health. In this condition the raised temperature is due to a high setting of the temperature regulatory centre in the brain.

The approach to a patient with FUO should be rational. All patients should ideally be admitted to a well-equipped hospital. The physician attending the patient should take a detailed clinical history and carry out a thorough physical examination. He should carefully look for any swellings in the body such as enlarged lymph nodes and meticulously examine the various organ systems of the body. Any clue could be vital for the diagnosis and the physician has to work like a detective.

Based on the history, clinical examination and the investigations already carried out, the physician comes to one or two most likely possibilities. The essential investigations are then directed towards the most likely diagnosis. It is not feasible nor desirable to carry out a large battery of investigations in every case of FUO.

The special tests for FUO are of two types - non-invasive and invasive. The non-invasive tests like CT scan, MRI and radiolabelled WBC scan, if indicated, may be done first. Biopsies are the invasive tests which may be done depending on the likely organs involved. These include bone marrow biopsy, liver and kidney biopsy, CT guided biopsy of the lymph nodes in the abdomen and chest.

In large series of patients with FUO, infections are the cause in 50%, solid tumours and haematological malignancies in 20%, collagen vascular diseases in 7% and miscellaneous causes in 12%. In 11% the cause of FUO remains undiagnosed at the time of discharge from the hospital. However, when the latter group of patients are followed, in the majority the diagnosis becomes clear.

The treatment of FUO depends on the likely cause. In cases of tuberculosis, infections of the valves of the heart, abscesses of the liver, spleen, kidney, appropriate anti-microbial drugs are given. In cases of connective tissue disorders like systemic lupus erythematosus and polyarteritis nodosa, drugs that suppress the immune system are given and in cases of cancer, anti-cancer drugs or surgical treatment is advised.