1st department of medicine of semmelweis university, budapest, hungary prof. ferenc szalay budapest,...

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