Pyrexia of unknown origin ( Fever evaluation) .pdf

170 © Royal College of Physicians 2018. All rights reserved.
ORIGINAL RESEARCH Clinical Medicine 2017 Vol 17, No 6: 170–8
CME INFECTIOUS DISEASES Clinical Medicine 2018 Vol 18, No 2: 170–4
Authors: A
specialist trainee in infectious diseases, Tropical and
Infectious Disease Unit, Royal Liverpool University Hospital,
Liverpool, UK; B
senior lecturer and honorary consultant in infectious
diseases, Tropical and Infectious Disease Unit, Royal Liverpool
University Hospital and Clinical Sciences Group, Liverpool School of
Tropical Medicine, Liverpool, UK
Authors: Cristina FernandezA
and Nick J BeechingB
The syndrome of pyrexia of unknown origin (PUO) was
first defined in 1961 but remains a clinical challenge for
many physicians. Different subgroups with PUO have been
suggested, each requiring different investigative strategies:
classical, nosocomial, neutropenic and HIV-related. This could
be expanded to include the elderly as a fifth group. The causes
are broadly divided into four groups: infective, inflammatory,
neoplastic and miscellaneous. Increasing early use of positron
emission tomography–computed tomography (PET-CT) and
the development of new molecular and serological tests for
infection have improved diagnostic capability, but up to
50% of patients still have no cause found despite adequate
investigations. Reassuringly, the cohort of undiagnosed
patients has a good prognosis. In this article we review the
possible aetiologies of PUO and present a systematic clinical
approach to investigation and management of patients,
recommending potential second-line investigations when the
aetiology is unclear.
Introduction
The definition of pyrexia of unknown origin (PUO) dates back
to 1961; it was described as a persistent fever above 38.3°C
(100°F) that evades diagnosis for at least 3 weeks, including
1 week of investigation in hospital.1
This definition has evolved
with faster and more accurate diagnostic techniques and
changing models of care, and a week of hospitalisation is no
longer considered essential. Different subgroups with PUO have
been suggested, each requiring different investigative strategies:
classical, nosocomial, neutropenic and HIV-related.2
Pyrexia of
unknown origin in the elderly tends to be considered under the
classical heading, but the presentation, underlying conditions
and subsequent management differ considerably from PUO in a
younger adult age group. Pyrexia of unknown origin in the over 65s
could be considered a fifth category.3,4
The causes of PUO can be considered in four categories:
infective, inflammatory, neoplastic and miscellaneous. The relative
ABSTRACT
Pyrexia of unknown origin
Key points
When investigating a patient with pyrexia of unknown origin
(PUO), consider possible aetiologies in each of the following
four broad categories: infective, inflammatory, neoplastic and
miscellaneous. Address each in turn. Pyrexia of unknown origin
is a diagnostic challenge and early involvement of specialists is
important
The balance of causes of PUO varies over time and across
different patient populations
Investigations should be undertaken based on the most likely
cause(s). Blanket investigations are not recommended as
positive or equivocal tests are difficult to interpret in the absence
of a suggestive exposure history and/or clinical syndrome. This
can be misleading and potentially cause patient harm
Empirical therapeutic trials are not recommended before a
diagnosis is made, unless the patient is believed to have miliary
tuberculosis (TB), central nervous system TB, temporal arteritis or
infective endocarditis with severe sepsis
The overall outcome of patients with a PUO is good, especially
when no cause is found
KEYWORDS: fever, pyrexia of unknown origin, fever of unknown
origin, pyrexia, diagnosis ■
prominence of each category has changed over time, with an
increasing proportion of patients who remain undiagnosed,
which may be up to 51% of cases.5
Infectious causes account
for 17–35% of cases, inflammatory causes 24–36%, neoplastic
causes 10–20% and miscellaneous causes 3–15%.6
An older
multimorbid population, increased global travel, HIV infection,
the increase in organ transplantation and immunomodulation for
many diseases, evolving diagnostics and changing antimicrobial
resistance patterns have all changed the management of patients
with PUO (Fig 1).
Clinical approach
The diagnostic approach to a patient with PUO should be
methodical. A thorough history is essential and will have to go
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© Royal College of Physicians 2018. All rights reserved. 171
CME Infectious diseases
back months or years to yield clues to potential aetiologies for
investigation. The pattern of fever (episodic, consistent etc)
and general health of the patient during and between episodes
of fever should be ascertained, together with any associated
past or current symptoms. Enquiry should include a detailed
past medical and surgical history, all medications the patient
takes or has taken including over-the-counter drugs, alternative,
herbal or ‘traditional’ medications, recreational drug use and
vaccinations. A comprehensive travel history is needed together
with occupational, environmental, animal and sexual exposures.
Illness in contacts and a family history of similar illnesses may
be relevant. This history should be revisited at regular intervals,
both to highlight clues that were previously missed or initially
not considered to be relevant and to review any changes in
symptoms.
Patients with a prolonged PUO are often clinically well
enough to lead a relatively normal life. However, at every
clinical encounter it must be reviewed whether the patient has
developed any ‘red flag’ symptoms; these include weight loss,
increased lethargy, drenching night sweats, inability to perform
activities of daily living, or changes in other symptomatology and
physical examination.
A comprehensive examination of the patient follows. The first
clinical encounter should include an ‘A, B, C’ approach to ensure
the patient is clinically stable. Physical features of a systemic
inflammatory response must be elucidated on examination and in
the first instance sepsis should be ruled out.
As well as a detailed examination of the respiratory,
cardiovascular and alimentary systems one must pay special
attention to other important sources of fever. This includes: full
examination of the spine and joints; top-to-toe examination
of the skin for rashes, ulcers, scars, bites, pressure areas and
abnormalities of the hair and nails; review of dentition; temporal
arteries; fundoscopy; breast examination, particularly in women;
and pelvic or rectal examination including the prostate in men.
Any implant is a potential site of infection and must be examined
if possible, including prosthetic joints, pacemakers, pacemaker
wires, central or peripheral vascular lines, shunts, grafts and
meshes.
Investigations should be conducted to confirm or rule out
the most likely diagnosis/diagnoses, based on the history and
examination findings. Investigation should proceed through at
least two stages of baseline tests followed by more specific tests,
after which each abnormal result should be weighed carefully –
the more tests that are done, the more false leads will emerge.
Early blanket testing for all possible aetiologies is inappropriate.
A baseline set of investigations includes full blood count with a
differential cell count, renal electrolytes and liver function tests,
C-reactive protein (CRP) and erythrocyte sedimentation rate
(ESR), clotting screen, creatine kinase, at least two blood cultures
(while not receiving antibiotics) and an HIV test. A chest X-ray,
ultrasound of the abdomen and a urine dipstick should also be
performed.
Potential second-line investigations include microbiological tests,
imaging and biopsies as described in Table 1. Each test should only
be performed when there is a reasonable pretest probability of the
condition being present and this often requires early involvement
of other appropriate clinical specialties in the care of patients with
PUO. The utility and availability of positron emission tomography–
computed tomography (PET-CT) has increased and it is often
used early in the list of second-line investigations to identify
metabolically active foci of infection, inflammation or cancer as
possible causes of PUO.12
Infective causes
The most common causes of PUO in immunocompetent
individuals are infective endocarditis (especially culture negative
endocarditis), discitis, osteomyelitis, occult abscesses and
infected implanted devices. Patients who have been hospitalised
in the last 6 months are at increased risk of haematogenous
spread of infections through invasive procedures and
intravascular devices. In all cases, a positive microbiological
diagnosis should be attempted prior to commencing
antimicrobial therapy, often involving a biopsy of the potentially
infected tissue or removal of the culprit device. In patients with
suspected endocarditis and negative blood cultures, fastidious
and slow-growing bacteria are common aetiological agents. In
these cases, extended cultures for HACEK organisms (a group
of fastidious Haemophilus-like organisms) and serology for
Coxiella burnetii (Q fever), Bartonella spp and Brucella spp are
recommended.13
Resistant organisms are becoming increasingly common and
must be considered in patients with recent (last 6 months) or
repeated hospitalisations, who have received repeated courses
of antimicrobials, and those who have been travelling abroad,
especially if they have had diarrhoea or been hospitalised
overseas.
Elderly patients account for an increasing proportion of patients
with PUO. It is important to not discount diagnoses such as
tuberculosis, HIV or syphilis on the basis of age alone.
Returning travellers
Up to one-quarter of returning travellers cite fever as the chief
reason for seeking care on return and are more likely to be
hospitalised than those without fever.14,15
The National Travel
Health Network and Centre (NaTHNaC) (https://travelhealthpro.
0
20
40
60
80
100
120
Causes
of
PUO
Children
>65
years
old
Tropics
Paent populaons
HIV
posive
paents
on
ART
a
Total
Unknown
Miscellaneous
Inflammatory
Neoplasc
Infecous
Fig 1. The relative causes of pyrexia of unknown origin (PUO) in differ-
ent patient populations expressed as percentages (data from
references5,7–11
). a
Many HIV positive patients have more than one causal
diagnosis for PUO and therefore the sum of percentages in this category is
100%. ART = antiretroviral therapy
3/24/18 6:17 PM

org.uk) provides travel information about current outbreaks and
potential exposures based on the area of travel.
A travel history should elicit where the patient has returned
from (including transits), the length of time spent in each place,
the type of accommodation used, use of bed nets, the activities
the patient undertook, what type of food and beverages they
consumed, and whether they suffered any arthropod or animal
bites. Details are needed of business and leisure activities including
animal and freshwater contact, sexual history and possible illness
in contacts. Vaccinations prior to travel, compliance with malaria
and other chemoprophylaxis and the use of antimicrobials
abroad are also important. Most patients with falciparum malaria
present within 2 months of return, but other species of malaria
may have incubation periods of a year or more, so travel history
should extend back for at least 2 years.16
Patients visiting friends
and relatives abroad are at increased risk of infections such as
typhoid and malaria and are also more likely to suffer other serious
preventable travel-related illnesses compared to other travellers.
Infections that may present months to years after exposure, such
as tuberculosis (TB), need to be considered and are more likely in
areas with large migrant populations. Systematic approaches to
investigating fever in the returning traveller are published in more
detail elsewhere.17
It is important to consider less exotic causes for a fever in
returning travellers such as urinary tract infections, inﬂuenza,
pneumonia, meningitis and non-infectious conditions, especially
deep venous thrombosis and pulmonary embolism.
Immunosuppressed patients
Immunosuppression can be caused by numerous conditions and
related medications including HIV infection, haematological
malignancies, organ transplantation, corticosteroids,
immunomodulators and chemotherapy agents.
Pyrexia of unknown origin in patients with HIV infection can
be caused by HIV seroconversion, opportunistic infections at low
CD4 cell count levels (especially 200x106
cells/L), malignancies
at all CD4 count levels, and immune reconstitution inﬂammatory
syndrome (IRIS) after commencing antiretroviral therapy. Patients
living with HIV often have a high epidemiological risk for infections
such as TB, invasive non-typhoidal salmonellosis and malaria,
which can occur at any CD4 count but may present atypically in
these patients.
The risk of immunosuppression in transplant recipients
is determined by the underlying medical condition which
necessitated transplant, the duration and type of drug-induced
immunosuppression pre- and post-transplant, and their
comorbidities. Acute and chronic transplant rejection can also
cause fever, the management of which may necessitate further
immunosuppression.
Infections in immunosuppressed patients present atypically, with
altered incubation periods, attenuated or more severe clinical signs
and symptoms, and differing yields from diagnostic tests. It is not
uncommon for immunosuppressed patients to have more than
one life-threatening infection.
Table 1. Potential second-line investigations for pyrexia of unknown origin
Infection Inflammatory Neoplastic Miscellaneous
Echocardiogram, preferably TOE
Line cultures if the patient has an
intravascular device
Lumbar puncture
Lymph node biopsy
Malaria screen (RDT and three malaria
films on consecutive days)
PET-CT
Serology for viral hepatitis
Specialised serological or molecular tests
Spinal MRI
Sputum test for culture (consider an
induced sputum test if the patient is not
expectorating)
Stool samples for culture, PCR and OCP
Syphilis serology
Two to three peripheral blood cultures
Urine culture, plus three early morning
urines for TB culture in sterile pyuria
Wound swabs
ANA
ANCA
Anti-CCP
Antiphospholipid antibodies (lupus
anticoagulant and anticardiolipin)
Complement levels
Cryoglobulins
CT chest, abdomen and pelvis
Ferritin
Joint aspiration to detect crystals
LDH
MR or CT angiography
PET-CT
Rheumatoid factor
Serum ACE level
Serum electrophoresis
Serum urate
Temporal artery biopsy
Urine for Bence Jones protein
Colonoscopy
CT chest, abdomen and
pelvis
Echocardiogram, preferably
TOE
LDH
PET-CT
Serum calcium
Serum electrophoresis
Tissue, lymph node and/
or bone marrow biopsy for
histology
Urine for Bence Jones
protein
Pituitary screen
Synacthen test
Thyroid function tests
Note: This is not a comprehensive list of investigations to be carried out in every patient with PUO but instead a list of tests that should only be performed when
there is a reasonable pretest probability of the condition investigated being present.
ACE = angiotensin converting enzyme; ANA = anti-nuclear antibodies; ANCA = antineutrophil cytoplasmic antibody; Anti-CCP: anti-cyclic citrullinated peptide;
CT = computed tomography; LDH = lactate dehydrogenase; MR(I) = magnetic resonance (imaging); OCP = ova, cysts and parasites; PET-CT = positron emission
tomography–computed tomography; PCR = polymerase chain reaction; RDT = rapid diagnostic test; TB = tuberculosis; TOE = transoesophageal echocardiogram
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© Royal College of Physicians 2018. All rights reserved. 173
Immunosuppressed patients have an increased incidence of the
infections which may present as PUO, especially:
bacterial: pulmonary and extrapulmonary TB, other
mycobacterial infections, non-typhoidal salmonellosis,
melioidosis, and syphilis
viral: arboviruses, Coxsackie virus, cytomegalovirus (CMV),
Epstein–Barr virus (EBV), and parvovirus
fungal: aspergillosis, candidiasis, cryptococcosis, endemic
mycoses, and histoplasmosis
parasitic: visceral leishmaniasis.
Non-infective causes
The non-infectious causes of PUO can be broadly categorised
as inflammatory disorders, solid tumours, haematological
malignancies and miscellaneous (Table 2). As the relative
incidence of infective causes of PUO decreases, non-infective
causes are becoming more prevalent and can account for up to
one-third of PUO cases.5,7
Numerous inflammatory disorders can cause fever, such
as systemic rheumatic diseases (eg polymyositis), vasculitic
processes (eg temporal arteritis), autoinflammatory disorders
(eg Still’s disease) or granulomatous processes (eg sarcoidosis).
These are often multisystem conditions requiring multiple
confirmatory investigations and a multidisciplinary approach to
management.
Fever associated with malignancy may be due to the malignant
process itself or an associated paraneoplastic process, as well
as opportunistic infections. Criteria for diagnosis of malignancy
related PUO, including a selective response to naproxen, have been
summarised elsewhere.18
Drug fever is an under-recognised cause of PUO, particularly
in the elderly. It usually commences 7–10 days after starting a
medication but can occur at any time, including months later. If
fever persists for more than 96 hours after its discontinuation,
the suspected drug is unlikely to be the cause.4
Many classes
of medications can cause fever through different mechanisms
including antibiotics, anticholinergics, non-steroidals, allopurinol,
anticonvulsants, anti-hypertensives, antiarrhythmics, and
antidepressants.
There are many rare conditions in the miscellaneous causes of
PUO, some of the most common of which are listed in Table 2. It
is essential to consider factitious (self-induced) fever, especially
in patients with good medical knowledge and apparently good
health despite wide-swinging fever patterns.19
Management
The management of PUO should be supportive until the cause has
been determined. Therapeutic trials of antimicrobials or steroids
are not recommended because they can mask symptoms and
signs of the underlying disease process. The overall mortality of
PUO is low, particularly in those well enough to be investigated as
outpatients.20
Box 1 lists good practice points in the management
of patients with PUO.
There are three occasions when empirical treatment is
appropriate: antituberculous therapy for suspected miliary or
CNS TB, antimicrobials for patients with suspected infective
endocarditis and signs of sepsis, and steroid treatment for possible
temporal arteritis. Empirical treatment for TB should always be
discussed with a specialist, as the risk of drug resistance needs to
be evaluated for each patient, together with the need for early
adjunctive steroid therapy for CNS and pericardial TB (at differing
dosing regimens).
One of the most important aspects of management is to
address the patient’s expectations of diagnosis and treatment.
It is important to warn them about the need for a methodical
stepwise approach to investigation, which can be frustrating for
both the patient and physician and which may not lead to a firm
diagnosis. Undiagnosed patients may be reassured that their
prognosis is likely to be good, despite possible continuation of
symptoms. ■
Table 2. Non-infective causes of pyrexia of unknown
origin
Category Aetiology
Inflammatory disorders Behçet’s disease
Familial Mediterranean fever
Felty’s syndrome
Giant cell arteritis and temporal
arteritis
Gout and pseudogout
Granulomatosis with polyangiitis
(Wegener’s disease)
Polyarteritis nodosa
Polymyositis
Rheumatoid arthritis
Sarcoidosis
Still’s disease
Systemic lupus erythematosus
Takayasu’s arteritis
Solid tumours Atrial myxoma
Colonic cancer
Hepatic carcinoma
Metastatic disease
Pancreatic cancer
Renal cell carcinoma
Haematological malignancy Leukaemia
Lymphoma
Multiple myeloma
Myeloproliferative disorders
Miscellaneous Drug fever
Factitious fever
Hypoadrenalism
Hypothalamic dysfunction
Inflammatory bowel disease
Thyroiditis
3/24/18 6:17 PM

Acknowledgment
NJB is partially supported by the National Institute of Health Research
Health Protection Unit in Emerging and Zoonotic Infections, a
collaboration between the University of Liverpool, Liverpool School of
Tropical Medicine and Public Health England. He is afﬁliated with the
Liverpool School of Tropical Medicine. Views expressed in this article
are those of the contributors and do not necessarily represent the
ofﬁcial position of the National Health Service, the National Institute
for Health Research, the Department of Health, or Public Health
England.
References
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2 Durack DT, Street AC. Fever of unknown origin—reexamined and
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3 Tal S, Guller V, Guervich A. Fever of unknown origin in older
patients. Clin Geriatr Med 2007;23:649–83
4 Todd S, Beeching NJ. Fever of unknown origin. Chapter 11. In:
Gosney M, Harper A, Conroy S (eds), The Oxford desk reference:
geriatric medicine. Oxford: OUP, 2012:247–9.
5 Bleeker-Rovers CP, Vos FJ, de Kleijn EM et al. A prospective multi-
center study on fever of unknown origin: the yield of a structured
diagnostic protocol. Medicine (Baltimore) 2007;86:26–38.
6 Beresford RW, Gosbell IB. Pyrexia of unknown origin: causes, inves-
tigation and management. Intern Med J 2016;46:1011–6.
7 Yamanouchi M, Uehara Y, Yokokawa H et al. Analysis of 256 cases
of classic fever of unknown origin. Intern Med 2014;53:2471–5.
8 Chow A, Robinson JL. Fever of unknown origin in children: a system-
atic review. World J Pediatr 2011;7:5–10.
9 Newsholme W, Brown M. Pyrexia of unknown origin: a review of
studies from the developing world. Trop Doct 2005;35:68–71.
10 Lozano F, Torre-Cisneros J, Santos J et al. Impact of highly active
antiretroviral therapy on fever of unknown origin in HIV-infected
patients. Eur J Clin Microbiol Infect Dis 2002;21:137–9.
11 Armstrong W, Katz J, Kazanjian P. Human immunodeficiency virus-
associated fever of unknown origin: a study of 70 patients in the
United States and review. Clin Infect Dis 1999;28:341–5.
12 Bleeker-Rovers CP, Vos FJ, Mudde AH et al. A prospective multi-
centre study of the value of FDG-PET as part of a structured diag-
nostic protocol in patients with fever of unknown origin. Eur J Nucl
Med Mol Imaging 2007;34:694–703.
13 Gould FK, Denning DW, Elliott TS et al. Guidelines for the diag-
nosis and antibiotic treatment of endocarditis in adults: a report
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tion presenting in Europe (2008–12): an analysis of EuroTravNet
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pre-travel consultation. Lancet Infect Dis 2015;15:55–64.
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2013;158:456–68.
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lines 2016. J Infect 2016;72:635–49.
17 Fink D, Wani RS, Johnston V. Fever in the returning traveller. BMJ
2018 Jan 25;360:j5773.
18 Foggo V, Cavenagh J. Malignant causes of fever of unknown origin.
Clin Med 2015;15:292–4.
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fever and self-induced infection: a report of 32 cases and review of
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Box 1. Good practice points in the management of
pyrexia of unknown origin
There are many pitfalls in the investigation and
management of pyrexia of unknown origin (PUO). The
following good-practice points are recommended.
Ensure a thorough history, examination and baseline
investigation panel have been done.
Return to the patient’s history and examination at regular
intervals.
Consider non-infectious causes of a fever early on in the
patient’s journey.
All patients with PUO should have an HIV test.
Exclude malaria in patients with a history of relevant travel
within the last 2 years.
A positive tuberculin or interferon gamma release assay is
not diagnostic for TB: microbiological confirmation through
bacterial culture or molecular testing is required.
Do not give empirical antimicrobial or steroid trials.
Be cautious with the interpretation of some serological tests
as some perform poorly with high false positive and false
negative rates.
Do not perform serological testing if there is no history of
exposure to the pathogen you are testing for.
Perform PET-CT testing early in the patient’s diagnostic
journey when there are no localising clues in the history or
examination.
Ensure that the patient is aware of the strong possibility of no
diagnosis being made.
Address for correspondence: Dr Nick Beeching, Clinical
Sciences Group, Liverpool School of Tropical Medicine,
Pembroke Place, Liverpool L3 5QA, UK.
Email: nicholas.beeching@lstmed.ac.uk
3/24/18 6:17 PM

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