1st department of medicine of semmelweis university, budapest, hungary prof. ferenc szalay budapest,...
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1st Department of Medicine of Semmelweis University, Budapest, Hungary
Prof. Ferenc Szalay
Budapest, 07.11.2005.
FEVER OF UNKNOWN ORIGINFEVER OF UNKNOWN ORIGIN
FUOFUO
ThermoregulationPathogenesis of feverFever onlyFever and RushFever and Lymphadenopathy
TOPICSof the
lecture
Fever and Febrile syndromes
Fever and Febrile syndromesThermoregulationPathogenesis of feverFever onlyFever and RushFever and Lymphadenopathy
Definition
TOPICSof the
lecture
Fever of unkown origin (FUO)
Fever and Febrile syndromesThermoregulationPathogenesis of feverFever onlyFever and RushFever and Lymphadenopathy
DefinitionClassicNew
TOPICSof the
lecture
Fever of unkown origin (FUO)
Fever and Febrile syndromesThermoregulationPathogenesis of feverFever onlyFever and RushFever and Lymphadenopathy
DefinitionClassicNew
Causes
TOPICSof the
lecture
Fever of unkown origin (FUO)
Fever and Febrile syndromesThermoregulationPathogenesis of feverFever onlyFever and RushFever and Lymphadenopathy
DefinitionClassicNew
CausesDiagnostic strategy
TOPICSof the
lecture
Fever of unkown origin (FUO)
To raise Body Temperature
To lower Body Temperature
Mechanisms of Heat RegulationMechanisms of Heat Regulation
To raise Body TemperatureHeat generation
Obligate heat productionMuscular workShivering
Mechanisms of Heat RegulationMechanisms of Heat Regulation
To raise Body TemperatureHeat generation
Obligate heat productionMuscular workShivering
Heat conservationVasoconstructionHeat preference
Mechanisms of Heat RegulationMechanisms of Heat Regulation
To raise Body TemperatureHeat generation
Obligate heat productionMuscular workShivering
Heat conservationVasoconstructionHeat preference
To lower Body TemperatureHeat loss
Obligate heat lossVasodilatationSweatingCold preference
Mechanisms of Heat RegulationMechanisms of Heat Regulation
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
MAJOR THERMOREGULATORY PATHWAYS II.
Behavioral Behavioral adaptationsadaptations
Hypothalamic thermoregulatory integrating center
Control of heat production
or loss
Motor Motor neuronsneurons
SympatheticSympathetic nervous systemnervous system
SympatheticSympathetic nervous systemnervous system
Control of heat
production
Muscle tone, shivering
Sceletal muscles
Skin blood vessels
Skin vasoconstriction,
vasodilataion
Control of heat loss
Skinsweat glands
Sweating
Control of heat loss
Fever >37.8 °C (100.2°)Elevated body temperature mediated by an increase in the hypothalamic
heat-regulating set point
HyperthermiaIncrease in body temp. (>41°) that overrides or bypasses the normal homeostatic mechanisms
Fever; Hyperthermia
PATHOGENESIS OF FEVER
InfectionTissue injury - infarction, traumaMalignancyDrugsImmune-mediated disordersOther inflammatory disordersEndocrine disordersFactitious of self-induced fever
CAUSES OF FEVERCAUSES OF FEVER
without localizing signs or symptomsViral Rhinovirus, adenovirus, parainfluenza
Enterovirus, ECHOInfluenzaEBV, CMVColorado tick fever
Bacterial Staphylococcus aureusListeria monocytogenesSalmonella thyphi, S. parathyphiStreptococci
Post animal exposureCoxiella burneti (Q fever)Leptospira interrogansBrucella speciesEhrlichia chaffeensis
Granulomatous infection Mycobacterium tuberculosisHistoplasma capsulatum
Infections presenting as fever
Maculopapular ErythematousEnterovirusEBV, CMV, Toxoplasma gondiiHIVColorado tick feverSalmonella thyphiLeptospira interrogansMeasles virusRubella virusHepatitis B virusTreponema pallidumParvovirus B19Human herpesvirus 6
Infections producingInfections producing Fever and Rush Fever and Rush 1.1.
VesicularVaricella-zoosterHerpes simplex virusCoxackie A virusVibrio vulnificus
Cutaneous petechiaeNeisseria gonorrhoeaN. meningitidisRickettsia rickettsii (RMSF)Ehrlichia chaffeensisEchovirusesViridans-streptococci (endocarditis)
Infections producingInfections producing Fever and Rush Fever and Rush 2.2.
Diffuse erythrodermaGroup A streptococci (scarlet fever, toxic shock syndr.)Staphylococcus aureus (toxic shock syndr.)
Distinctive rushEcthymia gangrenosum – Pseudomonas aeruginosaErythema chronicum migrans – Lyme disease
Mucous membrane lesionsVesicular pharyngitis – Coxackie A virusPalatal petechiae – rubella, EBV, Scarlet feverErythema – toxic shock syndr.Oral ulceronodular lesion – Histoplasma capsulatumKoplik’s spots – measles virus
Infections producingInfections producing Fever and Rush Fever and Rush 3.3.
Viral MeaslesRubellaHepatitis B
Bacterial Scarlet feverBrucellosisLeptospirosisTuberculosisSyphilisLyme disease
Infections withInfections with Fever and Lymphadenomegaly Fever and Lymphadenomegaly(generalized)(generalized)
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
Infections withInfections with Fever and Lymphadenomegaly Fever and Lymphadenomegaly(regional)(regional)
Definition changed 1961 Petersdorf RB et al.
1991 Durack DT et al.
More than 200 diseases
Major diagnostic challenge
FUOFUO
DEFINITION OF FUODEFINITION OF FUO
Petersdorf RB et al: Fever of unexplained origin: report on 100 cases. Medicine 1961;40:1-30.
DEFINITION OF FUODEFINITION 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 FUODEFINITION 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 FUODEFINITION 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.
DEFINITION OF FUODEFINITION OF 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
DEFINITIONSDEFINITIONS
Classical FUONosocomial FUONeutropenic FUOHIV-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
DEFINITIONSDEFINITIONS
• 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
• 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
• 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
Major disease categoriesInfectionsNeoplastic diseasesNon-infectious inflammatory diseases (NIID)
Minor categoriesFactitious feverDrug-related feverHabitual hyperthermia
(should always be considered before starting FUO work-up)
Classification of causative diseasesClassification of causative diseases
• INFECTIONS Systemic or Localized
CAUSES OF FUOCAUSES OF FUO
INFECTIONS 1.
Systemic infectionsMost 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 infectionsMost 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
• INFECTIONS Systemic or Localized
• NEOPLASTIC DISEASESHaematological neoplasms
Non-Hodgkin lymphoma LeukemiaHodgkin’s disease Other
CAUSES OF FUOCAUSES OF FUO
• INFECTIONS Systemic or Localized
• NEOPLASTIC DISEASESHaematological neoplasms Solid tumors
Non-Hodgkin lymphoma Renal carcinomaLeukemia ColonHodgkin’s disease LiverOther Other
CAUSES OF FUOCAUSES OF FUO
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
• INFECTIONS Systemic or Localized
• NEOPLASTIC DISEASESHaematological neoplasms Solid tumors
Non-Hodgkin lymphoma Renal carcinomaLeukemia ColonHodgkin’s disease LiverOther Other
• NON-INFECTIOUS INFLAMMATORY DISEASES (NIID)Collagen diseases, autoimmune dis., vasculitides, Crohn d.
CAUSES OF FUOCAUSES OF FUO
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
• INFECTIONS Systemic or Localized
• NEOPLASTIC DISEASESHaematological neoplasms Solid tumors
Non-Hodgkin lymphoma Renal carcinomaLeukemia ColonHodgkin’s disease LiverOther Other
• NON-INFECTIOUS INFLAMMATORY DISEASES (NIID)Collagen diseases, autoimmune dis., vasculitides, Crohn d.
• MISCELLANOUSGranulomatous, Whipple d.,Cardiac myxoma, Castleman dis.,etc.
CAUSES OF FUOCAUSES OF FUO
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
Allopurinol CaptoprilCimetidineClofibrate ErythromycinHeparinHydralazine Hydrochlorothiazide Isoniazid
MeperidineMethyldopaNifedipineNitrofurantoin PenicillinPhenytoin 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.
Agents commonly associated with drug-induced fever
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
• INFECTIONS Systemic or Localized
• NEOPLASTIC DISEASESHaematological neoplasms Solid tumors
Non-Hodgkin lymphoma Renal carcinomaLeukemia ColonHodgkin’s disease LiverOther Other
• NON-INFECTIOUS INFLAMMATORY DISEASES (NIID)Collagen diseases, autoimmune dis., vasculitides, Crohn d.
• MISCELLANOUSGranulomatous, Whipple d.,Cardiac myxoma, Castleman dis.,etc.
• UNDIAGNOSED
CAUSES OF FUOCAUSES OF FUO
Shift in the relative proportion of specific disease categories during the last decade:
Infections tumors NIID Undiagnosed
Geographical differencesIn developing countries, tropical area:
more infections
Distribution of the different disease catecories
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
DIAGNOSTIC STRATEGYDIAGNOSTIC STRATEGY
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.MINIMUM DIAGNOSTIC EVALUATION 1.
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.MINIMUM DIAGNOSTIC EVALUATION 2.
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 FUODIAGNOSTIC IMAGING IN PATIENTS WITH 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
Algorythm for the Diagnosis of FUOAlgorythm for the Diagnosis of FUO
The End