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8/18/2019 Clinical Markers in Infectious Diseases
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Clinical markers in Infectious Diseases
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White cell count and differential
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White cell count and differential
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White cell count and differential
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White cell count and differential
White cell count (WCC) hitung leukosit
• Definition: – The total number of leukocytes present in the peripheral circulation
• All haematology results need to be interpreted in the context of a thorough history
and physical examination, as well as previous results. Follow-up counts are oftenhelpful to assess marginal results as many significant clinical conditions will showprogressive abnormalities.
• The differential refers to the proportion of the total leukocyte count contributedby each elements
• When using the WCC as an indicator of possible infection, both the total count andthose of individual components must be taken into consideration
• Change in differential (with normal WCC) may be indicative of an infection
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White cell count and differential
Neutrophils
• For most adults neutrophils account for approximately 70% of all white
blood cells. The normal concentration range of neutrophils is 2.0 - 8.0 x
109/L (range can be different for different labs).
• The average half-life of a non-activated neutrophil in the circulation is
about 4-10 hours. Upon migration, outside the circulation, neutrophils will
survive for 1-2 days.
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White cell count and differential
NEUTROPENIA (LOW NEUTROPHIL COUNT)
• Neutropenia is potentially associated with life threatening
infection.
• It is most significant when the total neutrophil count is less
than 0.5 x 109/L, particularly when the neutropenia is due to
impaired production (e.g. after chemotherapy).
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DRUG INDUCING NEUTROPHILIA
Chemotherapy
melphalan
busulfan
methotrexate
carboplatin
cisplatin
cis-diammine-dichloroplatinum
paclitaxel
doxorubicin
cyclophosphamide
etoposide
venorelbine
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White cell count and differential
Classification of neutropenia Neutrophil count
Mild 1.0 – 2.0 × 109
/L
Moderate 0.5 – 1.0 × 109/L
Severe < 0.5 × 109/L
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White cell count and differential
NEUTROPHILIA (HIGH NEUTROPHIL COUNT)
• Neutrophils are the primary white blood cells that respond to abacterial infection. The most common cause of marked neutrophiliais a bacterial infection.
• Neutrophils generally exhibit characteristic changes in response toinfection. The neutrophils tend to be more immature, as they arebeing released earlier left shift
• Neutrophils will frequently be increased in any acute inflammation,therefore will often be raised after a heart attack, or other infarctand necrosis. Any stressor, from heavy exercise to cigarettesmoking, can elevate the neutrophil count.
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White cell count and differential
NEUTROPHILIA (HIGH NEUTROPHIL COUNT)
• A number of drugs have been demonstrated to increase the
neutrophil count, including steroids, lithium, clozapine and
adrenalin.
• Persistent elevation of neutrophils may be a sign of chronic myeloid
leukaemia (CML). Characteristic changes are a moderate increase in
neutrophil count (usually >50 x 109
/L), with a left shift and aprominence of myelocytes. Basophilia and/or eosinophilia may also
be present. Chronic mild neutrophilia without left shift is very
unlikely to be due to CML.
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White cell count and differential
Lymphocytes
• Lymphocytes normally represent 20 - 40% of circulating white
blood cells. The normal concentration of lymphocytes isbetween 1.0 - 4.0 x 109/L.
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White cell count and differential
LYMPHOCYTOPENIA (LOW LYMPHOCYTE COUNT)
• Low lymphocyte counts are not usually significant.
• Characteristic decreases in the lymphocyte count are usually seen late inHIV infection, as T lymphocytes (CD4+ T cells) are destroyed.
• Steroid and lithium administration may reduce lymphocyte counts. More
rarely lymphocytopenia may be caused by some types of chemotherapy or
malignancies. People exposed to large doses of radiation
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White cell count and differential
LYMPHOCYTOSIS (HIGH LYMPHOCYTE COUNT)
• Increases in the absolute lymphocyte count are usually due to acuteinfections, such as Epstein-Barr virus infection and viral hepatitis.
•
Less commonly, increased lymphocytes may be the result of pertussis andtoxoplasmosis or (rarely) chronic intracellular bacterial infections such astuberculosis or brucellosis.
• Chronic lymphocytic leukaemia (CLL) and other lymphoproliferative disordersshould be considered in patients with a persistent lymphocytosis.
• Drugs: haloperidol, aspirin, griseofulvin, levodopa, niacinamide, phenytoin
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White cell count and differential
Monocytes
• Monocytes constitute between 3 - 8% of all white cells in the blood.
• They circulate in the bloodstream for about one to three days and thentypically move into tissues (approx 8 - 12 hours) to sites of infection.
• The normal concentration of monocytes is between 0 - 1.0 x 109/L.
• Monocytes which migrate from the bloodstream to other tissues are
called macrophages.
• Low Monocytes: Not clinically significant if other cell counts are normal
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White cell count and differential
Monocytes
• High/elevated Monocytes level (i.e. > 1.5 x 109/L) infection andinflammatory processes (if seen in conjunction with other bloodcount changes)
• Isolated increases in the monocyte count, not accompanied byother changes in the blood count, are uncommon but may beassociated with: – Chronic infection including tuberculosis
– Chronic inflammatory conditions (e.g. Crohn’s disease, ulcerativecolitis, rheumatoid arthritis, SLE)
– Dialysis
– Early sign of chronic myelomonocytic leukaemia (rare)
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White cell count and differential
Eosinophils
• Eosinophils make up about 1-6% of white blood cells. The
normal concentration of eosinophils is 0 - 0.5 x 109/L.
• Eosinophils persist in the circulation for 8 - 12 hours, and can
survive in tissue for an additional 8 - 12 days in the absence of
stimulation.
• A low eosinophil count is not a cause for concern.
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White cell count and differential
EOSINOPHILIA (HIGH EOSINOPHIL COUNT)
• In developed countries the most common causes are allergic
diseases such as asthma and hay fever, but worldwide the
main cause of increased eosinophils is parasitic infection.
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ACUTE PHASE REACTANS
• Inflammation is a protective reaction of vascular connective tissueto damaging stimuli.
• The inflammatory response is associated with vasodilatation,increased vascular permeability, recruitment of inflammatory cells
(especially neutrophils in acute inflammation), and the release ofinflammatory mediators from these cells, including vasoactiveamines, prostanoids, reactive oxygen intermediates and cytokines.
• Cytokines derived from macrophages and monocytes includetumour necrosis factor alpha (TNF-a), interleukin-1 and interleukin-6. These cytokines are primarily responsible for mediating the'acute-phase response'. They cause a change in the production ofvarious plasma proteins by hepatocytes, including an increase in C-reactive protein.
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Acute-phase proteins
Protease inhibitors alpha1-antitrypsin
antichymotrypsin
Coagulation proteins fibrinogen
prothrombin
factor VIII
plasminogen
Complement proteins C1s, C2, C3, C4, C5
factor BC1 esterase inhibitor
plasminogen
Transport and storage
proteins
haptoglobin
haemopexin
caeruloplasmin
ferritin
transferrin
Miscellaneous C-reactive protein
procalcitonin
serum amyloid protein
fibronectin
alpha1-acid glycoprotein
albumin
pre-albumin
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ACUTE PHASE REACTANS
C-reactive protein
• An elevated concentration of C-reactive protein in the blood is
an indicator of inflammation.
• The bulk of C-reactive protein tests are requested for the
detection of inflammatory responses associated with
microbes, autoimmune diseases and drug allergies (especiallyto antibiotics).
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ACUTE PHASE REACTANS
C-reactive protein
• C-reactive protein plays a key role in the host's defence against infection.
• C-reactive protein reacts with the C-polysaccharide of Streptococcus pneumoniae.
• Protein binding activates the classical complement pathway and opsonises
(prepares) ligands for phagocytosis. It also neutralises the pro-
inflammatory platelet-activating factor and down-regulates polymorphs.
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ACUTE PHASE REACTANS
C-reactive protein
• The median normal concentration of C-reactive protein is 0.8 mg/L, with
90% of apparently healthy individuals having a value less than 3 mg/L and
99% less than 12 mg/L.
• There is often no clear correlation between C-reactive protein
concentrations and disease severity.
• C-reactive protein has a doubling time and a decay time of around six
hours, and maximal concentrations are reached in less than two days.
After the inflammation has resolved, concentrations fall rapidly. Once
inflammation and its cause have been identified and treatment is started,
there is usually no need for further C-reactive protein measurements.
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ACUTE PHASE REACTANS
C-reactive protein
Clinical Utility
• Monitoring the extent and activity of disease
– In inflammatory conditions, C-reactive protein may be used to monitor the
patient's response to therapy.
• Screening for infection
– As an adjunct to clinical assessment, a C-reactive protein test may be useful in
differentiating between bacterial and viral infections.
– A very high C-reactive protein (greater than 100 mg/L) is more likely to occur
in bacterial rather than viral infection,
– A normal C-reactive protein is unlikely in the presence of significant bacterial
infection. However, intermediate C-reactive protein concentrations (10-50
mg/L) may be seen in both bacterial and viral conditions.
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ACUTE PHASE REACTANS
C-reactive protein
Clinical Utility
• Detection and management of inter current infection
– The possibility of inter current infection must always be kept in mind,especially when immunosuppressants are being administered.
– Bacterial infections usefully monitored by C-reactive protein concentrations
include pyelonephritis, pelvic infections, meningitis and endocarditis.
– Serial C-reactive protein measurements are important adjuncts to the use of
temperature charts in clinical practice, as C-reactive protein concentrationsare not affected by antipyretic drug therapy or thermoregulatory factors.
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Conditions causing elevation of C-reactive protein
Major elevations
Bacterial infections pyelonephritis
pelvic infections
meningitisendocarditis
Hypersensitivity complications of infections rheumatic fever
erythema nodosum
Inflammatory disease rheumatoid arthritis
juvenile chronic arthritis
ankylosing spondylitis
psoriatic arthritissystemic vasculitis
polymyalgia rheumatica
Reiter's disease
Crohn's disease
familial Mediterranean fever
Transplantation renal transplantation
Cancer lymphoma
sarcoma
Necrosis myocardial infarction
tumour embolisation
acute pancreatitis
Trauma burns
fractures
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ACUTE PHASE REACTANS
Erythrocyte sedimentation rate
• The erythrocyte sedimentation rate is a surrogate marker of the acute
phase reaction.
• During an inflammatory reaction, the sedimentation rate is affected by
increasing concentrations of fibrinogen, the main clotting protein, and
alpha globulins. The test mainly measures the plasma viscosity by
assessing the tendency for red blood cells to aggregate and ‘fall’ through
the variably viscous plasma.
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ACUTE PHASE REACTANS
• Erythrocyte sedimentation rate
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ACUTE PHASE REACTANS
Erythrocyte sedimentation rate
• The sedimentation rate is often and significantly affected by manyfactors other than the acute phase reaction. Known influencesinclude: – plasma albumin concentration
– size, shape and number of red blood cells
– non-acute phase reaction proteins, in particular normal and abnormalimmunoglobulins.
• Raised erythrocyte sedimentation rates are observed in patients
without an acute phase reaction, for example when haematologicaldisorders including anaemia are present. Renal failure, obesity,ageing and female sex are associated with higher erythrocytesedimentation rates. C-reactive protein results are also higher withobesity but are not affected by renal failure.
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ACUTE PHASE REACTANS
C-reactive protein versus erythrocyte sedimentation rate
• The non-specificity of the erythrocyte sedimentation rate means the test is morelikely to be falsely positive (elevated in the absence of inflammation) than a C-reactive protein test.
• The erythrocyte sedimentation rate’s slow response to the acute phase reactionleads to false negatives early in an inflammatory process.
• Normalisation of an elevated erythrocyte sedimentation rate once animmunoglobulin response has occurred may take weeks to months.
•
Compared to the erythrocyte sedimentation rate, C-reactive protein is a moresensitive and specific marker of the acute phase reaction and is more responsiveto changes in the patient’s condition. There are only two circumstances where theerythrocyte sedimentation rate is superior – detecting low-grade bone and jointinfections, and monitoring disease activity in systemic lupus erythematosus.
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ACUTE PHASE REACTANS
Serum complement
• Complement C3 0.8 – 1.8 g/L
• Complement C4 0.2 – 0.4 g/L
• The complemet system plays an important role in promoting
bacterial cell lysis and removal of immune complexes
• Serum complement conc. Esp C3, are often reduced in serious
infection due to consumption in the host defence processes
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IDENTIFICATION OF PATHOGEN
• Microscopy
• Culture
• Serology
• Specific Infection
• UTI
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URINE EXAMINATION
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URINE EXAMINATION
Bacterial count• Infection is highly likely if bacterial count > 105 CFU/mL
• Bacterial count < 102 CFU/mL is unlikely to be associated with infection
• Bacterial count 102 - 105 CFU/mL: consider symptoms, age, sex
Culture• Mixed growth usually indicated contaminated sample
• Growth single organism in a pure culture indicates infection
White cells
•
Pyuria (> 10 white cells/uL) is commonly associated with bacterialinfection at any site of urinary tracts.
• Infection is usually confirmed with bacterial count and culture
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URINE EXAMINATION
Hematuria• The presence of RBC or Hb in urine
• Normal < 6 RBC/uL
• If > 500 RBC/ul: visible, frank hematuria
Proteins
• 1+ protein (300 mg/L) indicates infection
Cast
•
White cell and red cell cast indicate renal disesase
Glucose