All fever and murmur is possibly aAll fever and murmur is possibly a

All the types of
infectious disease whose etiologies are readily identified like typhoid,
malaria, dengue fever are easy to treat as they have particular drugs
identified to be given, therefore are better managed. Main difficulty occurs in
managing those infections whose etiologies are not identified, therefore are
termed as Fever Of Unknown Origin29.

          Peterdorf and Beeson in 1961 defined
Fever Of Unknown Origin as (1) Temperature of >38.30C (>1010F)
on several occasions, (2) >3 weeks of fever, (3) diagnosis could not be made
even after 7 days of investigation. After 30 years Durack and Street have give
a revised classification that includes (1) Classic FUO, (2) Nosocomial FUO, (3)
Neutropenic FUO, and (4) FUO associated with HIV infection30.

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diagnostic point of view, FUO can be infectious, rheumatic/ inflammatory,
neoplastic, miscellaneous. If patient presents with fatigue then it is more
likely of infectious/inflammatory in origin, and if associated with weight loss
can be neoplastic in origin. If the patient presents with fever and murmur is
possibly a case of Subacute Bacterial Endocarditis


Classic FUO:

         Certain diagnostic techniques are
important in dealing with fever, like strict and supervised temperature
charting and urine output monitoring. Thick blood smears made to examine
plasmodium and thin for plasmodium species specific , and also to look for
babesia, trypanosome, leishmania, leptospira, rickettsia and borrelia.
Specialized staining of mononuclear cells and granulocytes can help to identify
acellular bacteria, protozoal amastigotes and the inclusion bodies of erlichiosis
and anaplasmosis29.

       In any FUO management, ESR should be checked,
because marked elevation of ESR and anemia are frequently encountered in giant
cell arteritis and polymyalgia rheumatica which are common causes of FUO in
patients >50 years where as ESR elevation along with leucocytosis and anemia
are seen in Still’s disease.


Nosocomial  FUO:

         Is due to patients susceptibility
along with potential complication of hospitalization. More than 50% of
nosocomial FUO are infected, and around 25% are non infected. Management should
be focused on sites where occult infections may be sequestrated, along with
antibiotic  therapy with Vancomycin for
MRSA and Piperacillin/Tazobactum, Ticarcillin/Clavulanate, Imipenem as a broad
spectrum gram negative coverage29.


Neutropenic  FUO:

These patients are
susceptible to bacterial and fungal infections like septic thrombophlebitis and
perianal infections. Around 50-60% patients are infected whereas 20% are


HIV Associated FUO:

In this setting, the etiology can be Mycobacterium avium, Tuberculosis,
Toxoplasmosis, CMV, Pneumocystis infection, Salmonellosis, Cryptococcosis,
Histoplasmosis, Strongyloidiasis, non-Hodgkins lymphoma and drug fever. Around
>80% patients has infectious etiology.

In addition to classic causes, current causes
of FUO include underappreciated

or newly described entities associated with
prolonged and perplexing

 fevers 1,2,3. Newly emerging causes of FUOs
consist of either known

entities that uncommonly present
as FUOs or newly described FUO disorders

such as picornavirus infection in
children 4. Alternatively, disorders

occurring in other than the usual
peak age group for the disorder (eg, EBV

infections, mononucleosis in the
elderly) may present as FUOs. Virtually

any emerging infectious disease,
when accompanied by prolonged fevers,

can present as scrub/murine typhus
in children 5. Newly described infectious

diseases associated with prolonged
courses of fever may present as an

FUOdchikungunya fever, for example
6,7. Because of increased

international travel, entities
commonly recognized and diagnosed in the endemic

areas are not recognized by
physicians unfamiliar with their clinical

presentation in nonendemic areas
(eg, meliodosis) 8,9. Clinicians should

be familiar with the emerging and
newly described entities that may present

as FUOs (see Table 3).

Prolonged fevers in select

Among infectious causes of FUOs in children, viral
infections such

as EBV predominate. As in adults, CSD is an important
cause of FUO in

children because many children are in close proximity
to cats. Children

accompanying parents as returning travelers may
present with FUOs due

to malaria, typhoid fever, or TB. Common among the
noninfectious causes

of FUOs in children are neoplastic disorders. Age-related

disorders include Wilms’ tumor, neuroblastoma, and
lymphoma. Juvenile

rheumatoid arthritis is the most frequently
encountered rheumatic/inflammatory

cause of FUO in the pediatric age group. Lastly,

bowel diseases (particularly Crohn’s disease), which
may be difficult to diagnose

at an early stage, are not uncommon as the cause of
FUOs in children



Organ transplant

With organ transplants, the organ transplant pathogens
should be considered

in patients with fevers of prolonged duration. In
transplant recipients,

the severity of the associated host defense defect
determines the

sequence of opportunistic pathogens presenting
clinically with prolonged

fevers. Among the noninfectious causes of prolonged
fevers in transplant recipients,

neoplastic disorders secondary to immunosuppression,

emboli, and drug fevers (secondary to
immunosuppressive medications) are

prime considerations 12.



Returning travelers

Prolonged fevers in returning travelers reflect the
epidemiology of the recently

visited area 13,14. Among infectious diseases with the appropriate

epidemiologic history, typhoid fever, malaria, and
visceral leishmaniasis are

the most common causes of prolonged unexplained fevers
in returning travelers

8,15,16–18. Among noninfectious disorders are deep venous thrombosis

and/or pulmonary emboli caused by venous stasis from

long aircraft flights 19,20.




Because FUOs are caused by such a
wide variety of disorders, the diagnostic

approach to the FUO patient is
often extensive but is not focused or

directed by the most likely
diagnostic possibilities. A routine history and

physical examination are
inadequate in evaluating the FUO patient

21. The diagnostic approach to FUO
should consist of three phases.

The initial FUO evaluation should
include a relevant FUO history as

well as a physical examination
that looks particularly for diagnostic findings

relevant to FUO. Initial
nonspecific laboratory tests also provide clues

pointing toward a particular
diagnosis while simultaneously eliminating

other diagnoses from further
consideration. The initial evaluation should

narrow diagnostic possibilities
and determine the direction of the subsequent

diagnostic workup. The second
phase of FUO evaluation consists

of a focused history, physical
examination, and additional relevant nonspecific

laboratory tests in patients who
remain undiagnosed after the initial

evaluation 21,22.

As endocarditis
is a common cause of FUOs, many patients are subjected

TTE/TEE to rule out endocarditis. The diagnosis of SBE as a cause

FUO should be entertained only in patients that have a heart murmur. Blood
cultures for SBE also have utility for other infections and are reasonable to
obtain on most patients. The likelihood of SBE is greatest in patients with a
heart murmur and in those with a high- grade/continuous bacteremia (due to a
known endocarditis pathogen) with or without peripheral manifestations of SBE.
All too often, TTE/TEE is ordered in patients who have a heart murmur with
negative blood cultures to rule out the possibility of culture-negative
endocarditis. Culture-negative endocarditis is rare to begin with and is an
uncommon cause of SBE. The diagnosis of culture-negative endocarditis should be
entertained in patients who have a heart murmur, negative blood cultures, and
peripheral manifestations of SBE. TTE/TEE also may be helpful in elucidating
the etiology of marantic endocarditis. Marantic endocarditis presents with a
heart murmur and negative blood cultures with or without peripheral
manifestations of SBE. Marantic endocarditis may be due to the vegetations
associated with SBE (Liebman-Sachs vegetations) or sterile valvular vegetations
secondary to a distant neoplasm.

Imaging studies

Imaging tests have been very helpful in
localizing the pathology, which in

itself may suggest the diagnosis. Since
infectious and noninfectious disorders

have a characteristic pattern of organ
involvement, positive imaging tests

with CT/MRI scanning and/or gallium or indium
scanning may localize

the process to a single organ or may indicate
multi-organ involvement and

be of value in further directing the diagnostic
workup. PET scans may reveal

abnormalities missed by other imaging techniques, such as aortitis.



Focused diagnostic approach

Clinical  syndromic  approach

 FUO laboratory tests add further
refinement to the initial laboratory

in limiting diagnostic possibilities. With FUO syndromic diagnosis,

pattern of organ involvement should be apparent from aspects

the history, physical examination, and laboratory tests. The pattern of

involvement based on the focused FUO evaluation determines diagnostic

for prompt and definitive diagnostic testing. The focused

workup should be detailed but directed as the most likely diagnosis,

on each disorder’s pattern of organ involvement as determined by the focused
FUO history, physical examination, and selected nonspecific


Recurrent fevers of unknown origin:


Fevers of unknown origin that remained

A focused and phased FUO workup should
diagnose all but the most

rare and obscure causes of an FUO. FUOs that
remain undiagnosed over

long periods of time are unlikely to be due to
an infectious or neoplastic

etiology. FUOs that persist intermittently for
months or years are difficult

to diagnose but at least are benign in nature.
Undiagnosed FUOs may berecurrent or persistent. After a focused FUO workup, an
undiagnosed FUO of prolonged duration is usually due to a miscellaneous cause,
including periodic fever syndromes.The underlying cause of an FUO determines
its potential for recurrence.Infectious diseases causing FUOs are self-limiting
from either therapeutic/surgical intervention or natural resolution. Some
infectious diseases responsible for FUOs may present as relapsing fevers, others
may present as recurrent FUOs. Relapsing fevers remit, and patients have little
or no fever between episodes. The periodicity and fever pattern of relapsing
fevers may be clues to their infectious etiology. Certain infectious diseasesd for
example, relapsing fever (Borrelia recurrentis). In general, intracellular pathogens
(eg, viruses) that may cause FUOs have the potential to be recurrent,

depending on the
efficacy of host defense-suppressive mechanisms.


Empiric therapy:


The disorders responsible for FUOs
are numerous and their manifestations

protean; therefore, emphasis is
properly on the diagnostic approach

to determining the cause of the
FUO. With many FUOs, patients and physicians

frequently attempt to lower the
patient’s fever. Fever is a cardinal

sign that serves as the impetus to
determine a diagnosis in both acute

fevers and FUOs. Suppression of
fever serves no physiologic or clinical purpose. Antipyretics should be avoided
because they obscure the febrile

response and alter fever patterns
that may be important diagnostically.

Altering the febrile manifestation
of the FUO eliminates important diagnostic

information, often resulting in a
more difficult or delayed diagnosis.

Not only should fever not be
suppressed, but patients should be encouraged

to plot their fevers along with
simultaneous pulse rates, which often

demonstrate characteristic fever
patterns and may be helpful diagnostically 23,15.

In some situations, empiric
therapy in patients with FUOs is reasonable

and necessary. The empiric treatment
of true culture-negative endocarditis is

reasonable if the patient meets
the previously discussed criteria for culturenegative endocarditis. Empiric
therapy for SBE should not be started in patients who have fever, heart murmur,
and negative blood cultures without

peripheral manifestations of
endocarditis. Empiric therapy for temporal arteritis is vital and may prevent
permanent blindness. Vasculitic doses of

corticosteroids should be used in
the treatment of such patients. If miliary

TB is suspected and the patient is
deteriorating clinically, empiric anti-TB

therapy is reasonable and may be
life-saving. Miliary TB is a difficult diagnosis

to confirm and requires biopsy of
liver or bone marrow. Biopsy results

take time, and patients
deteriorating with potential miliary TB should be

given empiric trial of
anti-tuberculous therapy at least until biopsy resultsare available to rule out or confirm the
diagnosis of miliary TB. Most other

infectious diseases presenting as FUOs (eg, Q
fever, SBE) are usually not

rapidly progressive, and appropriate therapy
can be initiated after the diagnosis

is confirmed serologically or by PCR.

Should Remember:

Prolonged unexplained fevers have perplexed
clinicians from antiquity

to the present. FUOs remain a challenging
exercise in differential diagnosis.

The diagnostic workup should be directed by
features of the clinical

presentations, which almost always suggest an
infectious, rheumatic/inflammatory, neoplastic, or miscellaneous disorder.
Using the approach outlined in this article, clinicians can diagnose all but
the most obscure

causes of FUOs. Most undiagnosed FUOs are due
to a failure to consider

a diagnosis or a comprehensive but misguided

faced with FUOs should be familiar with the clinical and

laboratory findings associated with each
disorder included in the differential

diagnosis. Clinicians should also be aware of
time relationships in the appearance

and disappearance of clinical and laboratory
findings. Often, early or

late clinical or laboratory findings are
overlooked because physicians often recognize only the most common clinical

boratory tests (Table 5) 23,15,24,25,21,22,26-28.