Figure 1: Approach to the Febrile Patient

The evaluation of the febrile patient is paced according to severity of symptoms, underlying illnesses and results of history, physical exam and laboratory assessment. It should proceed in a stepwise fashion from non-invasive inexpensive testing to the more complex evaluation frequently needed in the evaluation of the patient with FUO. The acutely ill or immune compromised patient, pregnant women, and the patient receiving dialysis or living in a nursing home should receive a more in-depth initial investigation. The shaded box on the left side represents the number of febrile days.

ICH= immune compromised host, IE= infective endocarditis, CXR=chest x-ray, CAT=computer assisted tomography, TB=tuberculosis, TFT=thyroid function tests, DVT=deep venous thrombosis, PE= pulmonary embolism, TA=temporal arteritis, GI=gastrointestinal, GU=genitourinary, BC=blood culture, u/a=urinalysis, CA=cancer, CBC=complete blood count. Adapted form Marcel Dekker Inc in Medical Management of Infectious Diseases, Ed C Grace, 2003.

 

Figure 2: Empiric Antibiotics for Ill Appearing Patient at Risk for Occult Bacteremia

 

 

Table 1: Infections That May Present Non-focally 

  • Infectious endocarditis                                                                      

  • Staphylococcus aureus bacteremia                                                      

  • Rocky mountain spotted fever and other rickettsial illnesses  

  • Ehrlichiosis                                                                                                                                     

  • Viral infections: 

    • Hepatitis due to HAV, HBV, HCV, CMV, EBV

    • HIV                                                

  • Malaria  and travel related infections                                                                                            

  • Infections in the elderly                                                                   

HAV= hepatitis A virus, HBV = hepatitis B virus, HCV = hepatitis C virus, CMV = cytomegalovirus,

EBV = Epstein Barr Virus, HIV = human immunodeficiency virus

 

 

Table 2: Non-infectious Illnesses That May Present with Fever 

  • Drug fever

  • Malignancies:

    • AML

    • lymphoma

    • hepatocellular carcinoma or metastasis to the liver

    • renal cell carcinoma

  • Collagen vascular diseases:

  • Miscellaneous:

    • rheumatic fever

    • sarcoidosis

    • inflammatory bowel disease

    • thromboembolic disease

    • thyroid disease

    • gout

AML = acute myelogenous leukemia, SLE = systemic lupus erythematosus

 

 

Table 3: Drugs That Can Cause Fever 

Antimicrobial

Cardiovascular

  • quinidine

  • procainamide

  • hydralazine

  • methyldopa

  • nifedipine

  • triamterene

Central nervous system

  • carbamazepine

  • phenytoin

  • barbiturates

  • chlorpromazine

  • haloperidol

  • thioridazine

  • amphetamine

Anti-inflammatory

  • salicylates

  • ibuprofen

  • tolmetin

Anti-neoplastic

  • bleomycin

  • asparaginase

  • daunorubicin

  • procarbazine

  • cytarabine

  • streptozocin

  • 6-mercaptopurine

  • chlorambucil

  • hydroxyurea

Miscellaneous

  • allopurinol

  • antihistamine

  • iodide

  • cimetidine

  • levamisole

  • metoclopramide

  • clofibrate

 

 

  • folate

  • prostaglandin e2

  • ritodrine

  • interferon

  • streptokinase

  • propylthiouracil

 

 *bolded drugs are the most common causes of drug fever

 Used with permission by Marcel Dekker Inc in Medical Management of Infectious Diseases, Ed C Grace, 2003.

 

 

Table 4: Vasculitis Syndromes 

Syndrome

Population at

risk

Symptoms

Organs involved

Laboratory

assessment

Polyarteritis

 nodosa

middle-aged men>women

fever, wt loss, rash, abdominal pain, arthralgia

kidneys, GI tract, skin, peripheral nerves

leukocytosis anemia, ↑ESR, p-ANCA, HbsAg, U/A

Churg-Strauss

 

middle-aged men>women

fever, wt loss, rash, asthma

lungs, skin, peripheral nerves

eosinophilia, p-ANCA,

abnormal CXR

Wegener’s granulomatosis

male or female,

adolescent to middle aged

fever, wt loss, nasal ulcers, cough, sinusitis, hemoptysis, arthralgia

upper and lower respiratory tracts, kidney

Leukocytosis, anemia, ↑ESR

c-ANCA, U/A, abnormal CXR

Takayasu’s

arteritis

young female, more common in Orient

fever, wt loss, arthralgia, loss of peripheral pulses, pain over vessels

aortic arch and branches

arteriography

Henoch Schönlein purpura

children and young adults

palpable purpura, arthralgia, abdominal pain, bloody stool

skin, kidneys, GI tract

U/A

Essential mixed cryoglobulinemia

middle aged women

purpuric lesions, ulcers, arthralgia, Raynaud’s phenomenon

kidney,

skin

low C3, C4, CH50, U/A,

HCV antibody

Used with permission by Marcel Dekker Inc in Medical Management of Infectious Diseases, Ed C Grace, 2003.

ESR = erythrocyte sedimentation rate, ANCA = antinuclear cytoplasmic antibody, U/A = urinalysis, HbsAg = hepatitis B virus surface antigen, CXR = chest x-ray, GI = gastrointestinal, C = complement, HCV = hepatitis C virus

 

 

Table 5: Key Historical Questions  

  • Medical history:

    • previously diagnosed conditions

    • immunosuppressive states:

      • HIV

      • corticosteroids

      • malignancies

      • organ transplantation

    • surgeries

    • dental procedures

    • trauma

    • valvular heart disease

    • presence of prosthetic material or hardware

     

  • Recent contacts with persons having similar illness

  • Recent and past travel, places of residence and military service

  • Animal exposures at home, work or recreational

  • Work exposures

  • Recreational exposures including rustic living arrangements, animals, tick bites

  • Unusual dietary habits

  • TB exposure

  • History of high risk behavior:

    • multiple sexual partners

    • injection drug use

  • History of transfusions, immunizations

  • Complete list of medications including over the counter and “alternative” remedies.

  • Drug or other allergies

  • Ethnic origin and familial history of fevers, tuberculosis, collagen-vascular diseases, cancer, thrombosis, anemia

  • Living in a rural area

Used with permission by Marcel Dekker Inc in Medical Management of Infectious Diseases, Ed C Grace, 2003.

 

 

Table 6: Causes of  “Classic”  FUO by Etiologic Category 

Infection

Localized bacterial:

  • cat-scratch disease

  • cholecystitis/  cholangitis

  • dental abscess

  • hepatic abscess

  • intra-abdominal abscess

  • perinephric/ intrarenal abscess

  • pelvic abscess

  • osteomyelitis

  • prosthetic joint infection

  • sinusitis

  • tuberculosis

Systemic mycoses:

 

Endovascular:

  • bacterial aortitis

  • endocarditis

  • suppurative thrombophlebitis

  • vascular catheter infection

Systemic bacterial :

Viral:

Parasitic:

Neoplasm

  • Fever relatively common:

    • Hodgkin’s disease

    • Non-Hodgkin’s lymphoma

    • acute myelogenous leukemia

    • hepatocellular carcinoma

    • renal cell carcinoma

  • Occasional cause of fever:

    • colon carcinoma

    • hepatic metastases from any primary

    • breast carcinoma

 

Non-Infectious Inflammatory Conditions

  • Rheumatologic:

    • Still’s disease

    • rheumatic fever

    • SLE

    • rheumatoid arthritis

    • gout

    • polymyalgia rheumatica

 

  • Vasculitis: (Table 4)

    • temporal arteritis

    • polyarteritis nodosa

    • Churg-Strauss

    • Wegener’s granulomatosis

    • Takayasu’s arteritis

    • Henoch Schönlein purpura

    • cryoglobulinemia

 

  • Drug Fever (See Table 3)

  • Factitious Fever

  • Thromboembolism

    • DVT

    • PE

  • Endocrine

    • hyperthyroidism

    • subacute thyroiditis

    • adrenal insufficiency

    • pheochromocytoma

 

 

 

 

Used with permission by Marcel Dekker Inc in Medical Management of Infectious Diseases, Ed C Grace, 2003.

CMV = cytomegalovirus, EBV = Epstein Barr Virus, HAV = hepatitis A virus, HBV = hepatitis B virus, HCV = hepatitis C virus, HIV = human immunodeficiency virus, SLE = systemic lupus erythematosus, DVT = deep venous thrombosis, PE = pulmonary embolism

 

 

Table 7: Causes of “Nosocomial” FUO by Etiologic Category

  • Nosocomial infections:

  • Drug fever (Table 3)

  • Thromboembolic disease

  • Alcohol, barbiturate, benzodiazepine, narcotic withdrawal

  • Blood product transfusion

  • Pancreatitis

  • Phlebitis

  • Gout

  • Acute myocardial infarction and Dressler’s syndrome

  • Post-operative inflammation

 

 

Table 8: Causes of “Neutropenic” FUO by Etiologic Category

 

 

Table 9: Causes of “HIV” FUO by Etiologic Category

 

 

Table 10: Differential Diagnosis of Cryptic Fever by Age 

Fever in the younger adult:

  • EBV

  • CMV

  • HIV

  • viral hepatitis

  • rheumatic fever

  • Still’s disease

  • SLE

  • sarcoidosis

  • Crohn’s disease

  • Hodgkin’s disease

  • leukemia

  • adrenal insufficiency

  • hyperthyroidism

  • subacute thyroiditis

Fever in the elderly adult:

  • endocarditis

  • intraabdominal abscess

  • occult hepatobiliary infection

  • complicated UTI

  • tuberculosis

  • temporal arteritis/polymyalgia rheumatica

  • lymphoma

 

Used with permission by Marcel Dekker Inc in Medical Management of Infectious Diseases, Ed C Grace, 2003.

EBV = Epstein Barr Virus, CMV = cytomegalovirus, HIV = human immunodeficiency virus, SLE = systemic lupus erythematosus, UTI = urinary tract infection

 

 

Table 11: Infectious Etiologies of Fever in the Patient with Animal Contact 

Infection

Pathogen

Animal exposure

Transmission

Clinical signs and symptoms

Diagnosis

Brucellosis

Brucella  Melitensis

B. abortus

B. suis

goats, sheep

cattle

hogs

unpasteurized milk or cheese,  contaminated meat,aerosolized animal fluids

fever, chills, arthralgias, lymphadenopathy HSM, epididymoorchitis

Serum antibodies

Tularemia

Francisella tularensis

wild rabbits, small rodents

direct contact with infected tissues, inhalation of aerosol, tick bite

ulcero-glandular

ocular-glandular

pneumonia, typhoidal fever and prostration

Serum antibodies

Leptospirosis

Leptospira interrogans

rats

dogs

cattle, pigs

drinking or swimming in contaminated water

flu-like illness then

meningitis, hepatitis, hematuria

Isolation of spirochete from urine, blood, CSF,  serum antibodies

Q fever

Coxiella burnetii

cattle, sheep, goats

infected aerosol from parturient animals, ingesting contaminated milk

flu-like illness, pneumonia, hepatitis. no rash.

Serum antibodies

Psittacosis

Chlamydia psittaci

birds

infected aerosol from bird excreta

flu-like, splenomegaly, pneumonia

Serum antibodies

   Used with permission by Marcel Dekker Inc in Medical Management of Infectious Diseases, Ed C Grace, 2003.

   CSF = cerebrospinal fluid

 

 

Table 12: Laboratory Clues to the Etiology of Fever

Lymphocytosis:

Atypical lymphocytosis:

Eosinophilia:

  • parasitic disease

  • drug fever

  • vasculitis

  • lymphoma

  • renal cell carcinoma

Monocytosis:

  • tuberculosis

  • brucellosis

  • infective endocarditis

  • cytomegalovirus

  • inflammatory bowel disease

  • Hodgkin’s disease

  • myelodysplasia

  • solid tumors

Leukopenia:

  • miliary tuberculosis

  • brucellosis

  • typhoid fever

  • HIV

  • SLE

  • Felty’s syndrome

  • lymphoma

  • drug fever

Lymphopenia:

  • tuberculosis

  • human immunodeficiency virus

  • systemic lupus erythematosus

  • sarcoidosis

 

Thrombocytopenia:

  • Epstein-Barr virus

  • HIV

  • myeloproliferative disease

  • SLE

  • vasculitis

Elevated ESR:

  • infective endocarditis

  • temporal arteritis

  • rheumatic fever

  • Still’s disease

  • lymphoma

  • renal cell carcinoma

(If normal, these diagnoses unlikely)

Alkaline phosphatase:

  • obstructive, infectious, or infiltrative liver disease from any cause

  • Still’s disease

  • temporal arteritis

  • Hodgkin’s disease

  • renal cell carcinoma

  • subacute thyroiditis

Elevated transaminases:

 

  • leptospirosis

  • brucellosis

  • relapsing fever

  • drug fever

  • granulomatous hepatitis

Abnormal urinalysis:

Used with permission by Marcel Dekker Inc in Medical Management of Infectious Diseases, Ed C Grace, 2003.