Fever of Unknown Origin

(FUO)
Dr Budi Enoch SpPD
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.
While this classification has stood for more
than 30 years, Durack and Street have
proposed a revised system for classification
of FUO that better accounts for nonendemic
and emerging diseases, improved diagnostic
technologies, and adverse reactions to new
therapeutic interventions.
This updated classification includes
◦ (1) classic FUO,
◦ (2) nosocomial FUO,
◦ (3) neutropenic FUO, and
◦ (4) FUO associated with HIV infection
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.

Classic FUO
In 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.

nosocomial FUO
Neutropenic FUO is defined as a temperature of
38.3°C (101°F) on several occasions in a patient
whose neutrophil count is <500/L 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 is defined by a
temperature of 38.3°C (101°F) on several
occasions over a period of >4 weeks for
outpatients or >3 days

Neutropenic FUO
Coincident with the widespread use of antibiotics,
increasingly useful diagnostic technologies—both
noninvasive and invasive—have been developed.
Newer studies reflect not only changing patterns of
disease but also the impact of diagnostic techniques
that make it possible to eliminate many patients with
specific illness from the FUO category.
The ubiquitous use of potent broad-spectrum antibiotics
may have decreased the number of infections causing
FUO.
The wide availability of ultrasonography, CT, MRI,
radionuclide scanning, and positron emission
tomography (PET) scanning has enhanced the detection
of localized infections and of occult neoplasms and
lymphomas in patients previously thought to have FUO

Causes of Classic FUO

Infections  Localized pyogenic
infections:   Appendicitis  Cat-scratch
disease Cholangitis  Cholecystitis Dental
abscess Diverticulitis/abscess  Lesser sac
abscess Liver abscess Mesenteric
lymphadenitis  Osteomyelitis Pancreatic
abscess Pelvic inflammatory disease
 Perinephric/intrarenal abscess Prostatic
abscess  Renal malacoplakia Sinusitis
Subphrenic abscess  Suppurative
thrombophlebitis Tuboovarian abscess
Causes of FUO in Adults in the
United States
Intravascular infections  
Bacterial aortitis  Bacterial endocarditis
Vascular catheter infection
Systemic bacterial infections  
Bartonellosis Brucellosis Campylobacter
infection Cat-scratch disease/bacillary
angiomatosis (B. henselae)
Gonococcemia Legionnaires' disease
Leptospirosis Listeriosis Lyme disease
Melioidosis Meningococcemia Rat-bite
fever Relapsing fever Salmonellosis
Syphilis Tularemia Typhoid fever
Vibriosis Yersinia infection
Mycobacterial infections  M. avium/M. intracellulare infections
Other atypical mycobacterial infections Tuberculosis
Other bacterial infections  Actinomycosis Bacillary angiomatosis
Nocardiosis Whipple's disease
Rickettsial infections Anaplasmosis  Ehrlichiosis  Murine typhus
  Q fever Rickettsialpox Rocky Mountain spotted fever  Scrub typhus
Mycoplasmal infections
Chlamydial infections  Lymphogranuloma venereum  Psittacosis
TWAR (C. pneumoniae) infection
Viral infections
Chikungunya fever Colorado tick fever  
Coxsackievirus group B infection  
Cytomegalovirus infection
Dengue
Epstein-Barr virus infection  
Hepatitis A, B, C, D, and E  
HIV infection
Human herpes virus infection  
Lymphocytic choriomeningitis
Parvovirus B19 infection  
Picornavirus infection
Fungal infections
Aspergillosis Blastomycosis Candidiasis
Coccidioidomycosis Cryptococcosis
Histoplasmosis Mucormycos
Paracoccidioidomycosis Pneumocystis
infection Sporotrichosis
Parasitic infections
Amebiasis Babesiosis Chagas' disease
Leishmaniasis Malaria Strongyloidiasis
Toxocariasis Toxoplasmosis Trichinellosis
Presumed infections, agent undetermined
Kawasaki's disease (mucocutaneous lymph
node syndrome)
Kikuchi's necrotizing lymphadenitis
Neoplasms  Malignant
   Colon cancer
   Gall bladder carcinoma
   Hepatoma
   Hodgkin's lymphoma
   Immunoblastic T-cell lymphoma
   Leukemia
   Lymphomatoid granulomatosis
   Malignant histiocytosis
   Non-Hodgkin's lymphoma
   Pancreatic cancer
   Renal cell carcinoma
   Sarcoma
Benign
   Atrial myxoma
   Castleman's disease
   Renal angiomyolipoma
Habitual Hyperthermia    (Exaggerated circadian rhythm)
Collagen Vascular/Hypersensitivity Diseases
   Adult Still's disease
   Behçet's disease
   Erythema multiforme
   Erythema nodosum
   Giant-cell arteritis/polymyalgia rheumatica
   Hypersensitivity pneumonitis
   Hypersensitivity vasculitis
   Mixed connective-tissue disease
   Polyarteritis nodosa
   Relapsing polychondritis
   Rheumatic fever
   Rheumatoid arthritis
   Schnitzler's syndrome
   Systemic lupus erythematosus
   Takayasu's aortitis
   Weber-Christian disease
   Granulomatosis with polyangiitis (Wegener's)
Granulomatous Diseases
   Crohn's disease
   Granulomatous hepatitis
   Midline granuloma
   Sarcoidosis
Miscellaneous Conditions
   Aortic dissection
Drug fever
   Gout
   Hematomas
   Hemoglobinopathies
   Laennec's cirrhosis
   PFPA syndrome: periodic fever, adenitis, pharyngitis,
aphthae
   Postmyocardial infarction syndrome
   Recurrent pulmonary emboli
   Subacute thyroiditis (de Quervain's)
   Tissue infarction/necrosis
Inherited and Metabolic Diseases
   Adrenal insufficiency
   Cyclic neutropenia
   Deafness, urticaria, and amyloidosis
   Fabry disease
   Familial cold urticaria
   Familial Mediterranean fever
   Hyperimmunoglobulinemia D and periodic
fever
   Muckle-Wells syndrome
   Tumor necrosis factor receptor–associated
periodic syndrome (familial Hibernian fever)
   Type V hypertriglyceridemia
Thermoregulatory Disorders  Central
   Braintumor
   Cerebrovascular accident
   Encephalitis
   Hypothalamic dysfunction
Peripheral
   Hyperthyroidism
   Pheochromocytoma
Factitious Fevers
"Afebrile" FUO <38.3°C (100.94°F)
stepwise flow chart depicting the diagnostic workup and
therapeutic management of FUO is provided in Fig. 18-1.
In this flow chart, reference is made to "potentially diagnostic
clues," as outlined by de Kleijn and colleagues; these clues may
be key findings in the history (e.g., travel), localizing signs, or
key symptoms.
Certain specific diagnostic maneuvers become critical in dealing
with prolonged fevers.
If factitious fever is suspected, temperature-taking should be
supervised, and simultaneous urine and body temperatures
should be measured.
Thick blood smears should be examined for Plasmodium; thin
blood smears, prepared with proper technique and quality
stains and subjected to expert microscopy, should be used to
speciate Plasmodium and to identify Babesia, Trypanosoma,
Leishmania, Leptospira, Rickettsia, and Borrelia.
Specialized Diagnostic Studies
"Potentially diagnostic clues," as outlined by de Kleijn and
colleagues (1997, Part II), may be key findings in the history,
localizing signs, or key symptoms. bNeedle biopsy of liver as
well as any other tissue indicated by "potentially diagnostic
clues." cInvasive testing could involve laparoscopy. dEmpirical
therapy is a last resort, given the good prognosis of most
patients with FUO persisting without a diagnosis. Abbreviations:
ANA, antinuclear antibody; CBC, complete blood count; CMV,
cytomegalovirus; CRP, C-reactive protein; CT, computed
tomography; Diff, differential; EBV, Epstein-Barr virus; ESR,
erythrocyte sedimentation rate; FDG, fluorodeoxyglucose F18;
NSAIDs, nonsteroidal anti-inflammatory drugs; PET, positron
emission tomography; PMN, polymorphonuclear leukocyte; PPD,
purified protein derivative; RF, rheumatoid factor; SPEP, serum
protein electrophoresis; TB, tuberculosis; TIBC, total iron-
binding capacity; VDRL, Venereal Disease Research Laboratory
test.
Approach to the patient with
classic FUO
The focus here is on classic FUO. Other modifiers
of FUO—neutropenia, HIV infection, a nosocomial
setting—all vastly affect the risk equation and
dictate therapy based on the probability of
various causes of fever and on the calculated
risks and benefits of a guided empirical approach.
The age and physical state of the patient are
factors as well: the frail, elderly patient may
merit a trial of empirical therapy earlier than the
robust young adult

Treatment: Fever of Unknown Origin

The emphasis in patients with classic FUO is on continued
observation and examination, with the avoidance of
"shotgun" empirical therapy.
Antibiotic therapy (even that for tuberculosis) may irrevocably
alter the ability to culture fastidious bacteria or mycobacteria
and delineate ultimate cause.
However, vital-sign instability or neutropenia is an indication for
empirical therapy with a fluoroquinolone plus piperacillin or the
regimen mentioned above (see "Nosocomial FUO"), for
example.
Cirrhosis, asplenia, disease-modifying biologic therapy,
intercurrent immunosuppressive drug use, or exotic travel or
environmental exposures (e.g., cave interiors) may all tip the
balance toward earlier empirical anti-infective therapy.
If the TST is positive or if granulomatous hepatitis or other
granulomatous disease is present with anergy (and sarcoid
seems unlikely), then a therapeutic trial for tuberculosis should
be undertaken, with treatment usually continued for up to 6
weeks. A failure of the fever to respond over this period
suggests an alternative diagnosis.
sudah ya.........