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Verantwoord gebruik van laboratorium testen bij koorts van onbekende oorsprong (FUO)

Verantwoord gebruik van laboratorium testen bij koorts van onbekende oorsprong (FUO). Daniël C Knockaert, MD, PhD University hospital Leuven Belgium. Koorts van onbekende oorsprong. FUO ≠ (acute) koorts zonder focus. F.U.O. : FEVER OF UNKNOWN ORIGIN P.U.O. : PYREXIA OF UNKNOWN ORIGIN

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Verantwoord gebruik van laboratorium testen bij koorts van onbekende oorsprong (FUO)

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  1. Verantwoord gebruik van laboratorium testen bij koorts van onbekende oorsprong (FUO) Daniël C Knockaert, MD, PhD University hospital Leuven Belgium

  2. Koorts van onbekende oorsprong FUO ≠ (acute) koorts zonder focus F.U.O. : FEVER OF UNKNOWN ORIGIN P.U.O. : PYREXIA OF UNKNOWN ORIGIN F.E.C.I. : FEBRIS E CAUSA IGNOTA F.E.O. : FIEVRE D'ETIOLOGIE OBSCURE F.P.I. : FIEVRE PROLONGEE INEXPLIQUEE

  3. Fever of unknown origin Illness of more than 3 week’s duration. Fever greater than 38.3° C (101°F) on several occasions. Cause uncertain after 1 week of in-hospital investigation. Peterdorf and Beeson. Medecine1961;40, 1-30.

  4. Habitual hyperthermia “Psychogenic fever” young women neurotic traits low grade fever 38 - 38.5° C months to years influence of physical and intellectual activity fatigue myalgia Reimann JAMA 1932, 99, 1860.

  5. FUO redefined • CLASSICAL FUO • duration 3 weeks • fever 38.3° C (101° F) • causeuncertainafter3 daysdespiteappropriatein-hospitalinvestigationor3 out-patientvisits • NOSOCOMIAL FUO • NEUTROPENIC FUO • HIV-ASSOCIATED FUO D.T. Durack & A.C. Street. CurrClin topics Infect Dis1991; 11, 35-51.

  6. NOSOCOMIAL FUO • hospitalizedpatients • fever 38.3°C (101°F)onseveral occasions • infectionnot present orincubatingonadmission • diagnosis uncertainafter 3 daysdespiteappropriateinvestigations(includingat least 48-h incubation of microbiologicalcultures) • NEUTROPENIC FUO • lessthan 500 neutrophils mm-3 • fever 38.3°C (101°F)onseveral occasions • diagnosis uncertainafter 3 daysdespiteappropriateinvestigations(includingincludingat least 48-h incubation of microbiologicalcultures) • HIV-ASSOCIATED FUO • confirmed HIV infection • fever 38.3°C (101°F)onseveral occasions • duration of > 4 weeks (out-patients), or > 3 days(hospitalizedpatients) • diagnosis uncertainafter 3 daysdespiteappropriateinvestigations(includingat least 48-h incubation of microbiologicalcultures) D.T. Durack & A.C. Street. CurrClin Topics Infect Dis 1991, 11, 35-51

  7. NOSOCOMIAL FUO • infections (respiratory, urinary, wound, catheter, pressure sores, sinusitis, Clostridium difficile …) • drug-induced fever • NEUTROPENIC FUO • infections (bacterial, fungal, viral, parasitic) • neoplastic fever • HIV-ASSOCIATED FUO • infections • drug-induced fever • neoplastic fever

  8. FUO: traditional definition (1)Medicine ’61;40:1-30 (2)Curr Clin Top Inf Dis ’91;11:35-51 Petersdorf and Beeson ’61(1) • Fever ≥38,3°C on several occasions • Illness ≥3 weeks’ duration • Diagnosis uncertain after 1 week of in-hospital investigation Durack and Street ’91 (2) Classical FUO • Fever ≥38,3°C on several occasions • Illness ≥3 weeks’ duration • Diagnosis uncertain after 3 d of in-hospital investigation or 3 out-patient visits (Nosocomial FUO) (Neutropenic FUO) (HIV-associated FUO)

  9. FUO: definition for the next decades? Illness of more than 3 weeks’ duration Temperature of at least 38.3°C or lower temperature with laboratory signs of inflammation on at least 3 occasions No diagnosis or reasonable (eventually confirmed) diagnostic hypothesis after an initial intelligent (in- or outpatient) diagnostic investigation* Exclusion of nosocomial fevers and severe immunocompromise. Oxford textbook of medicine 5th edition: in press

  10. The initial intelligent diagnostic investigation in- or outpatient Knockaert DC et al J Int Med 2003; 253:263

  11. Influence of definition on case mix in FUO Vanderschueren et al. Arch Int med 2003;163:1033

  12. Lancet 1997;350:575

  13. Vanderschueren S. Tijdsch v Geneesk 2007;63:736

  14. Vanderschueren S tijdsch v Geneesk 2007;63:736

  15. Knockaert DC et al J Int Med 2003; 253:263

  16. CAUSES of FUO • infections* • tumours big three • systemic inflammatory diseases rheumatological disorders,connective tissue diseases, vasculitides, sarcoidosis • miscellaneous • drug fever • factitious fever minor three • habitual hyperthermia • others * - not diagnosed - not effectively treated: endocarditis, osteomyelitis,abscess - slowly responding to treatment (e.g. tb, endocarditis)

  17. Causes of FUO

  18. Undiagnosed FUO Nederl Tijdsch Geneeskd 2008;152:869

  19. Interpretation of diagnostic studies in FUO • Positive • helpfulto diagnosis • non-contributory to diagnosis (eitherfalsepositiveorunexplainedbecause of lack of final diagnosis orlimitedinvestigation of the abnormal focus) • Negative • truenegative • falsenegative The concepts of Se, Sp, PPV, NPV cannotbeappliedbecausemany cases remainundiagnosed.

  20. Infectious causes of FUO tuberculosis localized bacterial infections endocarditis, abscess, dental and sinus infections, urinary tract infections (prostate, ...), osteomyelitis,… systemic bacterial infections (e.g. typhoid fever, brucellose, Borrelia ,syphilis, Whipple disease,…....) “Rickettsial” diseases (Coxiella, Bartonella, Erlichia, Anaplasma) viral diseases(CMV, EBV, HIV, Parvo B19, hepatitis) Chlamydia, mycoplasma parasitic diseases: universal parasites “tropical” parasites fungal diseases

  21. Endocarditis Culture negativeendocarditis • HACEK group • Abiotrophia • Bartonellasp • Brucella • Coxiella • Chlamydia sp • Mycoplasma • Consider SLE

  22. Parasites • Universal • Toxoplasma • Trichinella (myositis, conjunctivitis, eosinophilia) • Toxocara (visceral larva migrans) • Leishmania (pancytopenia and splenomegaly and MAS) • Tropical • Katayama fever (acute schistosomiasis) • Malaria (vivax, ovale) • Trypanosoma • ……… Serology must be guided by history and initial lab data

  23. Neoplastic causes of FUO haematological: diffuse : (aleukemic) leukemia myelodysplasia focal : lymphoma, myeloma solid tumours atrial myxoma No role for tumour markers!!! Low threshold for bone marrow biopsy (bone marrow smears may be false negative!!!

  24. SID’s as cause of FUO multisystem diseases rheumatological disorders connective tissue diseases vasculitides granulomatous diseases: sarcoidosis Beware of false positive immunological tests

  25. The limited value of routine immunological tests in FUO De Clerck LS Tijdsch v Geneeskd 2006;62:965

  26. Miscellaneouscauses of FUO deep venous thrombosis - pulmonary embolism hematoma (including dissecting aneurism) Crohn’s disease non-malignant lymphoproliferative disorders (Castleman’s disease, Kikuchi’s disease, inflammatory pseudotumor of lymph nodes, angio- immunoblastic lymphadenopathy Familial Mediterranean Fever hypersensitivity pneumonitis hyper IgD syndrome endocrine disorders(thyroiditis, Addison disease…..) .......

  27. Spectrum of causes of FUO Influenced by - the time of the study (diagnosticmeans) - geographic factors - age of the patients - duration of fever - type of hospital

  28. Influence of age on the disease spectrum of FUO Norman D. Clin Inf Dis 2000;31:148

  29. Diagnostic strategy • Look for • The most common causes (increasethe pretest probability by history and pysical examination, not by literature data):probabilistic approach rule out by negativevery sensitive tests (Snout) rule in by positive very specific tests (Spin) • The most serious causes : prognostic approach • The causes which can be effectively treated: pragmatic approach • Consider risks and costs

  30. The 15 most common of the more than 200 different causes of FUO Endocarditis, tuberculosis, abdominal abscess Epstein-Barr and cytomegalovirus infection Lymphoma, (aleukemic) leukemia Adult-onset Still disease, systemic lupus erythematosus, giant cell arteritis/polymyalgia rheumatica, sarcoidosis Crohn’s disease, subacute (De Quervain) thyroiditis habitual hyperthermia, drug fever

  31. Diagnostic approach of FUO do not carry out a battery of routine tests (serology, tumour markers….!!!) in a conventional sequence yet look for PDC’s (potentially diagnostic clues ) “Look where the money is” (Sutton’s law); “directed” investigation pattern recognition(requires experience) if no clues or negative directed investigation: - staged approach - total body inflammation scintigraphy - therapeutic trials - wait and see strategy

  32. Diagnostic value of laboratory tests in 199 patients with FUO * equivocal: pointing to the diagnosis but not directly diagnostic ** Ziehl-Nielsen staining and or Löwenstein culture Knockaert DC: PhD thesis 1991

  33. Vanderschueren et al. Arch Int med 2003;163:1033

  34. De Kleijn et al. Medicine 1997; 76: 401

  35. Diagnostic approach of FUO do not carry out a battery of routine tests (serology, tumour markers….!!!) in a conventional sequence yet look for potentially diagnostic clues “Look where the money is” (Sutton’s law); pattern recognition(requires experience and conssideration of “all” data) if no clues or negative directed investigation: - staged approach - total body inflammation scintigraphy - therapeutic trials - wait and see strategy

  36. Pattern recognition Cytopenia, LDH↑, plus extremelyelevatedferritin level: “macrophageactivationsyndrome” Cytopenia, splenomegaly, Mediterranean travel: leishmaniasis Throat pain, high WBC count (>15000/μl) plus extremelyelevatedferritin: Still’sdisease Cytopenia plus transaminasitis :“Rickettsial” diseases Orchitis and travel in the mediterraneancountries: brucellosis! Elderly man, CK↑, high WBC count: polyarteritisnodosa Abnormalliverfunction tests, lungabnormalities, ACE level ↑, travel in the mediterraneancountries : Q fever ♀, 50 yrold, lympho-monocytosis, LDH↑, grandchild of 2 yrsold: granny ‘s CMV Sarcoidosisafter travel to the soutern USA: histoplasmosis Sarcoidosisunresponsive to corticosteroids: Whippledisease

  37. Pattern recognition Episodisch koorts urticaria IgM paraproteine Botpijn of Osteosclerose Schnitzler syndroom

  38. Role of laboratory tests in FUO • The initialapproach • The focusedapproach: serology, specific cultures, PCR,… directedbyhistoryand physicalexam(zoönosis, tickbite, travel history, sexualrisks,….),……….. • The “secondday” approach: serology and immunological tests directedby data of the initial lab and technicalapproach • “Desperate” approach

  39. Lab tests for the initial approach Routine blood tests: ESR, CRP, WBC count including differential and platelet count, protein electrophoresis, blood chemistry, including creatinin, sodium, potassium,ferritin, enzymes (lactate dehydrogenase, bilirubin, liver enzymes, and creatinephosphokinase) Urinalysis, including microscopic examination Immunological tests: ANF, ANCA, RF, ACE Cultures: Routine blood and urine cultures while not receiving antibiotics, cultures of otherwise sterile fluids (e.g., from joints, pleura, or cerebrospinal space) whenever appropriate

  40. Protein Electrophoresis Spike: lymphoma more likely than plasmocytoma Schnitzler syndrome!!!! Polyclonal increase LED Sjögren syndrome Sarcoidosis Chronic liver disease (cirrhosis) HIV Leishmaniasis Atrial myxoma …………

  41. Initial approach for FUO Confirmation of fever Factitious fever ? History, physical exam routine blood tests Drug fever ?microscopic urinalysis cultures chest radiograph abdominal ultrasonography ANA, ANCA, RF, ACE tuberculin skin test consider additional tests abnormal normal Habitual hyperthermia? ↓ further investigation

  42. Role of laboratory tests in FUO • The initialapproach • The focusedapproach: serology, specific cultures, PCR,… directedbyhistoryand physicalexam(zoönosis, tickbite, travel history, sexualrisks,….): requiresknowledge of localepidemiology (eg Spain, NorthAfrica, Middle East: Q fever, brucella, leishmania!!!)

  43. Zoönoses Brucellosis Q fever Cat scratch disease Toxocara (visceral larva migrans) Toxoplasmose Rat bite fever Tularemia Psittacosis Leptospirosis Leishmaniasis

  44. Role of laboratory tests in FUO • The initialapproach • The focusedapproach: serology, specific cultures, PCR,… directedbyhistoryand physicalexam(zoönosis, tickbite, travel history, sexualrisks,….),……….. • The “secondday” approach: serology and immunological tests directedby data of the initial lab and technicalapproach • CMV, EBV serology in case of lymphocytosis (and abnormalliverfunction tests) • hepatitis serology in case of abnormalliverfunction tests • ACE in case of lungorhilarabnormalities

  45. Role of laboratory tests in FUO • The initialapproach • The focusedapproach: serology, specific cultures, PCR,… directedbyhistoryand physicalexam(zoönosis, tickbite, travel history, sexualrisks,….),……….. • The “secondday” approach: serology and immunological tests directedby data of the initial lab and technicalapproach • “Desperate” approach Serologyfor the classicalinfections: Brucellosis, Q fever, syphilis, HIV, parvo B19…

  46. Rare infectious causes of FUO Bartonellosis (incl. B. henselae, B. quintana), brucellosis, Campylobacter, gonococcemia, melioidosis, meningococcemia, listeriosis, tularaemia, yersiniosis Chlamydial infections (incl. psittacosis), erlichioses and rickettsioses (incl. Q fever) Atypical mycobacterioses, leprosy Febris recurrens, leptospirosis, Lyme disease, rat-bite fever, syphilis Actinomycosis, nocardiosis, Whipple disease, Human herpesvirus type 8, Parvovirus B19 Aspergillosis, blastomycosis, candidiasis, coccidioimycosis, cryptococcosis, histoplasmosis, mucormycosis, pneumocystosis, sporotrichosis Amaebiasis, babesiosis, echinococcosis, fascioliasis, malaria, leishmaniasis, schistosomiasis, toxocariasis, toxoplasmosis, trichinosis, trypanosomiasis Malakoplakia, xanthogranulomatous pyelonephritis Central nervous system infection, dental infection, upper respiratory tract infection, wound infection Intravenous catheter infection, infected vascular

  47. Immunological tests in FUO • ANA • ANCA • RF • ACE • Complement

  48. The limited value of routine immunological tests in FUO De Clerck LS Tijdsch v Geneeskd 2006;62:965

  49. ANA (F) anti nuclear antibody (factor) • ANA is a very sensitive test for SLE (95-100 %): allows to rule out not to rule in • ANA (low titer) are indeed common in the “normal” population • In view of the low prevalence of SLE (40-50 /100.000) routinelyorderedpositive ANA willbemostlyfalsepositive • Always consider the pretest probability • “No tests forautoantibodiesshouldbeperformed without a clinicalevaluationthatleads to a presumptive diagnosis – the test shouldnotbeusedfor random screening of patientswith SLE” (Kavanaugh A et al. Guidelinesforclinicaluse of the antinuclear antibody test and tests forspecificautoantibodies to nuclearantigens. ArchPathol Lab Med , 2000; 124: 71-81)

  50. Arch Pathol Lab Med 2000; 124: 71-81.

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