*FEVER OF UNDETERMINED ORIGIN (FUO)
Criteria for classical FUO:
Fever >101 F (38.3 C) on several occasions
Fever >2-3 weeks
Fever, undiagnosed after 1 week of routine study or 3 outpt visits or 3 days
in the hospital
(*REF: Arch IM 10-9-95;155:1989 De Kleijn E.M. - Netherlands)
Indium 111-labled polyclonal human IgG scintigraphy has the overall sensitivith
of 81% & specificity of 69%. The positive predictive value was 69% &
negative predictive value was 82%. It is helpful.
Fever of >101 F (38.3 C) occurs on several occasions in a hospitalized
pt, in whom infection was not present or incubating on admission. 3 days
of investigation, including at least 2 days' incubation of cultures is the
minimum duration for this dx.
Occult nosocomial infections (infected sinusitis in intubated pts, prosthetic
devices infection, acalculous cholecystitis, Clostridium difficile toxin
in the stool), infected IV lines, recurrent pulm. embolism, transfusion-related
viral infection, & drug fever are possible diagnoses .
Fever of >101 F (38.3 C) on several occasionis in a pt with <500
neutrophil/cc, with no diagnosis after 3 days of investigation, including
at least 2 days' incubation of cultures.
These pts are susceptible to bacterial & fungal bacteremic infections
& to infections involving catheters, including septic thrombophlebitis,
as well as to perianal infections. Candida & Aspergillus infections are
common. Viral infections due to herpes simplex or CMV are sometimes causes
of FUO in this group.
Fever of >101 F on several occasions over a period of >4 weeks for
outpts or >3 days' duration in the hospital pt with HIV infection, with
no diagnosis after 3 days of investigation, including at least 2 days' incubation
of cultures. Hiv infection alone may be a cause. Mycobacterium avium
intracellulare (MAI), toxoplasmosis, CMV, TB, Pneumocystis carinii,
salmonellosis, cryptococcosis, histoplasmosis, non-Hodgking's lymphoma, and
importantly, drug fever are all possible causes.
Differential Diagnosis of Diseases causing FUO
in adults in the U.S.
A. Infections (36% in 1952-57, 23%
1. Systemic infections
Mycoplasma infections: Tuberculosis, MAI, other atypical mycobacteria
Fungal infections: Aspergillosis, Blastomycosis, Candidiasis,
coccidiodomycosis, Cryptococcosis, Histoplasmosis, Mucormycosis,
Intravascular infections: Infective endocarditis, aortitis, vasc.
Systemic bacterial infections: BRUCELLOSIS, Campylobacter, Chlamydial
infection, Gonococcemia, Legionella, Leptospirosis, Listeriosis, Lyme disease,
Melioidosis, Meningococcemia, PSITTACOSIS (Chlamydial psittaci), Rat-bite
fever, Relapsing fever, Salmonellosis, Syphillis, Tularenia, Typhoid, Vibriosis,
Yersenia. Other bacteria: Actinomycosis, Cat-scratch disease, Nocardiosis,
Whipple's bacillus (Tropheryma whippelii) , Rickettsial pox, Q-fever, Rocky
Mountain Spotted Fever.
Viral infections: CMV, HIV, Hepatitis A,B,C,D,E, Herpes, Coxsackie
group B, Dengue, etc.
Parasitic infections: Amebiasis, Babesia, Chaga's disease, Leishmaniasis,
Malaria, Pneumocystis carinii, Strongyloides, Toxoplasmosis, toxocariasis,
2. Localized infections & abscesses
IV catheter site infection, skin abscess, Intraabdominal infections: liver
abscess or cholangitis, cholecystitis, empyema of gallbladder, pericholecystic
& subhepatic abscesses, right or left subphrenic abscesses, lesser sac
abscess; peri-appendiceal & peri-diverticular abscesses; tubo ovarian
abscess; pelvic inflammatory diseases & pelvic abscess; retroperitoneal
abscess; pancreatic abscess; mesenteric lymphadenitis;
Urinary tract infections: Perinephric abscess, Renal carbuncle, Pyelonephritis
with ureteral obstruction & pyonephrosis, Prostatic abscess
Dental or sinus infection/abscess; osteomyelitis.
B. Neoplasms (19% in 1952-57, 31%
in 1970-80, 7% in 1980-89)
1. Hematologic: Lymphoma, Hodgkin's disease, acute leukemia, multiple myeloma,
2. Non hematologic: hepatoma, hypernephroma, atrial myxoma, colorectal carcinoma,
widespread metastatic cancer, etc.
C. Collagen vascular disease
(13% in 1952-57, 16% in 1970-80, 22% in 1980-89)
1. Lupus (SLE), Rheumatoid arthritis, Polymyalgia rheumatica +/ temporal/giant
cell arteritis Adult Still's disease, Sarcoidosis, Inflammatory Bowel Disease,
Temporal Arteritis, & other vasculitis.
2. Behcet's disease, Erythema multiforme, erythema nodosum, polyarteritis
nodosa, relapsing polychondritis, Rheumatic fever, Takayasu's aortitis,
Weber-Christian disease, Wegener's granulomatosis.
D. Other specific causes (25% in
1952-57, 10% in 1970-80, 27% in 1980-89)
1. Granulomatous diseases: sarcoidosis, idiopathic granulomatous hepatitis,
starch peritonitis, & infectious granulomatous diseases as TB, brucellosis,
2. Inflammatory bowel disease
3. Drug fever
Antimicrobial: penicillins, cephalosporins,sulfonamides, B lactams,
Amphotericin B, etc.
Antihypertensive: hydralazine, methyldopa
Anticonvulsant: dilantin, barbiturates, carbamazepine, others
Misc: allopurinol, quinidine, procainamide, etc.
Frequent in HIV infection - especially TMP/SMX (Bactrim®), others .
May or may not be associated with eosinophilia and/or rash
4. Factitioius fever
5. Misc: Familial Mediterranean fever, Whipple's disease, thyrotoxicosis,
Neuroleptic Malignant Syndrome (NMS), post-seizure fever.
6. Recurrent pulm. embolism, post-MI syndrome, subacute thyroiditis, tissue
7. Thermorefulatory disorders: Central: brain tumor, CVA, encephalitis,
hypothalamic dysfunction. Peripheral: hyperthroidism, pheochromocytoma.
E. Undiagnosed (7% in 1952-57, 12%
in 1970-80, 23% in 1980-89)
History and Physical
1.Detailed medical history is critical: a.Exposures, b.Pets, travel,
sick contacts, c.Medications
2.Careful Examination: a.Attention to lymph nodes, skin and eyes, b.Assess
possible focus (pain, heat, redness)
3.Consider underlying disease: a.Bone trauma, b.Valvular lesions,
c.Congenital malformations, d.Immune status
Standard Fever Evaluation
1.History and physical examinations - repeat exam periodically
2.Laboratory Evaluation: CBC with diff., UA, blood & urine C/S,
LFT, serum chemistries.
4.Sputum for Gram stain and culture (if available); Stool Cultures
(especially C. difficile ) as indicated
5.I.V. Line assessment (Culture)
6.Consider Drug-Induced Fever
7.Tuberculosis Test (PPD) and control (eg. mumps, candida)
8.Further imaging, invasive procedures, serologies as dictated by evaluation
Extended Fever Evaluation
History and Physical: Assess possible focus (pain, heat, redness)
Intravenous (IV) catheter assessment (Culture)
If all Negative then consider Nuclear Medicine Scans
a.Indium (111In) WBC Scan
b.Patient's peripheral WBC (neutrophils survive only) labelled -.Labelled
WBC go to liver, spleen, bone marrow, but also to foci of inflammation
c.Gallium (67Ga) Scan
d.Gallium analog of iron.- Localizes to liver, spleen, large intestine, foci
of inflammation (many other places)
e.Bone (99mTc-MDP) Scan: to assess osteomyelitis, tumor infiltration
Abdominal (with Pelvic) CT Scan
a.Any symptoms of GI changes, dysfunction or previous Abdominal Surgery
b.May be diagnostic in up to 25% of cases
c.Exploratory laparotomy is rarely done since the advent of CT (and MRI)
a.Signs and Symptoms of Endocarditis
b.Transthoracic - Transesophageal
Bone Marrow - biopsy with cultures rule out infiltrating disease (malignancy,
Vascular biopsy - to evaluate for arteritis
HIV Test - additional causes of FUO should be considered in HIV+ persons
HIV Positive Patients with FUO
1.Infectious and non-infectious causes of FUO in HIV+ generally correlate
with CD4 count
a.Prescription drugs are often responsible for FUOs in HIV+ patients
b.In intravenous drug abusers with HIV, consider endocarditis and/or infected
c.Always consider portal of entry (intravenous lines) and implanted devices
2.Physical Exam should focus on the following:
a.Eyes - cytomegalovirus (CMV) retinitis
b.Mouth - candida, ulcerations (idiopathic, herpetic, neoplastic), teeth
(portal of entry)
c.Chest - pneumonia (early pneumonias may be asymptomatic)
d.Abdomen - lymphadenopathy (HIV responsive, infection, neoplastic),
e.Skin - herpes zoster, herpes simplex, drug rash
3.CD4+ Counts <200/µL
a.Mycobacterial blood culture (atypicals)
b.Serum cryptococcal antigen , Serum CMV antibody, Serum toxoplasma
e.Chest Radiography; Consider abdominal and pelvic CT scan
f.Consider blood gas analysis
4. If all tests are negative, proceed to further evaluations as outlined
in Extended Evaluation for FUO above
OutlineMed Inc. Copyright 1996-1998
1997 Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients
with Unexplained Fever
Infectious Diseases 1997;25:551-73 (348 kb PDF)