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Mean oral temperature 36.80.4C (98.20.7F)

low levels at 6 a.m. & higher levels at 4-6 p.m.

Maximal normal oral temperature

37.2C (98.9F) at 6 a.m. &

37.7C (99.9F) at 4 p.m.

An a.m. temperature of >37.2C (>98.9F) or a p.m.

temperature of >37.7C (>99.9F) is Fever

Most episodes of fever in humans are short-lived and do

not require diagnostic investigation or specific therapy.

Some are manifestations of more serious illnesses, most

of which can be readily diagnosed and effectively

However, a small but important subgroup of fevers are

both persistent and difficult to diagnose.

The first formal definition of FUO to gain broad

acceptance was proposed by Petersdorf and Beeson
nearly five decades ago:

fever higher than 38.3C (101F) on several

occasions, persisting without diagnosis for at least 3
weeks in spite of at least 1 weeks investigation in
Later investigators have modified and extended this
classical definition to reflect evolutionary changes in
clinical practice.

Changes include the conduct of most diagnostic tests in

the outpatient setting rather than in the hospital, the
increasing number of immunocompromised patients
(especially those with neutropenia), the proliferation of
increasingly complex surgical and intensive care
treatment protocols, and the advent of human
immunodeficiency virus (HIV) infection leading to the
acquired immunodeficiency syndrome (AIDS).
Accordingly, FUO is now defined as:
Fever >38.3C (101F) on at least two occasions
Illness duration of 3 weeks
No known immunocompromised state
Diagnosis that remains uncertain after thorough history-
taking, physical examination, and following obligatory
TC,DC,ESR,platelet,Hb, CRP
electrolytes, creatinine,
total protein, alkaline phosphatase, ALT, AST,LDH
creatine kinase, ferritin, ANA, and rheumatoid factor;
protein electrophoresis; urinalysis;
blood cultures; urine culture;
chest x-ray; abdominal USG; and
Tuberculin skin test (TST)
In response to this evolving environment, cases of
FUO are currently codified into four distinct
subclasses of the disorder:
1. Classical FUO,
2. Health careassociated FUO,
3. Immune-deficient FUO, and
4. HIV-related FUO .
Classical Fever of Unknown Origin

Classical FUO refers to the type of FUO defined by

Petersdorf and Beeson in 1961.

The only alteration to their definition required to

conform to modern medical practice is to incorporate
investigation in the outpatient setting, which today has
become the preferred venue for evaluation and
Classical FUO almost all fall within one of five categories:
1. infections,
2. neoplasms,
3. Connective tissue diseases,
4. miscellaneous other disorders, and
5. Undiagnosed illnesses.

Relative frequencies of individual diagnoses within these

five categories vary depending on the geographic region,
ages of the patients, type of medical practice, and other
The five main etiologic categories of
fever of unknown origin
Health CareAssociated Fever of
Unknown Origin

Condition in which patients first manifest fever during

active medical treatment for some other illness.

Frequently attributable to risk factors encountered in the

health care environment, including surgical procedures,
urinary and respiratory tract instrumentation,
intravascular devices, drug therapy, and immobilization.

Examples include drug fever, septic thrombophlebitis,

recurrent pulmonary emboli, and Clostridium difficile

Most often developing relatively early after admission to the

unit, in which case it tends to be of noninfective origin and
carries a favorable prognosis.

Prolonged fever, however, is associated with a worse


Health care associated sinusitis, often a complication of

mechanical ventilation arising from supine positioning and
the use of endotracheal, gastric, and feeding tubes is common
and should always be considered when evaluating FUO in
intensive care unit patients.

Fever may be the sole or most prominent feature of an adverse

drug reaction

Although occasionally present, neither rash nor eosinophilia

is common.

Several authors have suggested that there might be a

characteristic drug-induced fever pattern.

However, no such pattern has yet emerged, perhaps because

antipyretics and external cooling measures are so frequently
used to treat drug-induced fever.
Considerable variability has been reported in the length of
time between the onset of treatment with a drug and the onset
of drug-related fever.

Must not assume that because a patient has been taking a

certain medication for a long time, it cannot be the cause of

More common causes of drug induced fever are allopurinol,

carbamazepine, lamotrigine, phenytoin, sulfasalazine,
furosemide, antimicrobial drugs (especially sulfonamides,
minocycline, vancomycin, -lactam antibiotics, and
isoniazid), some cardiovascular drugs (e.g., quinidine), and
some antiretroviral drugs (e.g., nevirapine).

In patients with a recent stroke, fever is usually the result of

an infection, most commonly a urinary tract infection
related to urinary catheterization.

In some cases, a focus of infection cannot be identified, and

when the fever does not respond to empirical antibiotic
treatment it is presumed to be due to the stroke itself.

In a study Georgilis and associates observed that

noninfective fevers were most often associated with
intracranial mass effects and tended to occur earlier after
the onset of stroke than fevers due to infection.
Immune-Deficient Fever of Unknown Origin

Immunosuppressed patients have perhaps the highest

incidence of FUO of any group of patients.

Because of impaired immune responses, signs of

inflammation other than fever are notoriously absent
or diminished in such patients,

Leading to atypical clinical manifestations and absence

of radiologic abnormalities in what otherwise would be
readily diagnosed infections.

Neutropenia is a dangerous condition that can be

considered a special subclass of immunodeficiency.

The number of patients with episodes of neutropenia

resulting from cytotoxic therapy or from various
malignancies affecting the bone marrow is rising.

Many such episodes are short-lived, because they either

respond quickly to treatment or are manifestations of
rapidly fatal infections.

Because bacteremia and sepsis are frequent causes,

empirical broad-spectrum antibiotics should be
administered promptly, without waiting for the results of
cultures, when fever develops in neutropenic patients.
Possible Causes of Fever in Neutropenic Patients
Human Immunodeficiency VirusRelated Fever of
Unknown Origin

Episodes of fever are commonplace in patients infected with

HIVa special subgroup of immunodeficient patients, now so
numerous that a separate category of FUO is justified.

The primary phase of HIV infection is characterized by a

mononucleosis-like illness in which fever is a prominent feature.

All too often, primary HIV infection eludes diagnosis because the
illness is nonspecific and precedes seroconversion.

Once symptoms of the primary phase of the HIV infection

resolve, HIV-infected patients enter a long period of subclinical
infection during which they are usually afebrile.
In later phases of untreated HIV infection, episodes of fever
become common, often signifying a superimposed illness.

Many of these are potentially devastating opportunistic

infections, which tend to present in atypical fashion owing to
the tendency of the disordered immune response or prior
therapy, or both to distort their clinical manifestations.

Once highly active antiretroviral therapy (HAART) has been

started and HIV viral load effectively suppressed, the
frequency of FUO in HIV-infected patients falls markedly.
Diseases Established as the Etiology of Fever in
Cases of HIV-Associated Fever of Unknown Origin

Differential diagnosis is extensive

Its important to remember that FUO is far more often

caused by an atypical presentation of a rather
common disease than by a very rare disease.
All Reported Causes of FUO
Bacterial, nonspecific
Abdominal abscess, adnexitis, apical granuloma, appendicitis,
cholangitis, cholecystitis, diverticulitis, endocarditis, endometritis,
epidural abscess, infected vascular catheter, infected joint prosthesis,
infected vascular prosthesis, infectious arthritis, infective myonecrosis,
intracranial abscess, liver abscess, lung abscess, malakoplakia,
mastoiditis, mediastinitis, mycotic aneurysm, osteomyelitis, pelvic
inflammatory disease, prostatitis, pyelonephritis, pylephlebitis, renal
abscess,septic phlebitis, sinusitis, spondylodiscitis,
xanthogranulomatous urinary tract infection
Bacterial, specific
Actinomycosis, atypical mycobacterial infection, bartonellosis,
brucellosis, Campylobacter infection, Chlamydia pneumoniae
infection, chronic meningococcemia, ehrlichiosis, gonococcemia,
legionellosis, leptospirosis, listeriosis, louseborne relapsing fever
(Borrelia recurrentis), Lyme disease, melioidosis (Pseudomonas
pseudomallei), Mycoplasma infection, nocardiosis, psittacosis, Q
fever (Coxiella burnetii), rickettsiosis, Spirillum minor infection,
Streptobacillus moniliformis infection, syphilis, tick-borne
relapsing fever (Borrelia duttonii), tuberculosis, tularemia, typhoid
fever and other salmonelloses,Whipples disease (Tropheryma
whipplei), yersiniosis
Aspergillosis, blastomycosis, candidiasis, coccidioidomycosis,
cryptococcosis, histoplasmosis, Malassezia furfur
infection,paracoccidioidomycosis, Pneumocystis jirovecii
pneumonia, sporotrichosis, zygomycosis
Amebiasis, babesiosis, echinococcosis, fascioliasis, malaria,
schistosomiasis, strongyloidiasis, toxocariasis, toxoplasmosis,
trichinellosis, trypanosomiasis, visceral leishmaniasis
Colorado tick fever, coxsackievirus infection, cytomegalovirus
infection, dengue, Epstein-Barr virus infection, hantavirus
infection, hepatitis (A, B, C, D, E), herpes simplex, HIV infection,
human herpesvirus 6 infection, parvovirus infection, West Nile
virus infection
Noninfectious Inflammatory Diseases
Systemic rheumatic and autoimmune diseases
Ankylosing spondylitis, antiphospholipid syndrome, autoimmune
hemolytic anemia, autoimmune hepatitis, Behcets disease,
cryoglobulinemia, dermatomyositis, Felty syndrome, gout, mixed
connective-tissue disease, polymyositis,pseudogout, reactive arthritis,
relapsing polychondritis, rheumatic fever, rheumatoid arthritis,
Sjogrens syndrome,systemic lupus erythematosus, Vogt-Koyanagi-
Harada syndrome
Allergic vasculitis, Churg-Strauss syndrome, giant cell
vasculitis/polymyalgia rheumatica, granulomatosis with
polyangiitis,hypersensitivity vasculitis, Kawasakis disease,
polyarteritis nodosa, Takayasu arteritis, urticarial vasculitis
Granulomatous diseases
Idiopathic granulomatous hepatitis, sarcoidosis

Autoinflammatory syndromes
Adult-onset Stills disease, Blau syndrome, CAPS(cryopyrin-associated
periodic syndromes), Crohns disease, DIRA (deficiency of the
interleukin 1 receptor antagonist), familial Mediterranean fever,
hemophagocytic syndrome, hyper-IgD syndrome (HIDS, also known as
mevalonate kinase deficiency), juvenile idiopathic arthritis, PAPA
syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and
acne), PFAPA syndrome (periodic fever, aphthous stomatitis,
pharyngitis, adenitis),recurrent idiopathic pericarditis, SAPHO
(synovitis, acne, pustulosis, hyperostosis, osteomyelitis), Schnitzlers
syndrome,TRAPS (tumor necrosis factor receptorassociated periodic
Hematologic malignancies
Amyloidosis, angioimmunoblastic lymphoma, Castlemans disease,
Hodgkins disease, hypereosinophilic syndrome,
leukemia,lymphomatoid granulomatosis, malignant histiocytosis,
multiple myeloma, myelodysplastic syndrome, myelofibrosis, non-
Hodgkins lymphoma, plasmacytoma, systemic mastocytosis, vaso-
occlusive crisis in sickle cell disease
Solid tumors
Most solid tumors and metastases can cause fever.

most commonly causing are breast, colon, hepatocellular,lung,

pancreatic and renal cell carcinomas.

Benign tumors
Angiomyolipoma, cavernous hemangioma of the liver,
craniopharyngioma, necrosis of dermoid tumor in Gardners
ADEM (acute disseminated encephalomyelitis), adrenal insufficiency,
aneurysms, anomalous thoracic duct, aortic dissection, aortic-enteral fistula,
aseptic meningitis (Mollarets syndrome), atrial myxoma, brewers yeast
ingestion, Caroli disease, cholesterol emboli, cirrhosis, complex partial status
epilepticus, cyclic neutropenia, drug fever, Erdheim-Chester disease,
extrinsic allergic alveolitis, Fabrys disease, factitious disease, fire-eaters
lung, fraudulent fever, Gauchers disease, Hamman-Rich syndrome (acute
interstitial pneumonia), Hashimotos encephalopathy, hematoma,
hypersensitivity pneumonitis, hypertriglyceridemia, hypothalamic
hypopituitarism, idiopathic normal-pressure hydrocephalus, inflammatory
pseudotumor, Kikuchis disease, linear IgA dermatosis, mesenteric
fibromatosis, metal fume fever, milk protein allergy, myotonic dystrophy,
nonbacterial osteitis, organic dust toxic syndrome, panniculitis, POEMS
(polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin
changes), polymer fume fever, postcardiac injury syndrome, primary biliary
cirrhosis, primary hyperparathyroidism, pulmonary embolism, pyoderma
gangrenosum, retroperitoneal fibrosis, Rosai-Dorfman disease, sclerosing
mesenteritis, silicone embolization, subacute thyroiditis (de Quervains),
Sweet syndrome (acute febrile neutrophilic dermatosis), thrombosis,
tubulointerstitial nephritis and uveitis syndrome (TINU), ulcerative colitis.
Thermoregulatory Disorders
Brain tumor, cerebrovascular accident, encephalitis, hypothalamic

Anhidrotic ectodermal dysplasia, exercise-induced hyperthermia,
hyperthyroidism, pheochromocytoma
Clinical Evaluation of Fever of Unknown Origin

The evaluation of a patient with FUO typically includes

A. comprehensive history,
B. repeated physical examinations,
C. verification that the patient actually has fever,
D. consideration of the fever pattern,
E. a host of laboratory investigations,
F. key imaging studies, and
G. invasive diagnostic procedures.

Comprehensive history is a cornerstone of the evaluation of

any complex illness such as FUO.

History can be especially important in determining the choice

of the initial laboratory investigations.

Particular attention should be given to

fever pattern (continuous or recurrent) and duration,
Country of origin, recent and remote travel,
associated with travel or hobbies, and animal contacts.
exposure to pets and other animals,
the work environment, and
Recent contact with people exhibiting similar symptoms.
Family history for possible hereditary causes of fever
for example, familial Mediterranean fever.

Past medical history for prior episodes of FUO and for

any previously diagnosed conditions, such as lymphoma,
rheumatic fever, or intra-abdominal disorders,
complications or reactivation of which might account for
the source of fever.

Complete list of the patients medications must be

obtained, so that each may be evaluated as a potential
source of drug-induced fever.

A complete physical examination should be performed,

with special attention to the
lymph nodes,
temporal arteries,
liver, spleen, sites of previous surgery,
entire skin surface, and mucous membranes.

Key physical abnormalities in patients with FUO are so

subtle as to require repeated examinations to be
Examples of Subtle Physical Findings Having Special
Significance in Patients with Fever of Unknown Origin

In a series of 347 patients admitted to the National Institutes

of Health for investigation of prolonged fever, 35% were
ultimately determined either not to have significant fever at
all, or to have fever of factitious origin.

The degree of fever, nature of the fever curve, apparent

toxicity, and response to antipyretics has not been found to
provide enough specificity to guide the diagnosis of FUO.

However, the course of the fever curve may be helpful in

determining whether the disease is escalating or waning.
Commonly believed that there is a relationship
between high fever and the likelihood of bacteremia
in adults;

Numerous examples of bacteremia in which there is

little or no fever and nonbacteremic conditions, such
as drug-induced fever, thrombophlebitis, and
recurrent pulmonary emboli, in which extremely
high fevers sometimes are encountered.

The literature is replete with algorithms indicating which

laboratory tests should be performed to evaluate FUO.

Although useful as general guides, blind application of

such algorithms may result in performance of an
excessive number of tests.

Should be selectively applied using clues gleaned from

the history and physical examination to direct the choice
and sequence of tests.
In addition to the evaluation to establish the presence of an FUO , following
minimum diagnostic evaluation is recommended :

Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)

Serum lactate dehydrogenase
Tuberculin skin test or interferon-gamma release assay
HIV antibody assay and HIV viral load for patients at high risk
Three routine blood cultures drawn from different sites over a period of at
least several hours without administering antibiotics, if not already performed
Rheumatoid factor
Creatine phosphokinase
Heterophile antibody test in children and young adults
Antinuclear antibodies
Serum protein electrophoresis
Computed tomography (CT) scan of abdomen
CT scan of chest

Imaging studies have been used primarily to localize


Structures appearing abnormal on CT are almost

always confirmed as such on laparotomy or biopsy.

Magnetic resonance imaging (MRI) is especially useful

for evaluation of the central nervous system and in the
abdomen, the spleen and lymph nodes.

Noninvasive method allowing delineation of foci in all parts of

the body on the basis of functional changes in tissues.

Plays an important role in the diagnosis of patients with FUO

in clinical practice.

Conventional methods used are

67Ga-citrate scintigraphy &
99mTc-labeled leukocyte scintigraphy.

CT and MRI routinely provide information only on part of

body, while scintigraphy readily allows whole-body imaging.
Fluorodeoxyglucose Positron Emission

o Has become an established imaging procedure in FUO

o FDG accumulates in tissues with a high rate of glycolysis,

which occurs not only in malignant cells but also in
activated leukocytes, and thus permits the imaging of acute
and chronic inflammatory processes.

o Compared with conventional scintigraphy, FDG-PET offers

the advantages of higher resolution, greater sensitivity in
chronic low-grade infections, and a high degree of accuracy in
the central skeleton.

Histopathologic examination of tissues obtained by

excisional biopsy, needle biopsy, or laparotomy can provide
a definitive diagnosis in some cases.

The majority of patients with FUO undergo at least one

such procedure, even though the diagnostic yield is only
fair, with an average of two or three, sometimes even more,
separate biopsies required to establish a final diagnosis.

Exploratory laparotomy, once a prominent procedure in the

workup of FUO, is rarely performed today, unless localized
abdominal physical signs or imaging findings, or both, are

Therapeutic trials of antimicrobials or glucocorticoids,

while tempting in the effort to "do something," rarely
establish a diagnosis.

Diagnostic yield of blood cultures and cultures of biopsy

material will be reduced following the initiation of

Antimicrobial agents could be expected to suppress, but

not cure, an infectious process such as an occult abscess
since adjunctive drainage would usually be required.
Antibiotics can have effects on other infections than the ones
to which therapy is directed.

Example- Rifampin used in a therapeutic trial for

tuberculosis may suppress staphylococcal osteomyelitis or
diminish the ability to detect difficult-to-isolate organisms
causing endocarditis.

Therapeutic trial of glucocorticoids for an inflammatory

process should not replace relevant biopsies for steroid-
responsive disease such as sarcoidosis, other granulomatous
diseases, or vasculitis.

A fundamental principle - therapy should be withheld, whenever

possible, until the cause of the fever has been determined, so that
treatment can be tailored to a specific diagnosis.

Nonspecific treatment rarely cures FUO, and has the potential to

delay reaching a specific diagnosis.

This ideal is, however, frequently ignored in clinical practice

because the road to diagnosis of FUO is, by definition, often long
and frustrating.

As a result, clinicians may feel compelled to treat symptoms

empirically, even though the agents used may obscure the very signs
and symptoms upon which the diagnosis depends.

Antibiotic or antituberculous therapy diminish ability to culture

fastidious bacteria or mycobacteria.

Hemodynamic instability or neutropenia is a good indication for

empirical antibiotic therapy.

If the TST is positive or if granulomatous disease is present with

anergy and sarcoidosis seems unlikely, a therapeutic trial for
tuberculosis should be started.

If fever does not respond after 6 weeks of empirical

antituberculous treatment, another diagnosis should be

Interleukin (IL) 1 is key cytokine in local and systemic inflammation and febrile

Pathologic role of IL-1-mediated inflammation in a growing list of diseases.

Anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist

(IL-1Ra), blocks activity of both IL-1 and IL-1.
So extremely effective in treatment of many autoinflammatory syndromes,
such as familial Mediterranean fever, cryopyrin-associated periodic
syndrome,tumor necrosis factor receptorassociated periodic
syndrome,hyper-IgD syndrome, and Schnitzlers syndrome.
Therapeutic trial can be considered in patients whose FUO has not been
diagnosed after later-stage diagnostic tests.
Can provide improved control without the metabolic, immunologic, and
gastrointestinal side effects of glucocorticoid administration.

Determined by the cause of the fever and by the nature of any

underlying disease or diseases.

Elderly patients and those with malignant neoplasms have the

poorest prognosis.

The time required to establish the diagnosis is less important.

Diagnostic delay affects the prognosis adversely in intra-

abdominal infections, miliary tuberculosis, disseminated fungal
infections, and recurrent pulmonary emboli.

Patients in whom FUO remains undiagnosed after extensive

evaluation generally have a favorable outcome, characteristically
with resolution of their fever in 4 or more weeks without

Harrison's Principles of Internal Medicine, 19E

Mandell, Douglas and Bennett`s Principles and
Practice of Infectious Disease