Pyrexia of unknown origin and diagnosis
Pyrexia of unknown origin and diagnosis
Pyrexia of unknown origin and diagnosis
When a patient has an elevated body temperature for aperiod of longer than 3 weeks without a cause being foundthe diagnostic problem is called pyrexia (or fever) ofunknown origin (PUO).A febrile patient may lose the normal diurnal variationin body temperature or may sometimes have an exaggerateddiurnal pattern, with a rise during the night causingdrenching night sweats (common in tuberculosis and lymphoma)followed by a rapid fall. Many patterns of feverare described but they are rarely helpful in diagnosis.Causes of PUOThe most common causes of PUO vary according to theage of the patient, and published incidences vary with thetype of institution at which the problem is studied. Infectionis usually the most common cause in children, whereasinfection and neoplastic disease are equally important inadults. Connective tissue disease can present with fever atany age: Still's disease and SLE are commoner causes inchildren and young adults, and polymyalgia and giant cellarteritis more frequent in the elderly.InfectionMost bacterial infections cause an illness which is clinicallymanifest within 3 weeks, but there are some exceptions.Bacterial endocarditis can cause low-grade illness, particularlyin the elderly. Most cases can be diagnosed by bloodculture, but occasionally blood cultures are repeatedly negative.Infection in the biliary tract may be associated withonly minor clinical signs and little abnormality of liverfunction tests.Intracellular bacteria, such as Brucella and some Salmonellaspecies, can cause recurrent septicaemia, but this canusually be diagnosed by blood culture. Deep-seated abscessis a possible cause of PUO, and modern imaging techniquesare helpful in locating the collection.Tuberculosis is still a major cause of PUO in developingcountries and in some temperate countries such as the UK.Often the granulomatous lesions of tuberculosis are toosmall to cause pulmonary radiological abnormalities, andthe site of infection is often outside the lungs. In recentyears tuberculosis has become a common feature of HIVinfection.Viral infections rarely cause PUO (within the definition),with the important exception of HIV. The historyshould therefore enquire into sexual practices, intravenousdrug abuse and transfusions.Fungal infections rarely cause PUO without a predisposingcause, but they may do so as a complication ofimmunosuppressive disease or therapy. An exception is histoplasmosis.NeoplasiaLymphomas frequently produce a prolonged period offever before any other manifestation emerges. Leukaemiascan also cause PUO, but this is sometimes caused by a complicatinginfection. Many occult solid tumours can presentas PUO, among them hypernephroma, pancreatic carcinoma,intestinal tumours, bronchial carcinoma, ovariantumours and sarcomas. Fever is particularly likely whenthere are hepatic metastases. Atrial myxoma is a rarebenign tumour which occasionally produces anillness similar to bacterial endocarditis.Connective tissue (autoimmune) diseaseMost diseases in the category of connective tissue diseasecan present with PUO before the characteristic diseasepattern emerges. SLE, rheumatoid arthritis and Still'sdisease (including the adult form), polyarteritis nodosa,temporal arteritis and polymyalgia rheumatica should beconsidered depending on the clinical setting.MiscellaneousGranulomatous conditions. Granulomatous conditionsinclude sarcoidosis, granulomatous hepatitis and Wegener'sgranulomatosis. Sarcoidosis often lacks overt signs in theearly phase of the disease and should be considered,particularly in ethnic groups with a high prevalence, suchas West Indians.Factitious. One of the most odd forms of human behaviouris the habitual feigning, or the deliberate inducement,of illness. Factitious fever is caused in two ways: In the first the fever disappears when the temperature ismeasured by someone other than the patient, with thepatient under continuous observation. The patient iseither saying that fever exists when it does not, or ismanipulating the thermometer. In the other, more serious form the patient induces truefever by self-injury or self-infection. The methodsused are diverse, but faeces are the usual source oforganisms and infection is induced by rubbing or injectingorganisms into the skin or blood. Suspicion isaroused when mixed and varying organisms which couldbe faecal are found in an unexpected site, or when infectionpersists despite treatment that would normally beeffective.The condition is more common in young females than inmales, and the deceit may be helped by some medicalknowledge. There are sometimes personal problems, whichsuggest that this behaviour is a plea for attention or help.When suspicion grows that fever is factitious it is wise toavoid directly confronting the patient with the possibility.Usually it will be denied, and sometimes confrontation canprecipitate a psychiatric crisis, even resulting in suicide. Itis preferable to attempt to solve the associated problemsif they can be identified and to create a situation in whichit is difficult for the patient to continue to provoke sepsis,e.g. by removing intravenous catheters or covering inflamedsites. The patient should be made to realize that themanoeuvres are understood, if possible without a directaccusation. The best efforts to resolve factitious fever oftenfail, and patients either return intermittently or presentthemselves to another medical team.Bowel disease. Inflammatory bowel disease is usuallyassociated with incriminating symptoms such as weight lossand diarrhoea, but these may be slow to emerge. Whipple'sdisease, caused by the periodic acid-Schiff-positive Grampositivebacterium now known as Tropheryma whippelii,usually presents with polyarthralgia and diarrhoea inmiddle-aged men, but initially there may be only PUO andabdominal pain . Intestinal lymphoma may alsopresent with the latter symptoms.Drug reaction. Once thought of, drug reaction is astraightforward cause of PUO. The possibility that thefever is caused by a drug is tested by withdrawal.Multiple pulmonary emboli. When frequent smallembolic events occur, pyrexia may be the sole manifestionbefore the pulmonary circulation is greatly compromised.
Other causes. Other occasional causes of PUO are alcoholichepatitis, familial Mediterranean fever and occulthaematoma. There are some young women whose normalevening temperature runs above the normal range by upto 0.5C. This usually comes to light after an infection withslow recovery. Once it is established that there is no underlyingpathology the patient can be reassured. Tropicalcauses are discussed below.DiagnosisA careful history and examination of the patient is essential,and it is important to return to the patient repeatedlyto go over parts of the history and to look for emergentphysical signs. Simple screening tests which may need tobe repeated at intervals include full blood count, ESR andCRP, routine biochemistry of blood and urine, culturesof blood, urine and other relevant samples, and chestradiograph.Additional investigations are guided by the clinical findings.There are two approaches. One is to perform testswhich are more or less specific for particular diseases, e.g.exclude autoantibodies in autoimmunity or antibodies toparticular pathogens. The other is to investigate a particularsite which seems to be generating symptoms or signs.The latter is more often helpful, and it is in this area thatadvances in imaging techniques change the methods for diagnosing PUO.Ultrasound is particularly useful for abdominal examination,both in the detection of solid tissue abnormalities,such as tumours of the kidney or pancreas, lymph nodeenlargement or infiltration of the liver, and in locating collectionsof pus (subphrenic, perinephric, intrahepatic etc.).CT scanning supplements, and is in some situations superiorto, ultrasound, for example when intestinal gas limitsthe views on abdominal ultrasound. MR scanning is oftenmore sensitive than CT and is clearly superior for detectinglesions in soft tissue and bone. CT scanning and ultrasoundare used to guide the needle during tissue biopsy.
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