Tuesday, July 26, 2016
I. Introduction.A. C lassic Fever of Unknown Origin (FUO ) Definition. A temperature record on
multiple occasions that is greater than 38.3°C (101°F) for more than 3-weeks’ duration despite 1 week of logical diagnostic evaluation in the hospital.
B. R evised Classic FUO Definitions and Further Classifications. A fever lasting more than 3 weeks with recordings greater than 38.3°C (101°F) despite logical diagnostic evaluation during 3 days in the hospital or 3 outpatient clinic evaluations.
1. Classic FUO. Defined above with the most common etiologies within 3 main categories: infection, malignancy, or collagen-vascular disease.
2. Nosocomial FUO. Usually a fever occurring in a patient that has been hospitalized for at least 24 hours without a defined source prior to admission or 3 days of evaluation. The more common etiologies of a nosocomial fever include urinary tract infections, catheter-related infections, pneumonia,Clostridium difficile colitis, pulmonary embolism, DVT, septic thrombophlebitis,
gastrointestinal bleed, or medication-induced fever.
3. Neutropenia FUO. A recurrent or persistent fever in a patient with neutropenia (absolute neutrophil count less than 500 cells/mm³ or 0.5 3 109/L] despite 3 days of logical diagnostic evaluation. The more common etiologies include nosocomial etiologies (as above) as well as opportunistic bacterial infections (see below), aspergillosis, candidiasis (eg, hepatosplenic
candidiasis), or HSV/VZV.
4. HIV-related FUO. A recurrent or persistent fever for greater than 4 weeks in a patient seropositive for HIV despite 3 days of logical diagnostic evaluation in the hospital. The more common etiologies include: Mycobacterium avium-intracellulare complex (MAC), CMV, Pneumocystis jiroveci p., lymphoma, Kaposi sarcoma, toxoplasmosis, cryptococcus, or medications.
II. Ca uses of FUO .While greater than 200 possible causes for FUO have been reported, the following lists are the more common causes to be considered initially.A cause may not be found in as many as 20% to 30% of cases. The causes are listed by the three main etiologic categories:
A. Infection. This group of causes has been estimated to occur in 28% of FUO cases. The etiologies to initially consider include:
1. Tuberculosis (Mycobacterium tuberculosis; pulmonary and extrapulmonary disease.
2. Abdominal or pelvic abscess (most common cause in the elderly age group).
3. Sinusitis (most commonly with chronic infections or hospitalized patients with nasogastric tubes).
4. Dental abscess (usually oral bacterial flora and may or may not be associated with a recent dental procedure).
5. Endocarditis (most commonly culture negative endocarditis).
6. Osteomyelitis (most commonly chronic osteomyelitis).
7. Hepatitis or chronic biliary tract infections
8. Prostatitis (especially with a recent prostate procedure and is characterized by chronic pelvic pain).
9. HIV infection or sexually transmitted disease
10. CMV (cytomegalovirus; especially in immunocompromised patients).
11. EBV (Epstein-Barr virus; especially following posthematopoietic stem cell transplantation).
12. HSV or VZV (herpes simplex virus and varicella-zoster virus; most commonly associated with reactivation infections in immunocompromised patients).
13. Rocky Mountain spotted fever or Lyme disease (Rickettsia rickettsii or Borrelia burgdorferi; usually associated with outdoor activities and a tick bite).
14. Q fever (Coxiella burnetii; associated with exposure to farm animals [cattle, sheep, or goats] and is characterized by flu-like symptoms with fevers, pneumonia, and hepatitis).
15. Brucellosis (Brucella spp; associated with exposure to animals [goats, sheep, bison, or swine] and is characterized by intermittent fevers, gastrointestinal symptoms [eg, nausea, abdominal pain], and joint effusions).
16. Leptospirosis (Leptospira interrogans; usually associated with rodents or colonized dogs [the organism resides in the renal tubules and is shed in the urine] during recreational activities and is characterized by malaise, headaches, myalgias, abdominal pain, and conjunctival
erythema).
17. Psittacosis (Chlamydophila psittaci; usually associated with birds, especially parrots, and is characterized by fevers, chills, malaise, myalgias, and nonproductive cough).
18. Malaria (Plasmodium spp; transmitted by the Anopheles mosquito and usually characterized by periodic fevers, chills, and rigors).
19. Leishmaniasis (a group of obligate intracellular parasites that are transmitted by sand flies [genera Phlebotomus and Lutzomyia]; commonly associated with cutaneous lesions [eg, a necrotic ulcer] but can be associated with fevers, chills, diarrhea, weight loss, and hepatosplenomegaly).
20. Babesiosis (Babesia spp; an intraerythrocyte parasitic infection transmitted by the bite of an Ixodes tick and characterized by fevers, chills,night sweats, fatigue, weakness, and anemia).
21. Enteric fever (Salmonella enterica, serovar Typhi; associated with travel and characterized by fevers, headaches, myalgias, malaise, and gastrointestinal pain).
22. Toxoplasmosis (Toxoplasma gondii; most commonly a reactivation infection in immunocompromised patients).
23. Rat-bite fever (Streptobacillus moniliformis; patients have an exposure to rats and the disorder is characterized by fevers, headaches, chills, polyarthralgias, and a maculopapular rash on the hands and/or feet).
24. Catscratch disease (Bartonella henselae; a disorder characterized by fevers and localized adenopathy with an exposure to cats).
25. Whipple disease (Tropheryma whippelii; a disorder characterized by
fevers, arthralgia, abdominal pain, chronic diarrhea, weight loss, and generalized lymphadenopathy).
26. Mycobacterium avium-intracellulare complex (MAC; usually associated with fevers and cavitary pulmonary disease in immunocompromised patients).
27. Pneumocystis jirovecii pneumonia (almost exclusively associated with acute hypoxic pneumonia in immunocompromised patients, especially acquired immune deficiency syndrome patients with a CD4 cell count below 200 cells/mm3).
28. Cryptococcus neoformans (commonly associated with chronic corticosteroid use or immunocompromised patients and usually presents as fevers with meningitis or pulmonary pneumonia).
29. Aspergillosis (Aspergillus spp; opportunistic pathogens that can be associated with fevers and pulmonary cavities or endocarditis).
30. Candidiasis (Candida spp; opportunistic pathogens that can be associated with fevers and catheter infections, endocarditis, or hepatosplenic candidiasis).
B. Malignancy. This group typically accounts for 17% of cases. The etiologies to
initially consider include:
1. Leukemia (more commonly chronic leukemia).
2. Lymphoma (most common cause in this group—Hodgkin and non- Hodgkin lymphoma).
3. Renal cell carcinoma.
4. Colorectal cancers.
5. Myelodysplastic syndrome.
6. Pancreatic carcinoma (most commonly not associated with biliary or pancreatic duct obstruction).
7. Metastatic cancer with or without known primary.
C. C ollagen Vascular Disease. This group is estimated to account for 21% of
cases. The etiologies to initially consider include:
1. Temporal arteritis (more common over the age of 50).
2. Rheumatoid arthritis.
3. SLE.
4. Polymyalgia rheumatic.
5. Vasculitis.
6. Polychondritis.
7. Polymyositis.
8. Adult Still disease or adult juvenile rheumatoid arthritis.
9. Sjögren syndrome or Behçet syndrome.
D. Miscellaneous. This group accounts for 5% to 10% of cases. The etiologies
to initially consider include:
1. Crohn disease or ulcerative colitis.
2. Thyroiditis.
3. Sarcoidosis.
4. Amyloidosis.
5. Gout or pseudogout.
6. Addison disease.
7. Hemochromatosis.
8. Medications. The fever usually resolves within 2 to 5 days of discontinuation of the medication. More common medications to consider include:
a. Antibiotics (penicillin, cephalosporin, sulfonamide, tetracycline, and rifampin)
b. Anticonvulsants (phenytoin, carbamazepine, and barbiturates)
c. Antihistamines
d. Nonsteroidal anti-inflammatory drugs (NSAIDs)
e. Iodine and iodide agents (eg, contrast dye)
III. C linical Manif estations of FUO . While documentation of fever is required to establish the diagnosis of FUO, there is no significant relationship between the fever pattern and underlying etiology. However, some associations have been suggested:
A. D ouble Quotidian Fever. Defined as a fever with two peaks within 24 hours;
conditions to consider include endocarditis, malaria, military Mycobacterium
tuberculosis, adult Still disease, and leishmaniasis.
B. S ustained Fever. Defined as a continuously elevated temperature and most
commonly associated with CNS injury (eg, stroke, bleed, etc) or pneumonia
(most commonly secondary to a gram-positive pathogen).
C. Pel-Ebstein Fever. A daily fever that resolves only to reoccur again with a
similar pattern; consider Hodgkin disease.
D. Periodic or Relapsing Fever. Consider endocarditis, malaria, lymphoma, Lyme disease, RMSF, or rat-bite fever.
E. E arly Morning Fever Spike. Consider Mycobacterium tuberculosis, polyarteritis nodosa, brucellosis, or salmonellosis. In general, there are no classic symptoms or signs pathognomonic for a particular FUO etiology, and conditions or causes may be a typical or atypical presentation for a particular disease. It should also be emphasized that no symptom or sign be regarded as irrelevant in a patient suspected of FUO.
IV. App roach to the Patient with FUO
A. H istory. The most important initial approach to the patient with FUO is documenting the fever and recording a complete, accurate, and comprehensive history. Physicians must be meticulous and systematic when obtaining information for the following key elements:
1. Age. Certain illnesses may be more likely associated with particular age groups (eg, malignancy, temporal arteritis, and intra-abdominal abscess may be more likely in persons over the age of 50).
2. History of present illness. While most patients exhibit atypical manifestation, it is important to establish in chronological fashion the onset of symptoms and events that may be related to the fever.
3. Past medical history. This area should focus on any recent or chronic medical illness or infection; and any prior diagnosis of malignancy; and any prior surgery or complication related to surgery; and any implanted prosthetic device, prosthetic valve, pacemaker or implantable defibrillator,
cosmetic implanted surgical device, indwelling venous catheter, or implanted vascular graft.
4. Medications. A complete list of prescription, over-the-counter, and herbal medications should be documented. Drug-related fevers are more common in the elderly and HIV seropositive patient groups.
5. Allergies. Medication allergies may suggest a drug fever while environmental allergies may suggest an atopic condition.
6. Social history. This should include information about the patient’s country of origin, immigration status, prior country or state of residence, travel history (with relevant exposure, vaccination, and prophylaxis history), vaccination status, occupation and occupational risks, smoking status,alcohol and drug exposure, hobbies or leisure activities, pet or animal exposure, dietary (usual or unusual) habits, and sexual activity.
7. Family history. It is important to establish any recent or prior illness in family members and any unusual hereditary cause for fever (eg, familial Mediterranean fever).
B. Physical Examination. A complete physical examination should be performed with attention to all body systems. While physicians should be meticulous and conduct the examination in a systematic approach, repeat examinations are often helpful as diagnostic clues may be either atypical or obscure for the cause of the FUO. Areas of the physical examination that require careful attention and common associations include:
1. Dermatologic examination.
a. Rose spot (typhoid or psittacosis)
b. Hyperpigmentation (hemochromatosis, Addison disease, or Whipple disease)
c. Petechial rash (RMSF)
d. Erythema multiforme (Lyme disease)
e. Vesicular rash on an erythematous base (HSV or VZV)
2. Cardiovascular examination. A new diastolic murmur or change with existing murmur may suggest endocarditis or atrial myxoma.
3. Oral-pharyngeal examination.
a. Gingivitis and/or poor dentition (odontogenic infection or HSV)
b. Mucous membrane ulcers (inflammatory bowel disease, Behçet disease, or HSV [most commonly located on the vermillion border])
c. Tongue tenderness (amyloidosis or temporal arteritis)
4. Abdominal examination.
a. Hepatomegaly (alcoholic liver disease, lymphoma, hepatoma, relapsing fever, Q fever, typhoid fever)
b. Splenomegaly (leukemia, lymphoma, rheumatoid arthritis, sarcoidosis, alcoholic liver disease, endocarditis, CMV, EBV, brucellosis, RMSF, pssittacosis, or typhoid fever). Fever and hepatosplenomegaly in a neutropenia patient should raise concern for hepatosplenic candidiasis.
5. Lymphatic examination. While lymphoma, adult Still disease, Whipple
disease, HIV, toxoplasmosis, CMV, EBV, or tuberculosis present with generalized lymphadenopathy, catscratch disease is usually associated with a localized adenopathy.
6. Musculoskeletal examination.
a. Joint pain (gout or pseudogout, SLE, rheumatoid arthritis, rat-bite fever, Lyme disease, Whipple disease, or brucellosis). Joint pain or arm pain in children associated with raising the arms above the head may suggest Takayasu disease.
b. Calf-tenderness (DVT, polymyositis, or RMSF)
c. Costovertebral tenderness (perinephric abscess or pyelonephritis.
d. Spine
i. Bruit (tumor or AV fistula)
ii. Tenderness (vertebral osteomyelitis, endocarditis, brucellosis, or typhoid fever)
e. Sternal tenderness (leukemia, myeloproliferative disorder, osteomyelitis,or brucellosis)
f. Thigh tenderness (brucellosis or polymyositis)
g. Cartilage tenderness (polychondritis, Raynaud syndrome, or CMV)
h. Trapezius tenderness (subdiaphragmatic abscess)
7. Ophthalmologic examination.
a. Subconjunctival hemorrhage (endocarditis)
b. Uveitis (SLE, Behçet disease, sacoidosis, adult Still disease, or tuberculosis)
c. Conjunctivitis (histoplasmosis, tuberculosis, catscratch disease, chlamydia infection, or SLE)
d. Conjunctival suffusion (leptospirosis, RMSF, or relapsing fever)
e. Dry eyes (Sjogren syndrome, polyarteritis nodosa, SLE, or rheumatoid arthritis)
8. Vital signs. While most vital signs are nonspecific to the cause of FUO, the pulse should increase 15 to 20 beats/min for each 1 degree increase in core body temperature greater than 39°C. A lower than normal increase (or no increase) is termed relative bradycardia. Causes include:
a. Beta-blockers or drug fevers
b. CNS-related disease (eg, hemorrhagic stroke)
c. Typhoid fever
d. Malaria
e. Leptospirosis
f. Psittacosis
C. L aboratory Studies. There is no diagnostic gold standard workup for the etiology of FUO. While the following represents a minimum diagnostic evaluation, laboratory testing or imaging should be guided by findings from a complete history and physical examination.
1. CBC with differential cell count. Leukocytosis may suggest infection or leukemia. Leukopenia may be associated with leukemia, lymphoma, or tuberculosis. Thrombocytosis (greater than 600,000 mm³) may be associated with cancer, bone marrow disease, tuberculosis, or infections with yeast or molds.
2. Peripheral blood film/thick and thin films. Nucleated RBCs in the absence of hemolysis may suggest bone marrow disease. Films may also be helpful to identify morphologic abnormalities, hemolytic changes, Babesia spp, and malaria.
3. Basic metabolic panel. Routinely ordered but nonspecific. An elevated calcium level may suggest cancer or pseudogout. An elevated uric acid level may suggest gout.
4. Liver functions test. Alkaline phosphatase may be most important as it may be elevated with temporal arteritis, thyroiditis, or tuberculosis. Abnormal liver enzymes may also suggest alcoholic liver disease, biliary tract and hepatic cirrhosis, liver abscess, hemochromatosis, EBV, or CMV.
5. TSH. Abnormalities may suggest thyroiditis.
6. Urinalysis and microscopy. Routinely ordered but nonspecific for etiologies of FUO. Blood may suggest glomerulonephritis, urinary tract cancer,and urinary tract infection (especially with pyuria). Pyelonephritis may be suggested by the presence of white blood cell casts.
7. Blood and urine cultures. Routinely ordered as three sets of blood cultures and a clean-catch midstream culture.
8. PSA. Elevations may be associated with prostate cancer, bacterial prostatitis, Cryptococcus, or extra-pulmonary tuberculosis.
9. ESR. Nonspecific test that is elevated with infections (greater than 70 mm/ hr may suggest osteomyelitis) or inflammation (eg, temporal arteritis).
10. Antinuclear antibodies and rheumatoid factor.
11. HIV antibody.
12. CMV serology or serum PCR.
13. EBV heterophil antibody test or serology.
14. Viral hepatitis serology (especially when considering chronic hepatitis B or C infections).
15. Q fever, RMSF, Lyme disease, brucellosis, leptospirosis, Whipple disease, as well as rat-bite fever and catscratch disease serology might
be useful depending on the exposure risk.
16. A skin purified protein derivative (PPD) or interferon gamma release assay (eg, QuantiFERON-TB Gold) is important for tuberculosis screening.
D. R adiography Studies
1. Plain-film chest imaging. A 2-view chest image is routinely ordered that
may be helpful to identify tuberculosis or malignancy.
2. CT scan. Imaging of the abdomen and pelvis with contrast is important early in the evaluation as two of the most common causes of FUO include intra-abdominal abscesses or lymphoproliferative disorders.
3. Echocardiography. Transthoracic (TTE) or transesophageal (TEE) imaging in association with the review of Duke criteria is important for the evaluation of endocarditis (see endocarditis chapter).
4. Ultrasonography. A noninvasive imaging study that may be helpful to evaluate biliary tract or pelvic etiologies for FUO.
5. Venous Doppler study. A noninvasive imaging study that may be helpful to evaluate for venous thrombosis.
V. T reatment. The treatment for FUO consists of identifying the underlying
cause and formulating a treatment plan for that particular condition.
multiple occasions that is greater than 38.3°C (101°F) for more than 3-weeks’ duration despite 1 week of logical diagnostic evaluation in the hospital.
B. R evised Classic FUO Definitions and Further Classifications. A fever lasting more than 3 weeks with recordings greater than 38.3°C (101°F) despite logical diagnostic evaluation during 3 days in the hospital or 3 outpatient clinic evaluations.
1. Classic FUO. Defined above with the most common etiologies within 3 main categories: infection, malignancy, or collagen-vascular disease.
2. Nosocomial FUO. Usually a fever occurring in a patient that has been hospitalized for at least 24 hours without a defined source prior to admission or 3 days of evaluation. The more common etiologies of a nosocomial fever include urinary tract infections, catheter-related infections, pneumonia,Clostridium difficile colitis, pulmonary embolism, DVT, septic thrombophlebitis,
gastrointestinal bleed, or medication-induced fever.
3. Neutropenia FUO. A recurrent or persistent fever in a patient with neutropenia (absolute neutrophil count less than 500 cells/mm³ or 0.5 3 109/L] despite 3 days of logical diagnostic evaluation. The more common etiologies include nosocomial etiologies (as above) as well as opportunistic bacterial infections (see below), aspergillosis, candidiasis (eg, hepatosplenic
candidiasis), or HSV/VZV.
4. HIV-related FUO. A recurrent or persistent fever for greater than 4 weeks in a patient seropositive for HIV despite 3 days of logical diagnostic evaluation in the hospital. The more common etiologies include: Mycobacterium avium-intracellulare complex (MAC), CMV, Pneumocystis jiroveci p., lymphoma, Kaposi sarcoma, toxoplasmosis, cryptococcus, or medications.
II. Ca uses of FUO .While greater than 200 possible causes for FUO have been reported, the following lists are the more common causes to be considered initially.A cause may not be found in as many as 20% to 30% of cases. The causes are listed by the three main etiologic categories:
A. Infection. This group of causes has been estimated to occur in 28% of FUO cases. The etiologies to initially consider include:
1. Tuberculosis (Mycobacterium tuberculosis; pulmonary and extrapulmonary disease.
2. Abdominal or pelvic abscess (most common cause in the elderly age group).
3. Sinusitis (most commonly with chronic infections or hospitalized patients with nasogastric tubes).
4. Dental abscess (usually oral bacterial flora and may or may not be associated with a recent dental procedure).
5. Endocarditis (most commonly culture negative endocarditis).
6. Osteomyelitis (most commonly chronic osteomyelitis).
7. Hepatitis or chronic biliary tract infections
8. Prostatitis (especially with a recent prostate procedure and is characterized by chronic pelvic pain).
9. HIV infection or sexually transmitted disease
10. CMV (cytomegalovirus; especially in immunocompromised patients).
11. EBV (Epstein-Barr virus; especially following posthematopoietic stem cell transplantation).
12. HSV or VZV (herpes simplex virus and varicella-zoster virus; most commonly associated with reactivation infections in immunocompromised patients).
13. Rocky Mountain spotted fever or Lyme disease (Rickettsia rickettsii or Borrelia burgdorferi; usually associated with outdoor activities and a tick bite).
14. Q fever (Coxiella burnetii; associated with exposure to farm animals [cattle, sheep, or goats] and is characterized by flu-like symptoms with fevers, pneumonia, and hepatitis).
15. Brucellosis (Brucella spp; associated with exposure to animals [goats, sheep, bison, or swine] and is characterized by intermittent fevers, gastrointestinal symptoms [eg, nausea, abdominal pain], and joint effusions).
16. Leptospirosis (Leptospira interrogans; usually associated with rodents or colonized dogs [the organism resides in the renal tubules and is shed in the urine] during recreational activities and is characterized by malaise, headaches, myalgias, abdominal pain, and conjunctival
erythema).
17. Psittacosis (Chlamydophila psittaci; usually associated with birds, especially parrots, and is characterized by fevers, chills, malaise, myalgias, and nonproductive cough).
18. Malaria (Plasmodium spp; transmitted by the Anopheles mosquito and usually characterized by periodic fevers, chills, and rigors).
19. Leishmaniasis (a group of obligate intracellular parasites that are transmitted by sand flies [genera Phlebotomus and Lutzomyia]; commonly associated with cutaneous lesions [eg, a necrotic ulcer] but can be associated with fevers, chills, diarrhea, weight loss, and hepatosplenomegaly).
20. Babesiosis (Babesia spp; an intraerythrocyte parasitic infection transmitted by the bite of an Ixodes tick and characterized by fevers, chills,night sweats, fatigue, weakness, and anemia).
21. Enteric fever (Salmonella enterica, serovar Typhi; associated with travel and characterized by fevers, headaches, myalgias, malaise, and gastrointestinal pain).
22. Toxoplasmosis (Toxoplasma gondii; most commonly a reactivation infection in immunocompromised patients).
23. Rat-bite fever (Streptobacillus moniliformis; patients have an exposure to rats and the disorder is characterized by fevers, headaches, chills, polyarthralgias, and a maculopapular rash on the hands and/or feet).
24. Catscratch disease (Bartonella henselae; a disorder characterized by fevers and localized adenopathy with an exposure to cats).
25. Whipple disease (Tropheryma whippelii; a disorder characterized by
fevers, arthralgia, abdominal pain, chronic diarrhea, weight loss, and generalized lymphadenopathy).
26. Mycobacterium avium-intracellulare complex (MAC; usually associated with fevers and cavitary pulmonary disease in immunocompromised patients).
27. Pneumocystis jirovecii pneumonia (almost exclusively associated with acute hypoxic pneumonia in immunocompromised patients, especially acquired immune deficiency syndrome patients with a CD4 cell count below 200 cells/mm3).
28. Cryptococcus neoformans (commonly associated with chronic corticosteroid use or immunocompromised patients and usually presents as fevers with meningitis or pulmonary pneumonia).
29. Aspergillosis (Aspergillus spp; opportunistic pathogens that can be associated with fevers and pulmonary cavities or endocarditis).
30. Candidiasis (Candida spp; opportunistic pathogens that can be associated with fevers and catheter infections, endocarditis, or hepatosplenic candidiasis).
B. Malignancy. This group typically accounts for 17% of cases. The etiologies to
initially consider include:
1. Leukemia (more commonly chronic leukemia).
2. Lymphoma (most common cause in this group—Hodgkin and non- Hodgkin lymphoma).
3. Renal cell carcinoma.
4. Colorectal cancers.
5. Myelodysplastic syndrome.
6. Pancreatic carcinoma (most commonly not associated with biliary or pancreatic duct obstruction).
7. Metastatic cancer with or without known primary.
C. C ollagen Vascular Disease. This group is estimated to account for 21% of
cases. The etiologies to initially consider include:
1. Temporal arteritis (more common over the age of 50).
2. Rheumatoid arthritis.
3. SLE.
4. Polymyalgia rheumatic.
5. Vasculitis.
6. Polychondritis.
7. Polymyositis.
8. Adult Still disease or adult juvenile rheumatoid arthritis.
9. Sjögren syndrome or Behçet syndrome.
D. Miscellaneous. This group accounts for 5% to 10% of cases. The etiologies
to initially consider include:
1. Crohn disease or ulcerative colitis.
2. Thyroiditis.
3. Sarcoidosis.
4. Amyloidosis.
5. Gout or pseudogout.
6. Addison disease.
7. Hemochromatosis.
8. Medications. The fever usually resolves within 2 to 5 days of discontinuation of the medication. More common medications to consider include:
a. Antibiotics (penicillin, cephalosporin, sulfonamide, tetracycline, and rifampin)
b. Anticonvulsants (phenytoin, carbamazepine, and barbiturates)
c. Antihistamines
d. Nonsteroidal anti-inflammatory drugs (NSAIDs)
e. Iodine and iodide agents (eg, contrast dye)
III. C linical Manif estations of FUO . While documentation of fever is required to establish the diagnosis of FUO, there is no significant relationship between the fever pattern and underlying etiology. However, some associations have been suggested:
A. D ouble Quotidian Fever. Defined as a fever with two peaks within 24 hours;
conditions to consider include endocarditis, malaria, military Mycobacterium
tuberculosis, adult Still disease, and leishmaniasis.
B. S ustained Fever. Defined as a continuously elevated temperature and most
commonly associated with CNS injury (eg, stroke, bleed, etc) or pneumonia
(most commonly secondary to a gram-positive pathogen).
C. Pel-Ebstein Fever. A daily fever that resolves only to reoccur again with a
similar pattern; consider Hodgkin disease.
D. Periodic or Relapsing Fever. Consider endocarditis, malaria, lymphoma, Lyme disease, RMSF, or rat-bite fever.
E. E arly Morning Fever Spike. Consider Mycobacterium tuberculosis, polyarteritis nodosa, brucellosis, or salmonellosis. In general, there are no classic symptoms or signs pathognomonic for a particular FUO etiology, and conditions or causes may be a typical or atypical presentation for a particular disease. It should also be emphasized that no symptom or sign be regarded as irrelevant in a patient suspected of FUO.
IV. App roach to the Patient with FUO
A. H istory. The most important initial approach to the patient with FUO is documenting the fever and recording a complete, accurate, and comprehensive history. Physicians must be meticulous and systematic when obtaining information for the following key elements:
1. Age. Certain illnesses may be more likely associated with particular age groups (eg, malignancy, temporal arteritis, and intra-abdominal abscess may be more likely in persons over the age of 50).
2. History of present illness. While most patients exhibit atypical manifestation, it is important to establish in chronological fashion the onset of symptoms and events that may be related to the fever.
3. Past medical history. This area should focus on any recent or chronic medical illness or infection; and any prior diagnosis of malignancy; and any prior surgery or complication related to surgery; and any implanted prosthetic device, prosthetic valve, pacemaker or implantable defibrillator,
cosmetic implanted surgical device, indwelling venous catheter, or implanted vascular graft.
4. Medications. A complete list of prescription, over-the-counter, and herbal medications should be documented. Drug-related fevers are more common in the elderly and HIV seropositive patient groups.
5. Allergies. Medication allergies may suggest a drug fever while environmental allergies may suggest an atopic condition.
6. Social history. This should include information about the patient’s country of origin, immigration status, prior country or state of residence, travel history (with relevant exposure, vaccination, and prophylaxis history), vaccination status, occupation and occupational risks, smoking status,alcohol and drug exposure, hobbies or leisure activities, pet or animal exposure, dietary (usual or unusual) habits, and sexual activity.
7. Family history. It is important to establish any recent or prior illness in family members and any unusual hereditary cause for fever (eg, familial Mediterranean fever).
B. Physical Examination. A complete physical examination should be performed with attention to all body systems. While physicians should be meticulous and conduct the examination in a systematic approach, repeat examinations are often helpful as diagnostic clues may be either atypical or obscure for the cause of the FUO. Areas of the physical examination that require careful attention and common associations include:
1. Dermatologic examination.
a. Rose spot (typhoid or psittacosis)
b. Hyperpigmentation (hemochromatosis, Addison disease, or Whipple disease)
c. Petechial rash (RMSF)
d. Erythema multiforme (Lyme disease)
e. Vesicular rash on an erythematous base (HSV or VZV)
2. Cardiovascular examination. A new diastolic murmur or change with existing murmur may suggest endocarditis or atrial myxoma.
3. Oral-pharyngeal examination.
a. Gingivitis and/or poor dentition (odontogenic infection or HSV)
b. Mucous membrane ulcers (inflammatory bowel disease, Behçet disease, or HSV [most commonly located on the vermillion border])
c. Tongue tenderness (amyloidosis or temporal arteritis)
4. Abdominal examination.
a. Hepatomegaly (alcoholic liver disease, lymphoma, hepatoma, relapsing fever, Q fever, typhoid fever)
b. Splenomegaly (leukemia, lymphoma, rheumatoid arthritis, sarcoidosis, alcoholic liver disease, endocarditis, CMV, EBV, brucellosis, RMSF, pssittacosis, or typhoid fever). Fever and hepatosplenomegaly in a neutropenia patient should raise concern for hepatosplenic candidiasis.
5. Lymphatic examination. While lymphoma, adult Still disease, Whipple
disease, HIV, toxoplasmosis, CMV, EBV, or tuberculosis present with generalized lymphadenopathy, catscratch disease is usually associated with a localized adenopathy.
6. Musculoskeletal examination.
a. Joint pain (gout or pseudogout, SLE, rheumatoid arthritis, rat-bite fever, Lyme disease, Whipple disease, or brucellosis). Joint pain or arm pain in children associated with raising the arms above the head may suggest Takayasu disease.
b. Calf-tenderness (DVT, polymyositis, or RMSF)
c. Costovertebral tenderness (perinephric abscess or pyelonephritis.
d. Spine
i. Bruit (tumor or AV fistula)
ii. Tenderness (vertebral osteomyelitis, endocarditis, brucellosis, or typhoid fever)
e. Sternal tenderness (leukemia, myeloproliferative disorder, osteomyelitis,or brucellosis)
f. Thigh tenderness (brucellosis or polymyositis)
g. Cartilage tenderness (polychondritis, Raynaud syndrome, or CMV)
h. Trapezius tenderness (subdiaphragmatic abscess)
7. Ophthalmologic examination.
a. Subconjunctival hemorrhage (endocarditis)
b. Uveitis (SLE, Behçet disease, sacoidosis, adult Still disease, or tuberculosis)
c. Conjunctivitis (histoplasmosis, tuberculosis, catscratch disease, chlamydia infection, or SLE)
d. Conjunctival suffusion (leptospirosis, RMSF, or relapsing fever)
e. Dry eyes (Sjogren syndrome, polyarteritis nodosa, SLE, or rheumatoid arthritis)
8. Vital signs. While most vital signs are nonspecific to the cause of FUO, the pulse should increase 15 to 20 beats/min for each 1 degree increase in core body temperature greater than 39°C. A lower than normal increase (or no increase) is termed relative bradycardia. Causes include:
a. Beta-blockers or drug fevers
b. CNS-related disease (eg, hemorrhagic stroke)
c. Typhoid fever
d. Malaria
e. Leptospirosis
f. Psittacosis
C. L aboratory Studies. There is no diagnostic gold standard workup for the etiology of FUO. While the following represents a minimum diagnostic evaluation, laboratory testing or imaging should be guided by findings from a complete history and physical examination.
1. CBC with differential cell count. Leukocytosis may suggest infection or leukemia. Leukopenia may be associated with leukemia, lymphoma, or tuberculosis. Thrombocytosis (greater than 600,000 mm³) may be associated with cancer, bone marrow disease, tuberculosis, or infections with yeast or molds.
2. Peripheral blood film/thick and thin films. Nucleated RBCs in the absence of hemolysis may suggest bone marrow disease. Films may also be helpful to identify morphologic abnormalities, hemolytic changes, Babesia spp, and malaria.
3. Basic metabolic panel. Routinely ordered but nonspecific. An elevated calcium level may suggest cancer or pseudogout. An elevated uric acid level may suggest gout.
4. Liver functions test. Alkaline phosphatase may be most important as it may be elevated with temporal arteritis, thyroiditis, or tuberculosis. Abnormal liver enzymes may also suggest alcoholic liver disease, biliary tract and hepatic cirrhosis, liver abscess, hemochromatosis, EBV, or CMV.
5. TSH. Abnormalities may suggest thyroiditis.
6. Urinalysis and microscopy. Routinely ordered but nonspecific for etiologies of FUO. Blood may suggest glomerulonephritis, urinary tract cancer,and urinary tract infection (especially with pyuria). Pyelonephritis may be suggested by the presence of white blood cell casts.
7. Blood and urine cultures. Routinely ordered as three sets of blood cultures and a clean-catch midstream culture.
8. PSA. Elevations may be associated with prostate cancer, bacterial prostatitis, Cryptococcus, or extra-pulmonary tuberculosis.
9. ESR. Nonspecific test that is elevated with infections (greater than 70 mm/ hr may suggest osteomyelitis) or inflammation (eg, temporal arteritis).
10. Antinuclear antibodies and rheumatoid factor.
11. HIV antibody.
12. CMV serology or serum PCR.
13. EBV heterophil antibody test or serology.
14. Viral hepatitis serology (especially when considering chronic hepatitis B or C infections).
15. Q fever, RMSF, Lyme disease, brucellosis, leptospirosis, Whipple disease, as well as rat-bite fever and catscratch disease serology might
be useful depending on the exposure risk.
16. A skin purified protein derivative (PPD) or interferon gamma release assay (eg, QuantiFERON-TB Gold) is important for tuberculosis screening.
D. R adiography Studies
1. Plain-film chest imaging. A 2-view chest image is routinely ordered that
may be helpful to identify tuberculosis or malignancy.
2. CT scan. Imaging of the abdomen and pelvis with contrast is important early in the evaluation as two of the most common causes of FUO include intra-abdominal abscesses or lymphoproliferative disorders.
3. Echocardiography. Transthoracic (TTE) or transesophageal (TEE) imaging in association with the review of Duke criteria is important for the evaluation of endocarditis (see endocarditis chapter).
4. Ultrasonography. A noninvasive imaging study that may be helpful to evaluate biliary tract or pelvic etiologies for FUO.
5. Venous Doppler study. A noninvasive imaging study that may be helpful to evaluate for venous thrombosis.
V. T reatment. The treatment for FUO consists of identifying the underlying
cause and formulating a treatment plan for that particular condition.
