TOC | ID 

*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.

Nosocomial FUO:
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 .

Neutropenic FUO:
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.

HIV-associated FUO:
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% in 1980-89)
1. Systemic infections

• Mycoplasma infections: Tuberculosis, MAI, other atypical mycobacteria
• Fungal infections: Aspergillosis, Blastomycosis, Candidiasis, coccidiodomycosis, Cryptococcosis, Histoplasmosis, Mucormycosis, Paracoccidiodomycosis, Sporotrichosis.
• Intravascular infections: Infective endocarditis, aortitis, vasc. catheter infection.
• 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, Trichinosis.

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, myelodysplastic syndromes
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, histoplasmosis, Etc.

2. Inflammatory bowel disease

3. Drug fever

• Antimicrobial: penicillins, cephalosporins,sulfonamides, B lactams, nitrofurantoin, INH,
• 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 infarction/necrosis.

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)

• 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. 
• 3.Chest Radiography
• 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

1. History and Physical: Assess possible focus (pain, heat, redness)
2. Standard Evaluation
3. Intravenous (IV) catheter assessment (Culture)
4. 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
5. 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) scanning
6. Echocardiogram
   • a.Signs and Symptoms of Endocarditis
   • b.Transthoracic - Transesophageal
7. Bone Marrow - biopsy with cultures rule out infiltrating disease (malignancy, infection)
8. Vascular biopsy - to evaluate for arteritis
9. HIV Test - additional causes of FUO should be considered in HIV+ persons (see below)

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 emboli
• c.Always consider portal of entry (intravenous lines) and implanted devices (eg. graft)

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), hypermotility
• 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 antibody
• 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

REF:

1997 Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Unexplained Fever  
Clinical Infectious Diseases 1997;25:551-73 (348 kb PDF)

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