3. Fever and Febrile syndromes
Thermoregulation
Pathogenesis of fever
Fever only
Fever and Rush
Fever and Lymphadenopathy
Definition
TOPICS
of the
lecture
Fever of unkown origin (FUO)
4. Fever and Febrile syndromes
Thermoregulation
Pathogenesis of fever
Fever only
Fever and Rush
Fever and Lymphadenopathy
Definition
Classic
New
TOPICS
of the
lecture
Fever of unkown origin (FUO)
5. Fever and Febrile syndromes
Thermoregulation
Pathogenesis of fever
Fever only
Fever and Rush
Fever and Lymphadenopathy
Definition
Classic
New
Causes
TOPICS
of the
lecture
Fever of unkown origin (FUO)
6. Fever and Febrile syndromes
Thermoregulation
Pathogenesis of fever
Fever only
Fever and Rush
Fever and Lymphadenopathy
Definition
Classic
New
Causes
Diagnostic strategy
TOPICS
of the
lecture
Fever of unkown origin (FUO)
7. To raise Body Temperature
To lower Body Temperature
Mechanisms of Heat Regulation
8. To raise Body Temperature
Heat generation
Obligate heat production
Muscular work
Shivering
Mechanisms of Heat Regulation
9. To raise Body Temperature
Heat generation
Obligate heat production
Muscular work
Shivering
Heat conservation
Vasoconstruction
Heat preference
Mechanisms of Heat Regulation
10. 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
Mechanisms of Heat Regulation
11. MAJOR THERMOREGULATORY PATHWAYS I.
Skin temperature
Peripheral
thermoreceptors
(in skin)
Central
thermoreceptors
(in hypothalamus, other areas
of CNS and abdominal organs)
Core temperature
Hypothalamic thermoregulatory
integrating center
12. MAJOR THERMOREGULATORY PATHWAYS II.
Behavioral
adaptations
Hypothalamic thermoregulatory integrating center
Control of
heat production
or loss
Motor
neurons
Sympathetic
nervous system
Sympathetic
nervous system
Control of
heat
production
Muscle tone,
shivering
Sceletal
muscles
Skin
blood vessels
Skin
vasoconstriction,
vasodilataion
Control of
heat loss
Skin
sweat glands
Sweating
Control of
heat loss
13. 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
24. Petersdorf RB et al: Fever of unexplained origin:
report on 100 cases. Medicine 1961;40:1-30.
DEFINITION OF FUO
25. 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
26. 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
27. 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.
DEFINITION OF FUO
28. 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
29. 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
DEFINITIONS
30. • 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
NOSOCOMIAL FUO
31. • 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
NEUTROPENIC FUO
32. • 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
HIV-associated FUO
33. 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)
Classification of causative diseases
35. 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
36. 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
37. • INFECTIONS Systemic or Localized
• NEOPLASTIC DISEASES
Haematological neoplasms
Non-Hodgkin lymphoma
Leukemia
Hodgkin’s disease
Other
CAUSES OF FUO
38. • INFECTIONS Systemic or Localized
• NEOPLASTIC DISEASES
Haematological neoplasms Solid tumors
Non-Hodgkin lymphoma Renal carcinoma
Leukemia Colon
Hodgkin’s disease Liver
Other Other
CAUSES OF FUO
39. 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
40. • INFECTIONS Systemic or Localized
• NEOPLASTIC DISEASES
Haematological neoplasms Solid tumors
Non-Hodgkin lymphoma Renal carcinoma
Leukemia Colon
Hodgkin’s disease Liver
Other Other
• NON-INFECTIOUS INFLAMMATORY DISEASES (NIID)
Collagen diseases, autoimmune dis., vasculitides, Crohn d.
CAUSES OF FUO
41. 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
42. • INFECTIONS Systemic or Localized
• NEOPLASTIC DISEASES
Haematological neoplasms Solid tumors
Non-Hodgkin lymphoma Renal carcinoma
Leukemia Colon
Hodgkin’s disease Liver
Other Other
• NON-INFECTIOUS INFLAMMATORY DISEASES (NIID)
Collagen diseases, autoimmune dis., vasculitides, Crohn d.
• MISCELLANOUS
Granulomatous, Whipple d.,Cardiac myxoma, Castleman dis.,etc.
CAUSES OF FUO
54. • INFECTIONS Systemic or Localized
• NEOPLASTIC DISEASES
Haematological neoplasms Solid tumors
Non-Hodgkin lymphoma Renal carcinoma
Leukemia Colon
Hodgkin’s disease Liver
Other Other
• NON-INFECTIOUS INFLAMMATORY DISEASES (NIID)
Collagen diseases, autoimmune dis., vasculitides, Crohn d.
• MISCELLANOUS
Granulomatous, Whipple d.,Cardiac myxoma, Castleman dis.,etc.
• UNDIAGNOSED
CAUSES OF FUO
55. 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
Distribution of the different disease catecories
56. Lymphoma 16 %
Collagen vascular disease 16 %
Abscess 13 %
Undiagnosed cause 9 %
Solid tumor 8 %
Thrombosis or hematoma 7 %
Granulomatous disease, nonmycobacterial 5 %
Endocarditis 5 %
Mycobacterial disease 5 %
Viral disease 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.
TEN LEADING CAUSES OF CLASSIC FUO
among Adults at Community Hospitals in the USA
58. 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 1.
59. 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.
MINIMUM DIAGNOSTIC EVALUATION 2.
60. 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.
DIAGNOSTIC IMAGING IN PATIENTS WITH FUO
61. 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
Algorythm for the Diagnosis of FUO
