FEVER OF UNKNOWN ORIGIN
FUO
Prof. Ferenc Szalay
1st Department of Medicine of Semmelweis
University, Budapest, Hungary
Budapest, 07.11.2005.
TOPICS Fever and Febrile syndromes
of the
Thermoregulation
lecture
Pathogenesis of fever
Fever only
Fever and Rush
Fever and Lymphadenopathy
TOPICS
of the
lecture
Fever and Febrile syndromes
Thermoregulation
Pathogenesis of fever
Fever only
Fever and Rush
Fever and Lymphadenopathy
Fever of unkown origin (FUO)
Definition
TOPICS
of the
lecture
Fever and Febrile syndromes
Thermoregulation
Pathogenesis of fever
Fever only
Fever and Rush
Fever and Lymphadenopathy
Fever of unkown origin (FUO)
Definition
Classic
New
TOPICS
of the
lecture
Fever and Febrile syndromes
Thermoregulation
Pathogenesis of fever
Fever only
Fever and Rush
Fever and Lymphadenopathy
Fever of unkown origin (FUO)
Definition
Classic
New
Causes
TOPICS
of the
lecture
Fever and Febrile syndromes
Thermoregulation
Pathogenesis of fever
Fever only
Fever and Rush
Fever and Lymphadenopathy
Fever of unkown origin (FUO)
Definition
Classic
New
Causes
Diagnostic strategy
Mechanisms of Heat Regulation
To raise Body Temperature
To lower Body Temperature
Mechanisms of Heat Regulation
To raise Body Temperature
Heat generation
Obligate heat production
Muscular work
Shivering
Mechanisms of Heat Regulation
To raise Body Temperature
Heat generation
Obligate heat production
Muscular work
Shivering
Heat conservation
Vasoconstruction
Heat preference
Mechanisms of Heat Regulation
To raise Body Temperature
Heat generation
Obligate heat production
Muscular work
Shivering
Heat conservation
Vasoconstruction
Heat preference
To lower Body Temperature
Heat loss
Obligate heat loss
Vasodilatation
Sweating
Cold preference
MAJOR THERMOREGULATORY PATHWAYS I.
Skin temperature
Core temperature
Peripheral
Central
thermoreceptors
(in skin)
thermoreceptors
(in hypothalamus, other areas
of CNS and abdominal organs)
Hypothalamic thermoregulatory
integrating center
MAJOR THERMOREGULATORY PATHWAYS II.
Hypothalamic thermoregulatory integrating center
Behavioral
adaptations
Control of
heat production
or loss
Motor
neurons
Sympathetic
nervous system
Sceletal
muscles
Skin
blood vessels
Skin
sweat glands
Muscle tone,
shivering
Skin
vasoconstriction,
vasodilataion
Sweating
Control of
heat loss
Control of
heat loss
Control of
heat
production
Sympathetic
nervous system
Fever
>37.8 °C (100.2°)
Elevated body temperature mediated by an
increase in the hypothalamic
heat-regulating set point
Hyperthermia
Increase in body temp. (>41°) that
overrides or bypasses the normal
homeostatic mechanisms
PATHOGENESIS OF FEVER
CAUSES OF FEVER
Infection
Tissue injury - infarction, trauma
Malignancy
Drugs
Immune-mediated disorders
Other inflammatory disorders
Endocrine disorders
Factitious of self-induced fever
Infections presenting as fever
without localizing signs or symptoms
Viral
Bacterial
Rhinovirus, adenovirus, parainfluenza
Enterovirus, ECHO
Influenza
EBV, CMV
Colorado tick fever
Staphylococcus aureus
Listeria monocytogenes
Salmonella thyphi, S. parathyphi
Streptococci
Post animal exposure
Coxiella burneti (Q fever)
Leptospira interrogans
Brucella species
Ehrlichia chaffeensis
Granulomatous infection
Mycobacterium tuberculosis
Histoplasma capsulatum
Infections producing Fever and Rush 1.
Maculopapular Erythematous
Enterovirus
EBV, CMV, Toxoplasma gondii
HIV
Colorado tick fever
Salmonella thyphi
Leptospira interrogans
Measles virus
Rubella virus
Hepatitis B virus
Treponema pallidum
Parvovirus B19
Human herpesvirus 6
Infections producing Fever and Rush 2.
Vesicular
Varicella-zooster
Herpes simplex virus
Coxackie A virus
Vibrio vulnificus
Cutaneous petechiae
Neisseria gonorrhoea
N. meningitidis
Rickettsia rickettsii (RMSF)
Ehrlichia chaffeensis
Echoviruses
Viridans-streptococci (endocarditis)
Infections producing Fever and Rush 3.
Diffuse erythroderma
Group A streptococci (scarlet fever, toxic shock syndr.)
Staphylococcus aureus (toxic shock syndr.)
Distinctive rush
Ecthymia gangrenosum – Pseudomonas aeruginosa
Erythema chronicum migrans – Lyme disease
Mucous membrane lesions
Vesicular pharyngitis – Coxackie A virus
Palatal petechiae – rubella, EBV, Scarlet fever
Erythema – toxic shock syndr.
Oral ulceronodular lesion – Histoplasma capsulatum
Koplik’s spots – measles virus
Infections with Fever and Lymphadenomegaly
(generalized)
Viral
Bacterial
Measles
Rubella
Hepatitis B
Scarlet fever
Brucellosis
Leptospirosis
Tuberculosis
Syphilis
Lyme disease
Infections with Fever and Lymphadenomegaly
(regional)
Pyogenic infection
Sta. aureus, Stre.
Tuberculosis
Scrofula (tbc. Cervical adenitis)
Cat-scratch disease
Bartonella
Ulceroglandular fever Tularemia
Oculoglandular fever Tul., sporotrichosis, etc.
Inguinal lymphadenopathy Syphilis, herpes
Plague
Yersinia pestis
FUO
Definition changed
1961 Petersdorf RB et al.
1991 Durack DT et al.
More than 200 diseases
Major diagnostic challenge
DEFINITION OF FUO
DEFINITION OF FUO
Petersdorf RB et al: Fever of unexplained origin:
report on 100 cases. Medicine 1961;40:1-30.
DEFINITION OF FUO
1. Fever ≥
38.3°C (>101°F) on several occasions
Petersdorf RB et al: Fever of unexplained origin:
report on 100 cases. Medicine 1961;40:1-30.
DEFINITION OF FUO
1. Fever ≥
38.3°C (>101°F) on several occasions
2. Duration ≥ 3 weeks
Petersdorf RB et al: Fever of unexplained origin:
report on 100 cases. Medicine 1961;40:1-30.
DEFINITION OF FUO
1. Fever ≥
38.3°C (>101°F) on several occasions
2. Duration ≥ 3 weeks
3. Failure to reach a diagnosis despite
1 week appropriate in-hospital investigation
or 3 outpatient visits
Petersdorf RB et al: Fever of unexplained origin:
report on 100 cases. Medicine 1961;40:1-30.
DEFINITIONS
Durack DT et al.: FUO- reexamined and redefinied. Curr Clin Top Inf Dis 1991;11:35-51.
Knockaert DC et al : FUO in adults: 40 years on. J Intern Med 2003;253:263-275
DEFINITIONS
Classical FUO
Nosocomial FUO
Neutropenic FUO
HIV-associated FUO
Durack DT et al.: FUO- reexamined and redefinied. Curr Clin Top Inf Dis 1991;11:35-51.
Knockaert DC et al : FUO in adults: 40 years on. J Intern Med 2003;253:263-275
NOSOCOMIAL FUO
• Hospitalized patient
• Fever ≥ 38.3°C (>101°F) on several occasions
• Infection not present or incubating on
admission
• Diagnosis uncertain after 3 days
despite appropriate investigations
(including at least 48-h incubation of microbiological cultures)
Examples: Septic thrombophlebitis, sinusitis,
Clostridium difficile colitis, drug fever
NEUTROPENIC FUO
• Less than 500 neutrophils mm-3
• Fever ≥ 38.3°C (>101°F) on several occasions
• Diagnosis uncertain after 3 days
despite appropriate investigations
(including at least 48-h incubation of
microbiological cultures)
Examples:
Perianal infection, aspergillosis, candidemia
HIV-associated FUO
• Confirmed HIV infection
• Fever ≥ 38.3°C (>101°F) on several occasions
• Duration of ≥4 weeks (outpatients) or
≥4 days in hospitalized patient
• Diagnosis uncertain after 3 days
despite appropriate investigations
(including at least 48-h incubation of
microbiological cultures)
Examples:
M. avium/M. intracellulare infection, tuberculosis, non-Hodgkin's
lymphoma, drug fever
Classification of causative diseases
Major disease categories
Infections
Neoplastic diseases
Non-infectious inflammatory diseases (NIID)
Minor categories
Factitious fever
Drug-related fever
Habitual hyperthermia
(should always be considered before starting FUO work-up)
CAUSES OF FUO
• INFECTIONS
Systemic or Localized
INFECTIONS 1.
Systemic infections
Most common:
Tuberculosis and endocarditis
Less common:
- Epstein-Barr virus and cytomegalovirus
- toxoplasmosis, brucellosis
- Q fever, cat-scratch disease, malaria
- HIV or opportunistic infections associated with AIDS
Tierney LM.(ed). Current Medical Diagnosis & Treatment. McGraw-Hill, 2005
INFECTIONS 2.
Localized infections
Most common:
Occult abscess (liver, spleen, kidney, brain, bone)
Less common:
- Cholangitis
- Osteomyelitis
- Urinary tract infection
- Paranasal sinusitis
LM. Tierney (ed). Current Medical Diagnosis & Treatment. McGraw-Hill, 2005
CAUSES OF FUO
• INFECTIONS Systemic or Localized
• NEOPLASTIC DISEASES
Haematological neoplasms
Non-Hodgkin lymphoma
Leukemia
Hodgkin’s disease
Other
CAUSES OF FUO
• INFECTIONS Systemic or Localized
• NEOPLASTIC DISEASES
Haematological neoplasms
Non-Hodgkin lymphoma
Leukemia
Hodgkin’s disease
Other
Solid tumors
Renal carcinoma
Colon
Liver
Other
NEOPLASMS
Most common:
- lymphoma (both Hodgkin's and non-Hodgkin's)
- leukemia
Less common:
- Primary and metastatic tumors of the liver
- Renal cell carcinomas
- Atrial myxoma
- Chronic lymphocytic leukemia
- Multiple myeloma
LM. Tierney (ed). Current Medical Diagnosis & Treatment. McGraw-Hill, 2005
CAUSES OF FUO
• INFECTIONS Systemic or Localized
• NEOPLASTIC DISEASES
Haematological neoplasms
Non-Hodgkin lymphoma
Leukemia
Hodgkin’s disease
Other
Solid tumors
Renal carcinoma
Colon
Liver
Other
• NON-INFECTIOUS INFLAMMATORY DISEASES (NIID)
Collagen diseases, autoimmune dis., vasculitides, Crohn d.
NIID - AUTOIMMUNE DISORDERS
Most common:
- systemic lupus erythematosus
- cryoglobulinemia
- polyarteritis nodosa
Less common:
- Giant cell arteritis
- Polymyalgia rheumatica
LM. Tierney (ed). Current Medical Diagnosis & Treatment. McGraw-Hill, 2005
CAUSES OF FUO
• INFECTIONS Systemic or Localized
• NEOPLASTIC DISEASES
Haematological neoplasms
Non-Hodgkin lymphoma
Leukemia
Hodgkin’s disease
Other
Solid tumors
Renal carcinoma
Colon
Liver
Other
• NON-INFECTIOUS INFLAMMATORY DISEASES (NIID)
Collagen diseases, autoimmune dis., vasculitides, Crohn d.
• MISCELLANOUS
Granulomatous, Whipple d.,Cardiac myxoma, Castleman dis.,etc.
MISCELLANEOUS CAUSES
-
drug-induced fever
sarcoidosis
Whipple's disease
familial Mediterranean fever
recurrent pulmonary emboli
alcoholic hepatitis
Thyroiditis
Castleman disease
factitious fever
LM. Tierney (ed). Current Medical Diagnosis & Treatment. McGraw-Hill, 2005
MISCELLANEOUS CAUSES
-
drug-induced fever
LM. Tierney (ed). Current Medical Diagnosis & Treatment. McGraw-Hill, 2005
Agents commonly associated with drug-induced fever
Allopurinol
Captopril
Cimetidine
Clofibrate
Erythromycin
Heparin
Hydralazine
Hydrochlorothiazide
Isoniazid
Meperidine
Methyldopa
Nifedipine
Nitrofurantoin
Penicillin
Phenytoin
Procainamide
Quinidine
AR Roth, and G M. Basello: Approach to the Adult Patient with Fever of
Unknown Origin Am Fam Physician. 2003 Dec 1;68(11):2223-8. Review.
MISCELLANEOUS CAUSES
-
drug-induced fever
sarcoidosis
LM. Tierney (ed). Current Medical Diagnosis & Treatment. McGraw-Hill, 2005
MISCELLANEOUS CAUSES
-
drug-induced fever
sarcoidosis
Whipple's disease
LM. Tierney (ed). Current Medical Diagnosis & Treatment. McGraw-Hill, 2005
MISCELLANEOUS CAUSES
-
drug-induced fever
sarcoidosis
Whipple's disease
familial Mediterranean fever
LM. Tierney (ed). Current Medical Diagnosis & Treatment. McGraw-Hill, 2005
MISCELLANEOUS CAUSES
-
drug-induced fever
sarcoidosis
Whipple's disease
familial Mediterranean fever
recurrent pulmonary emboli
LM. Tierney (ed). Current Medical Diagnosis & Treatment. McGraw-Hill, 2005
MISCELLANEOUS CAUSES
-
drug-induced fever
sarcoidosis
Whipple's disease
familial Mediterranean fever
recurrent pulmonary emboli
alcoholic hepatitis
LM. Tierney (ed). Current Medical Diagnosis & Treatment. McGraw-Hill, 2005
MISCELLANEOUS CAUSES
-
drug-induced fever
sarcoidosis
Whipple's disease
familial Mediterranean fever
recurrent pulmonary emboli
alcoholic hepatitis
Thyroiditis
LM. Tierney (ed). Current Medical Diagnosis & Treatment. McGraw-Hill, 2005
MISCELLANEOUS CAUSES
-
drug-induced fever
sarcoidosis
Whipple's disease
familial Mediterranean fever
recurrent pulmonary emboli
alcoholic hepatitis
Thyroiditis
Castleman disease
LM. Tierney (ed). Current Medical Diagnosis & Treatment. McGraw-Hill, 2005
MISCELLANEOUS CAUSES
-
drug-induced fever
sarcoidosis
Whipple's disease
familial Mediterranean fever
recurrent pulmonary emboli
alcoholic hepatitis
Thyroiditis
Castleman disease
factitious fever
LM. Tierney (ed). Current Medical Diagnosis & Treatment. McGraw-Hill, 2005
CAUSES OF FUO
• INFECTIONS Systemic or Localized
• NEOPLASTIC DISEASES
Haematological neoplasms
Non-Hodgkin lymphoma
Leukemia
Hodgkin’s disease
Other
Solid tumors
Renal carcinoma
Colon
Liver
Other
• NON-INFECTIOUS INFLAMMATORY DISEASES (NIID)
Collagen diseases, autoimmune dis., vasculitides, Crohn d.
• MISCELLANOUS
Granulomatous, Whipple d.,Cardiac myxoma, Castleman dis.,etc.
• UNDIAGNOSED
Distribution of the different disease catecories
Shift in the relative proportion of specific
disease categories during the last decade:
Infections  tumors  NIID  Undiagnosed 
Geographical differences
In developing countries, tropical area:
more infections
TEN LEADING CAUSES OF CLASSIC FUO
among Adults at Community Hospitals in the USA
Lymphoma
Collagen vascular disease
Abscess
16 %
16 %
13 %
Undiagnosed cause
Solid tumor
Thrombosis or hematoma
Granulomatous disease, nonmycobacterial
9%
8%
7%
5%
Endocarditis
Mycobacterial disease
Viral disease
5%
5%
5%
Remaining causes
11 %
Kazanjian PH. Fever of unknown origin: review of 86 patients treated in community
hospitals. Clin Infect Dis. 1992 Dec;15(6):968-73.
DIAGNOSTIC STRATEGY
MINIMUM DIAGNOSTIC EVALUATION 1.
1. Comprehensive history
including travel history, risk for
venereal diseases, hobbies, contact with pet animals and
birds, etc.
2. Comprehensive physical examination
including temporal arteries, rectal digital examination, etc.
3. Routine blood tests
complete blood count including differential, ESR or CRP,
electrolytes, renal and hepatic tests, creatine phosphokinase,
lactate dehydrogenase
4. Microscopic urinalysis
MINIMUM DIAGNOSTIC EVALUATION 2.
5. Cultures of blood, urine
and other normally sterile compartments if
clinically indicated, e.g. joints, pleura, cerebrospinal fluid
6. Chest radiograph
7. Abdominal (including pelvic) ultrasonography
8. Autoantibodies
ANA, ANCA, Reuma factor, etc.
9. Tuberculin skin test
10. Serological tests directed by local epidemiological data
. Knockaert DC et al: Fever of unknown origin in adults: 40 years on. J Intern Med.
2003;253:263-75. Review.
DIAGNOSTIC IMAGING IN PATIENTS WITH FUO
Imaging
Possible diagnoses
Chest radiograph
Tuberculosis, malignancy,
Pneumocystis carinii pneumonia
CT of abdomen or pelvis with contrast
agent
Abscess, malignancy
Gallium 67 scan
Infection, malignancy
Indium-labeled leukocytes
Occult septicemia
Technetium Tc 99m
Acute infection and inflammation of
bones and soft tissue
MRI of brain
PET scan
Malignancy, autoimmune conditions
Malignancy, inflammation
Transthoracic or transesophageal
echocardiography
Bacterial endocarditis
Venous Doppler study
Venous thrombosis
Roth AR and Basello GM. : Approach to the Adult Patient with Fever of Unknown Origin Am Fam Physician. 2003;68:2223-8. Review.
Algorythm for the Diagnosis of FUO
Complete history and physical assesment
Positive findings
Order appropriate and specific
diagnostic testing
No
CBC, electrolytes, LFT, blood culture, urinalasysis, urine
culture, ESR, PPD skin test, chest radigraph
Positive results
Order appropriate follow-up
diagnostic testing
No
CT of abdomen / pelvis with contrast
Assign most likely category
Infection Malignancies Autoimmune (NIID) Miscallenous