Pyrexia of unknown Origin
Introduction
Pyrexia (or fever) of unknown origin (FUO) is a medical condition defined by having
a temperature greater than 38.3°C on several occasions and a diagnosis that remains
elusive after 3 weeks of investigation in hospital or as an outpatient. This seemingly
simple definition hides a condition that can be diagnostically challenging for
physicians. Over 200 diseases have presented as FUO and establishing the correct
diagnosis requires a systematic approach combining astute clinical skills, appropriate
investigations and a willingness to reconsider diagnoses. This article will discuss the
epidemiology, history taking, examination findings, investigations and management of
patients presenting with FUO aiming to assist with the diagnostic process.
History and Epidemiology
The term FUO was first coined in 1961 in a seminal article by Petersdorf and Beeson
who defined it as a temperature higher than 38.3°C on several occasions, lasting for
more than 3 weeks and with a diagnosis that remained uncertain after 1 week of
investigations in hospital. This initial definition has been refined over time but
captures the essence of the condition.
FUO accounts for between 1-3% of medical admissions and often represents
diagnostic challenges faced by physicians. The usual age of presentation is between
20-50 years with a slight male predominance. Underlying diseases resulting in FUO
vary based on geographical location and patient population. In developed countries,
infections (viral, bacterial, fungal or parasitic) account for around 30% of cases while
non-infectious inflammatory disorders such as sarcoidosis or temporal arteritis
constitute 30-40% and malignancies around 10-15%. Rare diseases such as
inflammatory bowel disease, connective tissue disorders or solid organ abscesses
constitute the remainder.
History taking
A thorough history is key to the diagnosis of FUO. Important aspects to focus on
include:
- Onset and pattern of fever: Insight into how/when fever starts, frequency, duration
and associated symptoms can provide clues. For example, recurrent intermittent fever
may point towards infective or inflammatory conditions while hectic fever raises
suspicion for TB.
- Past medical and travel history: Previous illnesses, immunodeficiencies, surgeries,
injuries or overseas travel history are important as they increase risks of certain
diseases. A remote history of similar episodes in the past increases likelihood of
recurrent infections.
- Symptoms review: Careful enquiry about symptoms from different organ systems
provides diagnostic opportunities. For example, weight loss, night sweats increases
suspicion for tuberculosis whereas bone pain increases risk of lymphoma.
- Drug history: Medicines such as antibiotics, steroids or immunomodulators can
modify clinical picture or predispose to certain infections.
- Family history: Familial conditions such as vasculitides are more common than
thought.
- Sexual, social and occupational history: May provide clues regarding exposure risks
e.g. infections that are gender, region or occupation specific.
- Review of systems: Enquiry about symptoms from different organ systems is crucial
e.g. cough, headache, joint pains etc. that can provide diagnostic opportunities.
Examination
Physical examination is an important part of the evaluation in FUO. Both general and
systemic examination should be performed with focus on potentially abnormal
findings:
- Vital signs: Fever pattern, tachycardia, hypotension provide insights.
- Head, eyes, ears, nose, throat: May reveal lymphadenopathy, pharyngitis, oral ulcers,
cervical masses etc.
- Chest: Signs of pneumonia, pleural effusion, tuberculosis etc. Important to examine
axillae and supraclavicular regions for lymphadenopathy.
- Cardiovascular: Murmurs, rubs, peripheral embolic phenomena raise suspicion for
infective endocarditis, vasculitides etc.
- Abdomen: Hepatosplenomegaly, abdominal masses, ascites suggest abdominal
diseases like lymphoma, abscesses.
- Skin: Rashes, ulcers, joint pains suggest connective tissue diseases, vasculitides etc.
- Nervous system: Meningism, focal neurological signs relevant to CNS infections.
- Lymph nodes: Size, consistency, mobility provides clues to underlying pathology
e.g. sarcoidosis, lymphoma. Multiple, discrete, firm lymph nodes suggest malignancy.
Investigations
Establishing the correct diagnosis involves a stepwise and individualized approach.
Initial broad screening tests are followed by more specific tests guided by history and
examination findings:
- Complete blood count (CBC): May reveal anemia, leukocytosis, eosinophilia etc.
Neutrophil leukocytosis suggests infection or inflammation, lymphocytosis is seen in
viral illnesses.
- Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP): Non-specific
inflammation markers, elevated in majority of causes but not specific.
- Blood/ urine culture: Should be done in all patients even without localizing signs to
rule out occult bacteremia, UTI etc.
- Chest x-ray (CXR): Useful initial study, can detect occult pneumonia, TB etc.
- Abdominal ultrasound: Evaluates liver, spleen, kidneys, ascites, masses. Useful
initial screening test.
- Serological tests: ANA, RF, anti-CCP, vasculitis screen detect connective tissue
disorders, serum angiotensin converting enzyme (SACE) - sarcoidosis.
- Microbiological tests: Based on history-Blood/urine cultures and sensitivities, viral,
fungal, parasitic and atypical serologies e.g. Monospot, dengue, typhoid, malaria.
- Histopathology: Guided biopsies of enlarged lymph nodes, liver, skin/muscle
extremely helpful to establish underlying pathology in many causes.
- Imaging studies: Targeted based on history, exam and laboratory clues - USS
abdomen/pelvis, CT chest/abdomen/pelvis to look for occult abscesses,
lymphadenopathy, appendicitis etc. MRI brain if CNS involvement suspected.
If initial evaluation is non-revealing, further specialized tests may be needed based on
high index of suspicion e.g. Positron emission tomography (PET) scan, Video-assisted
thoracoscopy (VATS) for sarcoidosis diagnosis. Stepwise approach is key to
maximize diagnostic yield while minimizing cost and radiation exposure in FUO.
Causes
It is not possible to cover the extensive differential diagnosis for causes of FUO in
detail here. The most common causes based on location and prevalence vary include:
Infectious causes:
- Tuberculosis: Up to 15% of cases in developing countries.
- Abscesses: Liver, splenic or prostate abscesses common.
- Viral infections: Mononucleosis, hepatitis, cytomegalovirus.
- Bacterial infections: Q fever, brucellosis, infective endocarditis, Lyme disease.
- Fungal infections: Histoplasmosis.
- Parasitic infections: Malaria, toxoplasmosis.
Non-infectious inflammatory conditions:
- Sarcoidosis
- Rheumatological: Giant cell arteritis, polymyalgia rheumatica, vasculitides.
- Inflammatory bowel disease
Malignancies:
- Lymphoma
- Leukaemia
- Occult carcinoma
Miscellaneous:
- Drug fever
- Periodic fever syndromes
- Solid organ inflammation: Hepatitis, pancreatitis
-Miscellaneous rare causes
An open approach and careful reconsideration is needed due to the diverse causes
making early broad based evaluation essential. A high index of clinical suspicion aids
the diagnostic odyssey in FUO.
Management
Management of FUO requires a multidisciplinary approach involving internists,
microbiologists, surgeons and specialists depending on diagnosis:
- Antipyretics and supportive care form initial mainstay while awaiting diagnosis.
- Empiric broad spectrum antibiotics only if infection strongly suspected on clinical
grounds, with microbiological guidance to streamline. Indiscriminate use increases
drug resistance and cost without yield.
- Targeted diagnostic procedures guided by history, exam findings and test results e.g.
biopsies, drainage of abscesses.
- Immunosuppressants in cases of proven inflammation like vasculitis, sarcoid
pending response monitoring. Steroids have limited role due to increased infection
risk.
- Referral to specialists e.g. rheumatology, infectious disease as required with
multidisciplinary discussion to identify diagnostic gaps.
- Periodic clinical review with re-evaluation of initial diagnosis as new clues emerge
is critical given elusive nature.
- Psychosocial support important given protracted diagnostic odyssey impacting
quality of life.
While frustrating for patients and physicians, a stepwise and openminded approach
ultimately aids successful diagnosis in around 60-70% of FUO cases. Early
involvement of relevant specialists when required facilitates timely resolution.
Prognosis
Prognosis in FUO depends greatly on the underlying diagnosis which is established in
60-80% of cases with thorough and guided evaluation:
- Infection: Excellent prognosis with appropriate anti-microbials. Mortality risk from
drug resistant or atypical infections.
- Inflammatory conditions: Good control with immunosuppression. Risk of organ
damage from untreated conditions like vasculitis.
- Malignancy: Variable depending on cancer type and stage at diagnosis. Relatively
good if lymphoma or early solid cancers.
- Miscellaneous causes: Variable depending on factors like drug reaction, periodic
fever syndrome response to targeted therapy.
- Idiopathic: Around 10% remain without diagnosis. Usually self-limiting but risk of
recurrent fever bouts.
With diligent stepwise history, exam and guided testing approach, most cases yield
diagnosis and good clinical outcomes. Protracted search improves clinical acumen for
all physicians while poor response warrants specialty care and research into new
diagnostic techniques. Multidisciplinary approach forms pillar of successful prognosis
in FUO.
Conclusion
To summarize, FUO represents a diagnostic challenge often needing cautious and
iterative approach over weeks. Thorough history, examination and targeted
investigations judiciously utilizing basic and specialized tests are key to arriving at
correct diagnosis. Early involvement of relevant specialists facilitates timely
resolution. While frustrating, solving the diagnostic puzzle in FUO is immensely
rewarding for all involved. Careful reassessment of initial working hypothesis and
recognition of diagnostic gaps is critical given diverse etiologies. Adopting a
collaborative and structured stepwise method maximizes patient care through
successful diagnosis and appropriate, timely management in this diagnostic odyssey.
