Verantwoord gebruik van laboratorium testen bij koorts van onbekende oorsprong FUO

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

• 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

FUO ? (acute) koorts zonder focus
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Fever of unknown origin

• Illness of more than 3 weeks duration.
• Fever greater than 38.3 C (101F) on several
  occasions.
• Cause uncertain after 1 week of in-hospital
  investigation.
• Peterdorf and Beeson. Medecine 196140, 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.

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FUO redefined

• CLASSICAL FUO
• duration ? 3 weeks
• fever ? 38.3 C (101 F)
• cause uncertain after 3 days despite appropriate
  in-hospital investigation or 3 out-patient visits
• NOSOCOMIAL FUO
• NEUTROPENIC FUO
• HIV-ASSOCIATED FUO
• D.T. Durack A.C. Street.
• Curr Clin topics Infect Dis 1991 11, 35-51.

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• NOSOCOMIAL FUO
• hospitalized patients
• fever ? 38.3C (101F) 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)
• NEUTROPENIC FUO
• less than 500 neutrophils mm-3
• fever ? 38.3C (101F) on several occasions
• diagnosis uncertain after 3 days despite
  appropriate investigations (including including
  at least 48-h incubation of microbiological
  cultures)
• HIV-ASSOCIATED FUO
• confirmed HIV infection
• fever ? 38.3C (101F) on several occasions
• duration of gt 4 weeks (out-patients), or gt 3 days
  ( hospitalized patients)
• diagnosis uncertain after 3 days despite
  appropriate investigations (including at least
  48-h incubation of microbiological cultures)
• 
  D.T. Durack A.C. Street. Curr Clin
  Topics Infect Dis 1991, 11, 35-51

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• 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

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FUO traditional definition

• Petersdorf and Beeson 61(1)
• Fever 38,3C on several occasions
• Illness 3 weeks duration
• Diagnosis uncertain after 1 week of in-hospital
  investigation

• Durack and Street 91 (2)
• Classical FUO
• Fever 38,3C 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)

(1)Medicine 61401-30
(2)Curr Clin Top Inf Dis 911135-51
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FUO definition for the next decades?

• Illness of more than 3 weeks duration
• Temperature of at least 38.3C 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.

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The initial intelligent diagnostic investigation
in- or outpatient
Knockaert DC et al J Int Med 2003 253263
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Influence of definition on case mix in FUO
Vanderschueren et al. Arch Int med 20031631033
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Lancet 1997350575
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Vanderschueren S. Tijdsch v Geneesk 200763736
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Vanderschueren S tijdsch v Geneesk 200763736
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Knockaert DC et al J Int Med 2003 253263
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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)

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Causes of FUO
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Undiagnosed FUO
Nederl Tijdsch Geneeskd 2008152869
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Interpretation of diagnostic studies in FUO

• Positive
• helpful to diagnosis
• non-contributory to diagnosis (either false
  positive or unexplained because of lack of final
  diagnosis or limited investigation of the
  abnormal focus)
• Negative
• true negative
• false negative
• The concepts of Se, Sp, PPV, NPV can not be
  applied because many cases remain undiagnosed.

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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

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Endocarditis

• Culture negative endocarditis
• HACEK group
• Abiotrophia
• Bartonella sp
• Brucella
• Coxiella
• Chlamydia sp
• Mycoplasma
• Consider SLE

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• 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
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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!!!
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SIDs as cause of FUO

• multisystem diseases
• rheumatological disorders
• connective tissue diseases
• vasculitides
• granulomatous diseases sarcoidosis
• Beware of false positive immunological tests

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The limited value of routine immunological tests
in FUO
De Clerck LS Tijdsch v Geneeskd 200662965
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Miscellaneous causes of FUO

• deep venous thrombosis - pulmonary embolism
• hematoma (including dissecting aneurism)
• Crohns disease
• non-malignant lymphoproliferative disorders
  (Castlemans disease, Kikuchis disease,
  inflammatory pseudotumor of lymph nodes, angio-
  immunoblastic lymphadenopathy
• Familial Mediterranean Fever
• hypersensitivity pneumonitis
• hyper IgD syndrome
• endocrine disorders (thyroiditis, Addison
  disease..)
• .......

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Spectrum of causes of FUO

• Influenced by - the time of the study (diagnostic
  means)
• - geographic factors
• - age of the patients
• - duration of fever
• - type of hospital

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Influence of age on the disease spectrum of FUO
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Diagnostic strategy

• Look for
• The most common causes (increase the pretest
  probability by history and pysical examination,
  not by literature data) probabilistic approach
• rule out by negative very 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

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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
• Crohns disease, subacute (De Quervain)
  thyroiditis
• habitual hyperthermia, drug fever

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Diagnostic approach of FUO

• do not carry out a battery of routine tests
  (serology, tumour markers.!!!) in a conventional
  sequence yet look for PDCs (potentially
  diagnostic clues )
• Look where the money is (Suttons
  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
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Vanderschueren et al. Arch Int med 20031631033
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 (Suttons
  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 extremely elevated ferritin
  level macrophage activation syndrome
• Cytopenia, splenomegaly, Mediterranean travel
  leishmaniasis
• Throat pain, high WBC count (gt15000/µl) plus
  extremely elevated ferritin Stills disease
• Cytopenia plus transaminasitis Rickettsial
  diseases
• Orchitis and travel in the mediterranean
  countries brucellosis!
• Elderly man, CK?, high WBC count polyarteritis
  nodosa
• Abnormal liver function tests, lung
  abnormalities, ACE level ?, travel in the
  mediterranean countries Q fever
• ?, 50 yr old, lympho-monocytosis, LDH?,
  grandchild of 2 yrs old granny s CMV
• Sarcoidosis after travel to the soutern USA
  histoplasmosis
• Sarcoidosis unresponsive to corticosteroids
  Whipple disease

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Pattern recognition
Episodisch koorts
urticaria IgM paraproteine Botpijn of
Osteosclerose
Schnitzler syndroom
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Role of laboratory tests in FUO

• The initial approach
• The focused approach serology, specific
  cultures, PCR, directed by history and physical
  exam (zoönosis, tick bite, travel history, sexual
  risks,.),..
• The second day approach serology and
  immunological tests directed by data of the
  initial lab and technical approach
• Desperate approach

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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 creatine phosphokinase)
• 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

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Protein Electrophoresis

• Spike lymphoma more likely than plasmocytoma
• Schnitzler syndrome!!!!
• Polyclonal increase
• LED
• Sjögren syndrome
• Sarcoidosis
• Chronic liver disease (cirrhosis)
• HIV
• Leishmaniasis
• Atrial myxoma

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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

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Role of laboratory tests in FUO

• The initial approach
• The focused approach serology, specific
  cultures, PCR, directed by history and physical
  exam (zoönosis, tick bite, travel history, sexual
  risks,.)
• requires knowledge of local epidemiology (eg
  Spain, North Africa, Middle East Q fever,
  brucella, leishmania!!!)

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Zoönoses
Brucellosis Q fever Cat scratch disease Toxocara
(visceral larva migrans) Toxoplasmose Rat bite
fever Tularemia Psittacosis Leptospirosis Leishman
iasis
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Role of laboratory tests in FUO

• The initial approach
• The focused approach serology, specific
  cultures, PCR, directed by history and physical
  exam (zoönosis, tick bite, travel history, sexual
  risks,.),..
• The second day approach serology and
  immunological tests directed by data of the
  initial lab and technical approach
• CMV, EBV serology in case of lymphocytosis (and
  abnormal liver function tests)
• hepatitis serology in case of abnormal liver
  function tests
• ACE in case of lung or hilar abnormalities

45
Role of laboratory tests in FUO

• The initial approach
• The focused approach serology, specific
  cultures, PCR, directed by history and physical
  exam (zoönosis, tick bite, travel history, sexual
  risks,.),..
• The second day approach serology and
  immunological tests directed by data of the
  initial lab and technical approach
• Desperate approach
• Serology for the classical infections
  Brucellosis, Q fever, syphilis, HIV, parvo B19

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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 200662965
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) routinely ordered positive ANA will be
  mostly false positive
• Always consider the pretest probability
• No tests for autoantibodies should be performed
  without a clinical evaluation that leads to a
  presumptive diagnosis the test should not be
  used for random screening of patients with SLE
• (Kavanaugh A et al. Guidelines for clinical use
  of the antinuclear antibody test and tests for
  specific autoantibodies to nuclear antigens. Arch
  Pathol Lab Med , 2000 124 71-81)

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Arch Pathol Lab Med 2000 124 71-81.
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ANCAantineutrophil cytoplasmic antibodies

• ANCA is very sensitive for Wegener disease ,
  microscopic polyangiitis or Churg-Strauss
  syndrome a negative ANCA test decreases
  considerably the likelihood of these small vessel
  vasculitides
• A positive ANCA test (IF) has very poor
  diagnostic value (low specificty) and requires
  further analysis
• Staining pattern (IFimmunofluoresence)
• c-ANCA
• p-ANCA
• Anti-PR3 (Elisa) activity
• Anti-MPO (Elisa) activity
• (anti-elastase, anti -lactoferrin activity)

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ANCAantineutrophil cytoplasmic antibodies
Lancet 2006 368404
53
ANCAantineutrophil cytoplasmic antibodies
Lancet 2006368404
54
ANCAantineutrophil cytoplasmic antibodies

• ANCA is very sensitive (for Wegener disease ,
  microscopic polyangiitis or Churg-Strauss
  syndrome) a negative ANCA test decreases
  considerably the likelihood of these small vessel
  vasculitides
• A positive ANCA test (IF) has very poor
  diagnostic value (low specificty) and requires
  further analysis
• Staining pattern (IFimmunofluoresence)
• c-ANCA
• p-ANCA
• Anti-PR3 (Elisa) activity
• Anti-MPO (Elisa) activity
• (anti-elastase, anti -lactoferrin activity)

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ANCAantineutrophil cytoplasmic antibodies
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ANCAantineutrophil cytoplasmic antibodies

• Wegener disease c-ANCA and anti-PR3 positive
• generalised Wegener 75 -95
• limited active Wegener 60 70
• Wegener in remission 30
• Microscopic polyangiitis
• 60 anti MPO
• 30 anti-PR3
• Churg-Strauss syndrome
• 30 anti MPO
• 30 anti-PR3

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Rheuma factor
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Differential diagnosis of increased ACE level
ACE Se 0,6-0,7 Sp 0,85 LR 4
- 4,67
Knockaert DC, Acta clin Belg 20076226
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Immunological tests and FUO

• ANA
• ANCA
• RF
• Complement and FUO
• SLE
• Bacterial endocarditis
• Hidden abscess
• Shunt nephritis
• Cryoglobulinemia
• Hypocomplementic uriticarial vasculitis
• Hereditary angio-oedema

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Role of genetic testing in FUO
Knockaert DC et al J Int Med 2003 253263
61
Familiale auto-inflammatoire aandoeningen
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Which lab tests to repeat during the
investigation of FUO?

• WBC differential count
• CRP
• CK
• Urinalysis (hematuria)
• ANCA
• Beware of repeated cultures

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(No Transcript)
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Therapeutic trials

• - symptomatic antipyretic therapy NSAID !,
  beware of hepatotoxicity
  particularly in case of Still disease
• - therapeutic trial only in case of clinical
  deterioration
• antibiotics - assess the effect of broad
  spectrum antibiotics and stop if no effect
  after 3 to 4 days ! - consider the use of
  tetracyclines (or macrolides)
• antituberculous agents clearly indicated
• corticosteroids - never (?) without
  antituberculous agents
• - do not start too early!

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Evolution of fever in surviving undiagnosed cases
with F.U.O (n49)

• Spontaneous resolution during or shortly after
  hospitalization
• n31
• Persisting or recurring fever (gt 3 months after
  discharge)
• n18
• cured 10
• 3 treated with corticosteroids
• unresolved illness 8
• treated with corticosteroids (n1)
• treated with NSAID (n6)
• refused reinvestigation and died (n1)