PYREXIA OF UNKNOWN ORIGIN
Case vignette
A 66-year-old man of Greek descent has been investigated in hospital for a period of 1 week for a swinging fever of 1 month’s duration and associated headache, weight loss, arthralgia, myalgia and lethargy. He complains of drenching night sweats and rigors. The patient denies any localising symptoms. He has a background history of myocardial infarction treated with angioplasty and stent 1 year ago. He is currently on metoprolol 25 mg twice daily and aspirin 150 mg daily. He denies any allergies or family history of significant illness. He has recently travelled to the west coast of the United States for a family reunion. On examination his pulse rate is 100 bpm and his temperature is 38°C. His temperature chart shows a regular pattern of temperature spikes up to 39°C. No other significant signs are evident.
On further enquiry the patient reveals that he noticed an expanding erythematous maculopapular rash, which disappeared spontaneously. The lesion was painless. According to the detailed description, the lesion had a clear central core and a well-defined border.
Approach to the patient
Pyrexia of unknown origin is defined as intermittent or continuous fever for more than 3 weeks in a patient in whom the cause of the fever has not been identified in spite of repeated investigations for more than a week.
History
Ask about:
• the onset and duration of the illness
• any treatment received so far
• other associated symptoms that may give some clues to the likely aetiology of the fever—such as weight loss, cough, rashes
• symptoms that may help in the localisation of the focus
• the temporal pattern of the febrile episodes
• past medical history—focusing on infectious conditions, connective tissue diseases, vasculitic conditions and malignancies
• detailed medication history—looking particularly for drugs that may cause fever
• history of alcohol intake and recreational drug use
• pets, farm animals, hobbies, sexual activity
• travel—be familiar with region-specific rare infections such as kala-azar, Lassa fever, Q fever, Lyme disease
• specific features of rather rare diseases such as erythema migrans of Lyme disease (as was the case in the above case vignette) when there is a suspicion
• detailed family history—important in excluding diseases such as familial Mediterranean fever.
Examination
The condition could be due to multiple causes, both infective and non-infective (see box). A detailed physical examination should be carried out, looking first for a focus of sepsis. Look for areas of inflammation in the skin and check for lymphadenopathy and/or hepatosplenomegaly. Look for rashes, inflamed joints, painless mass lesions etc. Study the temperature chart. Perform the examination with a particular focus on the most likely body system to be involved, based on the overall clinical picture.
Some of the commonly encountered causes of undiagnosed persistent fever are occult abscesses in the abdomen, tuberculosis, cytomegalovirus (CMV) infection, HIV infection, haematological malignancy, solid cancer, pulmonary embolism, Wegener’s granulomatosis, undiagnosed vasculitis (especially polymyalgia rheumatica and giant cell arteritis), granulomatous conditions such as sarcoidosis, Still’s disease and drugs. The remainder of the physical examination should be focused on looking for features of non-infective causes of fever.
Causes of pyrexia of unknown origin
• Bacterial sepsis—e.g. bacterial endocarditis, subphrenic abscess, typhoid fever, brucellosis
• Viral sepsis—e.g. HIV, Epstein-Barr virus, parvovirus, Ross River virus, Barmah Forest virus
• Fungal sepsis
• Rickettsial sepsis—e.g. Q fever
• Mycobacterial sepsis—tuberculosis/atypical varieties
• Systemic vasculitis—e.g. Wegener’s granulomatosis, polyarteritis nodosa, Behçet’s disease
• Granulomatous conditions—e.g. sarcoidosis, Crohn’s disease
• Neoplasms—e.g. sarcoma, renal carcinoma, Hodgkin’s disease
• Drug fever—sulfa drugs, vancomycin, hydralazine, methyldopa
• Pulmonary embolism
• Haematoma
• Gout
• Dressler’s syndrome
• Alcoholic hepatitis
• Hypothalamic lesions—impaired thermoregulation
• Factitious fever
Investigations
Initial investigations should be aimed at excluding infection, and a standard septic work-up may already have been done. If the results are inconclusive, it is most appropriate to repeat the septic work-up. The standard septic work-up includes:
1. Full blood count and differential white cell count, to exclude leucocytosis or leucopenia
2. ESR and C-reactive protein (CRP), looking for persisting inflammation
3. At least three sets of blood cultures from different sites of the body at different intervals
4. Alerting the microbiology lab to the need for prolonged cultures for fungi and fastidious organisms
5. Chest X-ray
6. Urine analysis and midstream urine for microscopy and culture
7. Sputum microscopy and culture
8. Stool culture, for Salmonella
9. Lumbar puncture if neurological features are present.
If these investigations are non-diagnostic and the patient is still febrile, further investigations should be ordered, looking for specific diagnostic clues. These include:
1. CT of the thorax, abdomen and pelvis—looking for abscesses and unsuspected lymph node enlargement
2. Transoesophageal echocardiography—looking for valvular vegetations, to exclude subacute infective endocarditis
3. Gallium scan, looking for areas of active inflammation or lymphoma
4. Indium-labelled white cell scan, looking for foci of sepsis
5. Three-phase bone scan (or bone first gallium record)—looking for osteomyelitis or other bony lesions (inflammation or metastatic deposits)
6. Swabs as clinically indicated (e.g. cannula site)
7. Serology for CMV and HIV
8. Autoimmune serology
10. Temporal artery biopsy if there is clinical suggestion of temporal arteritis
11. Liver biopsy
Management
Very ill patients should be treated as for septicaemia, with broad-spectrum, potent parenteral antibiotic combinations. Otherwise, therapy should be guided by the clinical circumstances and the above investigational results.
THE IMMUNOCOMPROMISED HOST
Approach to the patient
There is a high likelihood that a patient presented as a long case will have some form of immunodeficiency, either as the primary presentation or as a comorbidity. Immunodeficiency could be granulocytopenia, cellular immunodeficiency (see box) or humoral immunodeficiency (see box).
Causes of cellular immunodeficiency
• Lymphoma
• Chronic lymphocytic leukaemia
• High-dose corticosteroid therapy
• Cytotoxic therapy
• HIV/AIDS
• Immunosuppression associated with solid organ or bone marrow transplantation. (Viral infections due to agents such as herpes simplex, varicella zoster and cytomegalovirus are common in this group of patients. In the setting of solid organ transplantation, the most common causative organism of opportunistic sepsis is cytomegalovirus—with the exception of heart transplantation, where it is toxoplasmosis. Other opportunistic infections of importance are Pneumocystis carinii pneumonia and reactivation of tuberculosis.)
Causes of humoral immunodeficiency
Therapy for humoral immunodeficiency may include IV infusion of immunoglobulins at regular intervals. Encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae usually cause sepsis in this setting. In terminal component complement and properdin deficiency, Neisseria meningitidis is the organism that causes the most sepsis.
History
Ask about:
• the current symptoms the patient presents with, to ascertain the focus of sepsis
• recurrent infections and, if known, investigations performed so far
• other medical conditions—diabetes mellitus, renal failure, HIV, haematological malignancy
• details of any relevant family history
• medications consumed—immunosuppressive agents
• alcohol abuse, recreational drug use
• sexual behaviour.
Examination
Search for the focus of sepsis. You should carry out a detailed examination of the systems involved. Check the temperature chart to ascertain the temporal pattern of the fevers. Look for clues to the predisposing condition, such as stigmata of liver disease or chronic renal failure, venepuncture marks of injecting drug use, lymphadenopathy, hepatosplenomegaly, splenectomy scar and central venous catheters.
The following is an outline of some of the different forms of immunodeficiency that can be expected in the long case setting and some information that may be useful in approaching the management of such patients.
Granulocytopenia
A patient is absolutely granulocytopenic by the classic definition when the neutrophil count goes below 0.5 × 109/L. The risk of sepsis is increased in this setting.
If a granulocytopenic patient is febrile, possible foci of sepsis are: oropharynx, lung, distal oesophagus, colon, perianal skin, intravenous cannula site and the urinary tract.
Management
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