Fever implies an elevated core temperature of greater than 38°C. Clinical features are used to guide appropriate investigations, which include:
• FBC and differential • U&Es, liver function, glucose and muscle enzymes
• ESR and CRP • HIV antibodies • Autoantibodies • CXR and ECG
• Urinalysis and culture • Blood culture • Throat swab
Additional tests are indicated by local symptoms and if the patient is immunocompromised.
Pyrexia of unknown origin
PUO is a common presenting problem and is defined as a temperature of greater than 38°C on multiple occasions persisting for more than 3 weeks with no diagnosis after initial investigation. Many causes of PUO are listed in Box 5.1. Two or more causes may coexist. Fever in old age merits special attention (Box 5.2).
Detailed history should include:
Recent travel: Malaria, respiratory infections, viral hepatitis, typhoid and dengue are the most common causes of imported fever in the UK.
Personal and social history: Exposure to STI, illicit drug use.
Occupational or recreational history: Animal exposure, unpasteurised milk consumption, watersports (leptospirosis).
5.2 Fever in old age
• Temperature measurement: fever may be missed because oral temperatures are unreliable. Rectal measurement may be needed, but core temperature is increas- ingly measured using eardrum reflectance.
• Delirium: common with fever, especially in those with underlying cerebrovascular disease or dementia.
• Prominent causes of PUO: TB, intraabdominal sepsis, UTI and endocarditis.
Noninfective causes include polymyalgia rheumatica, temporal arteritis and tumours.
• Common infective causes in the very frail (e.g. nursing home residents):
pneumonia, urinary infection, soft tissue infection and gastroenteritis.
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Investigations and management
Regularly review and expand history taking; this helps to select appropri- ate tests. Repeat physical examination regularly for emerging signs (e.g.
murmurs, lymphadenopathy, rashes). Initial investigations are listed above.
If these are inconclusive, those in Box 5.3 should be considered.
Lesions on imaging should normally be biopsied to detect pathogens by culture or nucleic acid detection.
5.1 Aetiology of pyrexia of unknown origin Infections (∼30%)
• Specific locations: abscess at any site, cholecystitis/cholangitis, UTI, prostatitis, den- tal, sinus, bone and joint infections, endocarditis
• Specific organisms: TB (esp. extrapulmonary), brucellosis, Tropheryma whipplei, viruses ( CMV, EBV, HIV- 1), fungi (Aspergillus, Candida)
• Specific patient groups: imported infections, for example, malaria, dengue, leishmania- sis, enteric fevers, Burkholderia pseudomallei, nosocomial infections, HIV- related infec- tions, for example, Pneumocystis jirovecii, disseminated Mycobacterium avium, CMV Malignancy (∼20%)
• Lymphoma, myeloma and leukaemia
• Solid tumours (renal, liver, colon, stomach, pancreas) Connective tissue disorders (∼15%)
• Older patients: temporal arteritis/polymyalgia rheumatica
• Younger patients: SLE, Still’s disease, polymyositis, vasculitis, Behçet’s disease • Rheumatic fever
Miscellaneous (∼20%)
• Inflammatory bowel disease, alcoholic liver disease, granulomatous hepatitis, pancreatitis
• Myeloproliferative disease, haemolytic anaemia
• Sarcoidosis, atrial myxoma, thyrotoxicosis, hypothalamic lesions • Familial Mediterranean fever, drug reactions, factitious fever No diagnosis or resolves spontaneously (15%)
5.2 Fever in old age
• Temperature measurement: fever may be missed because oral temperatures are unreliable. Rectal measurement may be needed, but core temperature is increas- ingly measured using eardrum reflectance.
• Delirium: common with fever, especially in those with underlying cerebrovascular disease or dementia.
• Prominent causes of PUO: TB, intraabdominal sepsis, UTI and endocarditis.
Noninfective causes include polymyalgia rheumatica, temporal arteritis and tumours.
• Common infective causes in the very frail (e.g. nursing home residents):
pneumonia, urinary infection, soft tissue infection and gastroenteritis.
Liver biopsy: May reveal TB, lymphoma or granulomatous disease, including sarcoidosis. It is unlikely to help unless the liver is biochemically or radiologically abnormal.
Bone marrow biopsy: Has a diagnostic yield in PUO of around 15%, the most common abnormalities being myelodysplasia, other haematologi- cal malignancies and TB. More rarely, brucellosis, typhoid fever or visceral leishmaniasis may be detected, emphasising the importance of culture as well as microscopy of samples.
Temporal artery biopsy: Should be considered in patients over 50 years of age, even if the ESR is not significantly elevated. Because arteritis is patchy, diagnostic yield is increased if a 1.5- cm section of artery is biopsied.
Prognosis
No cause is found in approximately 10% of PUO cases, but as long as there is no significant weight loss or signs of another disease, the long- term mortality is low.
Fever in the injection drug user
Infection is introduced by nonsterile (often shared) equipment. Risks increase with prolonged drug use and central injection in large veins, necessitated by thrombosis of peripheral veins. Fever is usually caused by soft tissue or respiratory infections.
Clinical assessment
Site: Femoral vein injections may cause DVT, of which 50% are septic.
Arterial injection may cause false aneurysm formation and compartment syndrome. Psoas abscess and septic arthritis also occur. Clostridium infec- tion has been recorded with SC or IM injection of heroin.
Technical details: Sharing of needles and spoons, and use of contami- nated drugs or solvents increase the risk of infection (e.g. HIV, HBV or HCV). Establish what has been injected, including what solvents were used.
Blood- borne viral test status: Check recent results and vaccinations.
Surreptitious self- treatment with antibiotics: May mask culture results.
Other symptoms: Breathlessness, myalgia, confusion and tachycardia may be caused by infection or to drug withdrawal.
Signs: These include:
• Rashes.
• Injection site abscess.
5.3 Additional investigations in PUO
• Serological tests: autoantibodies, complement, immunoglobulins, cryoglobulins • Echocardiography
• USS of abdomen
• CT/MRI of thorax, abdomen and/or brain
• Skeletal imaging: X-rays, CT/MRI spine, isotope bone scan • Labelled white- cell scan
• PET scan
• Biopsy: bronchoscopic, lymph node, liver, bone marrow, temporal artery, laparoscopic
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• Joint pain or swelling from injection.
• DVT or compartment syndrome in the legs.
• Local tenderness or referred pain from an abscess site, for example, flexion at the hip eliciting back pain suggests ilio- psoas abscess.
• New murmurs or evidence of cardiac decompensation: may suggest either right- or left- sided endocarditis (check nails for splinter haemor- rhages) or the cardiomyopathy of generalised sepsis. The jugular venous pressure may show V waves in tricuspid endocarditis.
• Pleural rub or effusion is seen in DVT with pulmonary embolism, or septic emboli from endocarditis or infected DVT.
• Stupor: occurs in drug overdose or hepatic encephalopathy; agita- tion with drug withdrawal; headache and drowsiness in meningitis or encephalitis; local paralysis or spasms with tetanus or botulism.
Management
Management is that of the underlying condition. Flucloxacillin is useful against Staphylococcus aureus, although vancomycin may be needed if MRSA is present. Nonadherence to prescribed antimicrobial regimens leads to a high rate of complications.
Fever in the immunocompromised host
Immunosuppression may be congenital; acquired through infection or hae- matological disease; or iatrogenic, induced by chemotherapy or immuno- suppression for autoimmune diseases or transplantation. These may be distinguished by history, and careful examination may reveal where infection has breached the skin or mucosal barriers.
Initial tests are as described earlier (p. 102). Immunocompromised patients often have attenuated physical signs, such as neck stiffness with meningitis. Chest and/or abdominal CT should be considered in addition to CXR according to symptoms. Cultures of blood, urine and stool are often helpful. Nasopharyngeal aspirates are sometimes diag- nostic, as immunocompromised hosts may shed respiratory viruses for prolonged periods. Skin nodules should be biopsied and stained for fungi. PCR should be performed for CMV and Aspergillus DNA, and antigen assays should be performed for Cryptococcus or Aspergillus in blood, and for Aspergillus and other invasive fungi or Legionella in urine. Antibody detection is unhelpful in immunocompromised patients.
Patients with respiratory symptoms should be considered for bronchoal- veolar lavage to detect Pneumocystis jirovecii, other fungi, bacteria and viruses.
Neutropenic fever is defined as a neutrophil count of less than 0.5 × 109/L, with fever greater than 38.5°C, and is covered on p. 797. Sepsis is discussed on p. 80.