Fever of unknown origin

Fever of Unknown Origin
Dr. Suprakash Das
M.D (Microbiology)

Definition
 Fever of unknown origin (FUO) was defined by Petersdorf
and Beeson in 1961 as
 (1) temperatures of >38.3°C (>101°F) on several occasions;
 (2) a duration of fever of >3 weeks; and
 (3) failure to reach a diagnosis despite 1 week of inpatient
investigation.
 Durack and Street have proposed a new system for
classification of FUO:
(1) Classic FUO;
(2) Nosocomial FUO;
(3) Neutropenic FUO; and
(4) FUO associated with HIV infection.

Definition
 Classic FUO
 Corresponds closely to the earlier definition of FUO, differing
only with regard to the prior requirement for 1 week’s study in the
hospital.
 The newer definition is broader, stipulating three outpatient
visits or 3 days in the hospital without elucidation of a cause or
1 week of “intelligent and invasive” ambulatory investigation.
 Nosocomial FUO
 A temperature of ≥38.3°C (≥101°F) develops on several occasions
in a hospitalized patient who is receiving acute care and in whom
infection was not manifest or incubating on admission.
 Three days of investigation, including at least 2 days’
incubation of cultures, is the minimum requirement for this
diagnosis.

Definition
 Neutropenic FUO
 Defined as a temperature of ≥38.3°C (≥101°F) on several
occasions in a patient whose neutrophil count is <500/μL or is
expected to fall to that level in 1–2 days.
 The diagnosis of neutropenic FUO is invoked if a specific cause is
not identified after 3 days of investigation, including at least 2
days’ incubation of cultures.
 HIV-associated FUO
 Defined by a temperature of ≥38.3°C (≥101°F) on several
occasions over a period of >4 weeks for outpatients or >3 days
for hospitalized patients with HIV infection.
 This diagnosis is invoked if appropriate investigation over 3 days,
including 2 days’ incubation of cultures, reveals no source.

Causes of Classic FUO in adults
Infectious
Neoplasms
Non-inflammatory diseases
Miscellaneous causes
Undiagnosed causes

Infections associated with FUO
Bacterial Infections
Localized pyogenic infections Intravascular infections
Appendicitis Perinephric/intrarenal
abscess
Bacterial aortitis
Cat-scratch disease Prostatic abscess Bacterial endocarditis
Cholangitis Subphrenic abscess Vascular catheter infection
Cholecystitis Tuboovarian abscess Bartonellosis
Diverticulitis Suppurative
thrombophlebitis
Brucellosis
Liver abscess Gonococcemia
Mesenteric
lymphadenitis
Legionnaires’ disease
Osteomyelitis Leptospirosis
Pancreatic abscess Listeriosis
Pelvic
inflammatory
disease
Lyme disease

BACTERIAL INFECTIONS
Intravascular infections Q fever
Melioidosis Rickettsialpox
Meningococcemia Rocky Mountain spotted fever
Rat-bite fever Mycoplasmal infections
Relapsing fever Chlamydial infections
Salmonellosis Lymphogranuloma venereum
Syphilis Psittacosis
Tularemia Mycobacterial infections
Yersinia infection M. avium/M. intracellulare
Rickettsial infections Tuberculosis
Anaplasmosis
Ehrlichiosis
Murine typhus

Fungal Infections Parasitic infections Viral infections
Aspergillosis Amebiasis Colorado tick fever
Blastomycosis Babesiosis Coxsackievirus group B
infection
Candidiasis Chagas’ disease Cytomegalovirus infection
Coccidioidomycosis Leishmaniasis Epstein-Barr virus infection
Cryptococcosis Malaria Dengue
Histoplasmosis Strongyloidiasis Hepatitis A, B, C, D, and E
Mucormycosis Toxocariasis Human herpesvirus 6
Paracoccidioidomycosis Toxoplasmosis Parvovirus B19
Pneumocystis infection HIV
Sporotrichosis

Diagnostic Approach to Classic Fever of
Unknown Origin
 First, verify the prolonged fever meets the fever-of unknown- origin
definition.
 The fever-of-unknown origin work-up should be symptom (history)
and sign (physical examination) driven.
 Second, based on history and physical clues, try to determine the
appropriate category for the fever.
 Each fever of unknown origin category has clinical hallmarks, for
example, usually, malignant/neoplastic disorders are associated with
early anorexia and significant weight loss.
 With infectious fevers of unknown origin, chills are common, but
weight loss less pronounced and anorexia late. Excluding vasculitis,
synovitis is the rheumatic/ inflammatory hallmark.
 Third, within the fever-of-unknown-origin category, try to determine
the pattern of organ involvement.
 Each disorder has a characteristic pattern of organ involvement that
suggests/limits diagnostic possibilities.

Diagnostic Approach to Classic Fever of
Unknown Origin
 For example, pattern of organ involvement of systemic lupus
erythematosus involves multiple organs but importantly, spares
the liver.
 Similarly, while splenomegaly is a cardinal subacute bacterial
endocarditis finding,
 hepatomegaly essentially rules out subacute bacterial
endocarditis on the basis of pattern of organ involvement alone.
 The most diagnostically difficult fevers of unknown origin have no
localizing signs.
 In the fever of unknown origin focused physical examination,
special attention should be given to the eyes, skin, nodes, liver, and
spleen.
 Testing should be selective and based on diagnostic probabilities,
not possibilities, for example, routine blood cultures.

History-
 Malignant/Neoplastic Disorders-
 Significant weight loss (>2 lbs/week), particularly if
accompanied by
 early anorexia, is a hallmark of malignant/neoplastic fevers
of unknown origin.
 Post-hot bath pruritus suggests a malignant/neoplastic
disorder. A malignant/neoplastic fever of unknown origin
should be considered in those with
 a history of adenopathy or malignancy.
 Infectious Diseases.
 The history should include
 prior/ invasive procedures or surgeries (abscesses),
 dentition (apical abscesses, subacute bacterial endocarditis),
 antecedent/ concomitant infections, and tuberculosis.

History-
 Animal or pet contact suggests
 Q fever,
 brucellosis,
 toxoplasmosis,
 cat scratch disease, or
 trichinosis.
 Mosquito or tick exposure suggests
 ehrlichiosis/anaplasmosis,
 babesiosis, or
 malaria,
 Rodent exposure suggests
 rat bite fever,
 relapsing fever, or
 leptospirosis.
 Blood transfusions may be an important clue to
 babesiosis,
 cytomegalovirus, or
 human immunodeficiency virus. In normal hosts, the only clue to
cytomegalovirus may be secretion exposure.

History-
 Immunosuppressive drugs predispose to particular pathogens, for
example,
 cytomegalovirus,
 tuberculosis.
 Disparate multiple symptoms/signs suggest multisystem disease, for
example, miliary tuberculosis or Whipple’s disease, rather than several
different disorders.
 Rheumatic/Inflammatory Disorders-
 With prominent arthralgias/ myalgias, a rheumatic/ inflammatory fever of
unknown origin is likely,
 but chills argue against a rheumatic/inflammatory etiology.

History-
 Rheumatic/Inflammatory Disorders-
 Dry cough also may be a subtle clue of giant cell
arteritis/temporal arteritis. With a fever of unknown origin,
 Oral ulcers suggest Behçet’s syndrome or systemic lupus
erythematosus.
 The pattern of organ involvement in a fever of unknown origin
with a history of joint symptoms and generalized
lymphadenopathy points to adult Still’s disease or systemic lupus
erythematosus.
 A history of acalculous cholecystitis in a fever of unknown origin
is an easily overlooked clue of systemic lupus erythematosus or
periarteritis nodosa.
 A family history is important if Behçet’s disease is being
considered.

History-
 Miscellaneous Disorders.
 If the history does not suggest a particular category, miscellaneous
causes of fever of unknown origin should be considered.
 Fever periodicity may be the only clue to cyclic neutropenia.
 A history of lymphadenopathy may suggest Rosai-Dorfman or
Kikuchi’s disease.
 Neck/jaw pain, easily dismissed as dental pain, may be a clue to
subacute thyroiditis.
 Factitious fever should be considered in medical personnel.
Specifically, inquire about
 inflammatory bowel disease (regional enteritis),
 alcoholism (cirrhosis), and
 medications (pseudolymphoma, drug fever).
 Some miscellaneous fevers of unknown origin are familial, for
example,
 familial Mediterranean fever or
 hyper-IgD syndrome.

Physical Examination
 Malignant/Neoplastic Disorders.
 Hectic fevers of lymphoma may resemble infection.
 Relative bradycardia may accompany lymphoma or central
nervous system malignancy.
 Eye examination may be helpful, for example,
 Roth spots (lymphoma, atrial myxoma),
 cytoid bodies (atrial myxoma), or
 retinal hemorrhages (preleukemia).
 A murmur is a key finding in
 subacute bacterial endocarditis,
 noninfectious culture-negative endocarditis, for example,
 marantic endocarditis or
 atrial myxoma.

A Roth spot is a hemorrhage, which is blood from ruptured blood vessels. It
affects your retina — the part of your eye that senses light and sends signals to
your brain that allow you to see. Roth spots are also called Litten's signs.

 Sternal tenderness
 points to a bone marrow disorder (preleukemia,
myeloproliferative disorders).
 Isolated hepatomegaly
 hepatoma,
 renal cell carcinoma, or
 liver metastases.
 Infectious Diseases.
 The approach to infectious fevers of unknown origin begins
with fever pattern analysis.
 Morning temperature spikes suggest
 miliary tuberculosis,
 typhoid/enteric fever, or
 Whipple’s disease.

 Relative bradycardia
 typhoid/enteric fever,
 malaria,
 babesiosis,
 leptospirosis, and
 Q fever.
 Twice daily fever spikes (double quotidian fevers)
 malaria,
 miliary tuberculosis, or
 visceral leishmaniasis.
 Two fever peaks per week (camel back fever curve)
 ehrlichiosis/ anaplasmosis,
 leptospirosis,
 brucellosis, or
 rat bite fever.

Performance of the
various types of fever
a) Fever continues
b) Fever continues to
abrupt onset and
remission
c) Remittent fever
d) Intermittent fever
e) Undulant fever
f) Relapsing fever

 Fundoscopic findings may be a clue to
 toxoplasmosis,
 tuberculosis,
 histoplasmosis, or
 cat scratch disease. Spinal tenderness points to subacute vertebral
osteomyelitis, typhoid/enteric fever, spinal tuberculosis, or brucellosis.
 Hepatomegaly alone suggests
 Q fever,
 visceral leishmaniasis,
 brucellosis,
 rat bite fever, or
 relapsing fever.
 Epididymo-orchitis/epididymal nodule is an easily overlooked sign of
 Epstein-Barr virus,
 renal tuberculosis, or
 brucellosis.

 Splenomegaly narrows diagnostic possibilities to
 Epstein-Barr virus,
 cytomegalovirus,
 brucellosis,
 histoplasmosis,
 malaria,
 Q fever,
 subacute bacterial endocarditis,
 cat scratch disease, and
 rat bite fever.

Rheumatic/Inflammatory Disorders.
 Morning temperature spikes are an important clue to
periarteritis nodosa
 double quotidian fever is a key finding in adult Still
disease.
In a fever of unknown origin, rash, if present, suggests
 sarcoidosis,
 systemic lupus erythematosus, or
 adult Still’s disease.
 Unequal pulse suggests Takayasu’s arteritis.
Lacrimal gland enlargement is a clue to
 late-onset rheumatoid arthritis,
 sarcoidosis, or
 systemic lupus erythematosus.

External eye/fundi may provide many diagnostic clues
in
cytoid bodies
 systemic lupus erythematosus,
 giant cell arteritis/temporal arteritis,
 periarteritis nodosa,
 adult Still’s disease),
Roth spots
 periarteritis nodosa), or
 retinal artery occlusion (Takayasu’s arteritis, giant
call arteritis/temporal arteritis, systemic lupus
erythematosus).

 Oral ulcers suggest
 Behçet’s disease or
 systemic lupus erythematosus.
 Lymphadenopathy suggests
 late-onset rheumatoid arthritis, or
 sarcoidosis.
 In a fever of unknown origin with systemic lupus erythematosus, a
murmur with negative blood cultures suggests possible
 Libman-Sacks endocarditis.
 Hepatomegaly without splenomegaly argues against a
rheumatic/inflammatory fever of unknown origin etiology.
 Epididymitis/epididymal nodules are subtle clues to
 systemic lupus erythematosus, or
 sarcoidosis

Nonspecific Laboratory Tests
 In each fever of unknown origin category, nonspecific tests
often provide useful diagnostic clues.
 Elevated erythrocyte sedimentation rate, serum ferritin,
alkaline phosphatase, and rheumatoid factor titers are
particularly useful in fever of unknown origin diagnosis.
 Diagnostic specificity of nonspecific laboratory
abnormalities is increased when considered together.
 A highly elevated erythrocyte sedimentation rate (>100
mm/h) narrows diagnostic possibilities to very few entities.
 Similarly, 6% atypical lymphocytes (drug fever,
toxoplasmosis) have a different differential than 36%
atypical lymphocytes (Epstein-Barr virus,
cytomegalovirus).
 Nonspecific findings may be exclusionary clues, for
example, eosinophilia argues strongly against
typhoid/enteric fever.

Complete blood count often contains easily
overlooked clues, for example,
 leukopenia,
 monocytosis,
 lymphocytosis-relative lymphopenia,
 eosinophilia,
 basophilia,
 atypical/abnormal lymphocytes,
 thrombocytosis, and
 thrombocytopenia.
In a fever of unknown origin, an isolated alkaline
phosphatase elevation suggests lymphoma.

 Serum protein electrophoresis also may provide diagnostic clues,
for example,
 elevated a1/a2 globulin elevations
 lymphoma,
 systemic lupus erythematosus);
 monoclonal gammopathy
 multiple myeloma,
 hyper-IgD syndrome,
 multicentric Castleman’s disease
 polyclonal gammopathy
 human immunodeficiency virus,
 cytomegalovirus,
 cirrhosis,
 sarcoidosis,
 malaria.

 Microscopic hematuria may be the only clue to
 subacute bacterial endocarditis,
 renal tuberculosis,
 brucellosis,
 periarteritis nodosa,
 lymphoma, or
 renal cell carcinoma.
 Naprosyn test –
 A common clinical problem is to differentiate infectious from
malignant/neoplastic fevers of unknown origin.
 While the work-up is in progress, the Naprosyn test may be done early to
differentiate infectious from malignant fever of unknown origin.
 During the 3-day Naprosyn test, if temperatures decrease markedly, then a
malignant/ neoplastic disorder is likely (positive Naprosyn test).
 However, if fevers remain elevated/only slightly decrease, an infectious
etiology is likely (negative Naprosyn test).

Imaging Studies
 With hepatic/ splenic enlargement, abdominal computed tomography
scans are helpful in detecting other abnormalities, for example,
 retroperitoneal adenopathy or
 intra-abdominal/ pelvic abscesses/masses.
 Gallium/indium scans are useful, but indium scans are relatively
insensitive (false negative) with bone infections, for example,
 chronic osteomyelitis and
 malignancies.
 Cardiac echocardiography is important in
 culture negative endocarditis, and
 atrial myxoma.
 Positron emission tomography-computed tomography scans are most
useful in detecting obscure infectious/ neoplastic fevers of unknown origin,
for example,
 lymphomas,
 Erdheim-Chester disease,
 Q fever
 endocarditis, or
 aortic graft infection.

Invasive Tests
 Lymph node biopsy is the most frequent invasive test.
 More likely to be diagnostic are posterior cervical, supra/infraclavicular, or
epitrochlear node biopsies.
 Hilar, mediastinal, or retroperitoneal node biopsies have a high diagnostic
yield.
 Bone marrow biopsy may be diagnostic, for example,
 myeloproliferative disorders,
 preleukemias (due to acute myelogenous leukemia),
 Gaucher’s disease,
 lymphoma,
 Erdheim-Chester disease,
 disseminated histoplasmosis,
 multicentric Castleman’s disease,
 Whipple’s disease, or
 typhoid/enteric fever.

Invasive Tests
 Epididymal nodule biopsy may be diagnostic of
 brucellosis,
 tuberculosis,
 leptospirosis,
 rat bite fever,
 relapsing fever,
 lymphoma,
 sarcoidosis, or
 familial Mediterranean fever.
 Ileal biopsy can be done for suspected
 ileocecal tuberculosis or
 regional enteritis.

Laboratory Clues in different FUOs
Categories

CLINICAL CLUE SUMMARIES OF
COMMON EASILY MISSED DIAGNOSES
FUO:(Malignant/NeoplasticDisorders)

Approach to the patient with
classic FUO

Nosocomial FUO
 The primary considerations in diagnosing nosocomial FUO
are the underlying susceptibility of the patient coupled with
the potential complications of hospitalization.
 The original surgical or procedural field is the place to
begin a directed physical and laboratory examination for
abscesses, hematomas, or infected foreign bodies.
 More than 50% of patients with nosocomial FUO are
infected.
 Intravascular lines, septic phlebitis, and prostheses are all
suspect.
 In this setting, the best approach is to focus on sites where
occult infections may be sequestered, such as the sinuses of
intubated patients or a prostatic abscess in a man with a
urinary catheter.
 Clostridium difficile colitis may be associated with fever
and leukocytosis before the onset of diarrhea.

Nosocomial FUO
 In ∼25% of patients with nosocomial FUO, the fever has a
noninfectious cause. Among these causes are
 acalculous cholecystitis,
 deep-vein thrombophlebitis, and
 pulmonary embolism.
 Drug fever,
 transfusion reactions,
 alcohol/drug withdrawal,
 adrenal insufficiency,
 thyroiditis,
 pancreatitis,
 gout, and
 pseudogout are among the many possible causes to consider.

Neutropenic FUO
 Neutropenic patients are susceptible to focal bacterial
and fungal infections, to bacteremic infections, to
infections involving catheters (including septic
thrombophlebitis), and to perianal infections.
 Candida and Aspergillus infections are common.
 Infections due to herpes simplex virus or CMV are
sometimes causes of FUO in this group.
 Although the duration of illness may be short in these
patients, the consequences of untreated infection may
be catastrophic;
 50–60% of febrile neutropenic patients are infected,
and 20% are bacteremic.

HIV-Associated FUO
 HIV infection alone may be a cause of fever. Infection due to
 Mycobacterium avium or
 Mycobacterium intracellulare,
 tuberculosis,
 toxoplasmosis,
 CMV infection,
 Pneumocystis infection,
 salmonellosis,
 cryptococcosis,
 histoplasmosis,
 non-Hodgkin’s lymphoma, and (of particular importance)
 drug fever are all possible causes of FUO.

Fever of unknown origin

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Fever of unknown origin

Similar to Fever of unknown origin (20)

More from Suprakash Das

More from Suprakash Das (20)

Recently uploaded

Recently uploaded (20)

Fever of unknown origin