Most patients with fever have associated symptoms that make diagnosis strightfoward. The
majority have viral respiratory infections or uncomplicated bacterial respiratory or urinary
infections. A careful history and a full examination have a great value.
If the diagnosis is not immediately obvious, particular attention should be paid to special
features of history and examination, listed further under PUO. First line investigations include
full blood count, urinalysis and chest X-ray. Antibiotics should never be started until
appropriate cultures have been sent.
Epidemiological data - recent overseas travel, exposure to human or animal contacts, known
outbreak of e.g. influenza, measles, bronchiolitis.
Clinical presentation:
Infection - acute onset of fever, an obvious focus of inflammation or sepsis or a predisposing
cause such as immunosupression.
Helpful features associated with fever in infections:
Tonsillitis – acute onset with high fever suggests streptococcal disease, more insidious onset
inf. mononucleosis. Tuberculosis – fever may resolve with bed rest. Brief, high spikes of
fever – bedsores. Fever without associated rise in pulse rate – typhoid fever, brucellosis,
factitious fever.
Rigors = uncontrollable shivering lasting up to half an hour, followed by profuse sweating,
associated with rapid rise of temperature, associated with malaria, lobar pneumonia,
cholecystitis, pyelonephritis, sepsis. (Chills = brief episodes of shivering.)
Headache is common with fever, usual in influenza, typhoid fever, meningitis, localized
headache in sinusitis and mastoiditis.
Delirium: confusion, hallucinations and nightmares are seen with fever, esp. in children, in
lobar pneumonia and sepsis. Abrupt withdrawal of alcohol due to illness in habituated persons
may contribute to confusion and delirium.
Meningism in intracranial infection, but esp. in children is frequent in other febrile conditions
such as strep. tonsillitis, pneumonia and pyelonephritis.
Febrile convulsions in children up to the age of six.
Abdominal pain often associated with fever in children, caused by alterations of intestinal
motility or tender intraabdominal lymhp nodes. Other causes such as appendicitis must be
Clinical examination - special attention to:
- respiratory tract (middle ear in children) incl. paranasal sinuses, lungs
- spleen for enlargement
- skin and buccal mucosa for rashes
- abdomen for tenderness
- neck for lymph nodes and stiffness
- eyes for photophobia
- fontanelle for bulging
Laboratory investigations appropriate to clinical symptoms, some providing rapid, some
later results.
Management, if the cause of fever is not quickly demonstrated:
a) Treat symptoms and observe closely – in not very ill pt., who may recover rapidly.
b) Keep the pt. under constant review while further results of investigations are awaited – in
moderately ill pt. Antimicrobial therapy may mask an important diagnosis.
c) Start empirical antimicrobial therapy after initial specimens have been taken – in
potentially life-threatening circumstances. The choice of antimicrobial therapy is based
upon judgement of possible infectious causes. Sometimes the response is taken as
confirmatory evidence of diagnosis.
is a fever which has persisted for at least 7-10 days and is still unexplained after one or
more medical consultations.
The possible causes of PUO:
Infections (45-55%):
tuberculosis – extrapulmonary, miliary
sepsis or abscess
imported diseases – typhoid fever, brucellosis, amoebic abscess
infective endocarditis
zoonoses with subacute or chronic course
2. Malignancies (12-20%):
- haematological: lymphoma, leukaemia, histiocytosis
- visceral: kidney, liver, pancreas
3. Connective tissue disorders, autoimmunity (10-15%):
- rheumatological: rheumatoid arthritis, SLE, polyarteritis nodosa, dermatomyositis,
temporal arteritis
- granulomatous: sarcoidosis, Crohn´s disease, granulomatous hepatitis
4. Hypersensitivity disorders:
- drugs: sulphonamides, penicillins, isoniazid, streptomycin, amphotericin B, phenytoin,
- environmental factors: fungus-infected hay (farmer´s lung), bird proteins (pigeon-fancier´s
5. Rare metabolic disorders:
porphyrias, familiar relapsing polyserositis (Mediterranean fever), VIPoma and
6. Factitious fever
Temperature – axillar, oral, rectal
To exclude or monitor fever, single or occasional readings are inadequate and three-hourly
temperature chart is helpful.
A) physiological – variations throughout the day, exposure to extreme weather conditions,
clothing, activity, ovulation
B) pathological
C) factitious – patient manipulate his temperature recordings
D) fraudulent – real, but deliberately induced fever
Pattern of fever:
continuous, constant – meningitis, pneumonia, typhoid fever
intermittent - malaria, relapsing fever
swinging with periods of remission – tuberculosis, chronic vasculitis, spiking - abscess
undulant – brucellosis, Hodgkin´s disease
Work-up plan:
1. History: (besides previous medical history and history of present illness)
Exposure to infection: contact with other cases, travel, food, water, occupation, recreation,
animals - pets, sexual risk contacts
Exposure to allergens: drugs, cotton, hay, bird protein, industrial dusts and vapours
Predisposition: family history of relapsing serositis, Reiter´s syndrome and connective tissue
Exposure to carcinogenic agents
Protection or resistance - after previous infection, active or passive immunization, use of
2. Physical examination
should be repeated at daily intervals in patients in hospital, looking particularly for:
heart murmurs
chest signs
lymph nodes
localized bone or joint pain – discomfort, stifness, in children reluctance to move
skin rashes, nail for splinters
mild meningism
mild localized abdominal tenderness
3. Routine investigations (before the label of PUO is applied, repeat them, particularly if
they were performed early in the course of illness):
- blood count, differential WBC count
- blood culture
- urine – biochemistry, microscopy of sediment, culture
- sputum microscopy, culture
- CSF, stool, aspirates culture, if indicated
- biochemical screen – renal and liver tests, electrolytes, thyroid tests
- chest X-ray
In patients at risk for tuberculosis or if suspected for any reason:
- sputum and early morning urine for acid-fast bacilli and tuberculosis culture on three
ocassions (+ PCR)
- CSF for AFBs if indicated(+PCR)
- tuberculin test
4. Second-line investigations (depending on clinical picture):
Tests for connective tissue and granulomatous disease:
rheumatoid factor, anti-nuclear antibodies, double-stranded-DNA antibodies, organ-specific
antibodies (smooth-muscle, mitochondria, thyroid), anti-neutrophil cytoplasmic antibodies
(ANCA), complement levels, immunoglobulins
Serology (depending on suspected agent):
viral – flu, adenovirus, herpes, mumps, measles, parvovirus, HIV
bacterial – mycoplasma, chlamydia, syphilis, leptospirosis, legionella, brucella
ultrasonography – upper abdomen, pelvis
computed tomography (+ guided aspiration if indicated)
magnetic resonance imaging
radioisotope scans (bone scan, radiolabelled leukocytes)
X-ray techniques
laparoscopy, bronchoscopy, GIT endoscopy, cystoscopy,
Biopsy - liver, lymph node, bone marrow, skin lesion, temporal artery
Therapeutic trial after all possible specimens were obtained:
1. To gain further evidence for a suspected diagnosis - expected response (suspected
specific infection – give drug with the narrowest possible spectrum).
2. A "blind" trial, when the patient´s condition is critical.
Antibiotics: reduced usefulness of diagnostic cultures
modification of infection without cure
adverse side-effects complicating the illness
Corticosteroids: reduced usefulness of immunological tests
progression of the infection with reduced signs of inflammation
In about 5 % no diagnosis was done and no improvement is obtained. About half of these
cases eventually recover and most of the others remain feverish but do not deteriorate.