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Clinical markers in Infectious Diseases

Clinical markers in Infectious Diseases


Laboratory test data may be used in:
diagnosis of diseases
assessment of the seriousness of illness
determination of appropriateness of therapy
monitoring treatment outcomes.

White cell count and differential

White cell count and differential

White cell count and differential

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 often
helpful to assess marginal results as many significant clinical conditions will show
progressive abnormalities.

The differential refers to the proportion of the total leukocyte count contributed
by each elements

When using the WCC as an indicator of possible infection, both the total count and
those of individual components must be taken into consideration

Change in differential (with normal WCC) may be indicative of an infection

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.

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).

DRUG INDUCING NEUTROPHILIA


Chemotherapy
melphalan
busulfan
methotrexate
carboplatin
cisplatin

cis-diammine-dichloroplatinum
paclitaxel
doxorubicin
cyclophosphamide
etoposide
venorelbine

White cell count and differential


Classification of neutropenia

Neutrophil count

Mild

1.0 2.0 10 /L

Moderate

0.5 1.0 10 /L

Severe

< 0.5 10 /L

White cell count and differential


NEUTROPHILIA (HIGH NEUTROPHIL COUNT)
Neutrophils are the primary white blood cells that respond to a
bacterial infection. The most common cause of marked neutrophilia
is a bacterial infection.

Neutrophils generally exhibit characteristic changes in response to


infection. The neutrophils tend to be more immature, as they are
being released earlier left shift
Neutrophils will frequently be increased in any acute inflammation,
therefore will often be raised after a heart attack, or other infarct
and necrosis. Any stressor, from heavy exercise to cigarette
smoking, can elevate the neutrophil count.

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 a
prominence of myelocytes. Basophilia and/or eosinophilia may also
be present. Chronic mild neutrophilia without left shift is very
unlikely to be due to CML.

White cell count and differential


Lymphocytes
Lymphocytes normally represent 20 - 40% of circulating white
blood cells. The normal concentration of lymphocytes is
between 1.0 - 4.0 x 109/L.

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 in
HIV 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

White cell count and differential


LYMPHOCYTOSIS (HIGH LYMPHOCYTE COUNT)

Increases in the absolute lymphocyte count are usually due to acute


infections, such as Epstein-Barr virus infection and viral hepatitis.

Less commonly, increased lymphocytes may be the result of pertussis and


toxoplasmosis or (rarely) chronic intracellular bacterial infections such as
tuberculosis or brucellosis.

Chronic lymphocytic leukaemia (CLL) and other lymphoproliferative disorders


should be considered in patients with a persistent lymphocytosis.

Drugs: haloperidol, aspirin, griseofulvin, levodopa, niacinamide, phenytoin

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 then
typically 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

White cell count and differential


Monocytes
High/elevated Monocytes level (i.e. > 1.5 x 109/L) infection and
inflammatory processes (if seen in conjunction with other blood
count changes)

Isolated increases in the monocyte count, not accompanied by


other changes in the blood count, are uncommon but may be
associated with:
Chronic infection including tuberculosis
Chronic inflammatory conditions (e.g. Crohns disease, ulcerative
colitis, rheumatoid arthritis, SLE)
Dialysis
Early sign of chronic myelomonocytic leukaemia (rare)

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.

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.

ACUTE PHASE REACTANS


Inflammation is a protective reaction of vascular connective tissue
to damaging stimuli.
The inflammatory response is associated with vasodilatation,
increased vascular permeability, recruitment of inflammatory cells
(especially neutrophils in acute inflammation), and the release of
inflammatory mediators from these cells, including vasoactive
amines, prostanoids, reactive oxygen intermediates and cytokines.
Cytokines derived from macrophages and monocytes include
tumour necrosis factor alpha (TNF-a), interleukin-1 and interleukin6. These cytokines are primarily responsible for mediating the
'acute-phase response'. They cause a change in the production of
various plasma proteins by hepatocytes, including an increase in Creactive protein.

Acute-phase proteins

Protease inhibitors
Coagulation proteins

Complement proteins

Transport and storage


proteins

Miscellaneous

alpha1-antitrypsin
antichymotrypsin
fibrinogen
prothrombin
factor VIII
plasminogen
C1s, C2, C3, C4, C5
factor B
C1 esterase inhibitor
plasminogen
haptoglobin
haemopexin
caeruloplasmin
ferritin
C-reactive protein
procalcitonin
serum amyloid protein
fibronectin
alpha1-acid glycoprotein

transferrin

albumin
pre-albumin

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 (especially
to antibiotics).

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 proinflammatory platelet-activating factor and down-regulates polymorphs.

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.

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.

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 concentrations
are not affected by antipyretic drug therapy or thermoregulatory factors.

Conditions causing elevation of C-reactive protein


Major elevations
Bacterial infections

pyelonephritis
pelvic infections
meningitis
endocarditis

Hypersensitivity complications of infections

rheumatic fever
erythema nodosum

Inflammatory disease

rheumatoid arthritis
juvenile chronic arthritis
ankylosing spondylitis
psoriatic arthritis
systemic 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

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.

ACUTE PHASE REACTANS


Erythrocyte sedimentation rate

ACUTE PHASE REACTANS


Erythrocyte sedimentation rate
The sedimentation rate is often and significantly affected by many
factors other than the acute phase reaction. Known influences
include:
plasma albumin concentration
size, shape and number of red blood cells
non-acute phase reaction proteins, in particular normal and abnormal
immunoglobulins.

Raised erythrocyte sedimentation rates are observed in patients


without an acute phase reaction, for example when haematological
disorders including anaemia are present. Renal failure, obesity,
ageing and female sex are associated with higher erythrocyte
sedimentation rates. C-reactive protein results are also higher with
obesity but are not affected by renal failure.

ACUTE PHASE REACTANS


C-reactive protein versus erythrocyte sedimentation rate

The non-specificity of the erythrocyte sedimentation rate means the test is more
likely to be falsely positive (elevated in the absence of inflammation) than a Creactive protein test.

The erythrocyte sedimentation rates slow response to the acute phase reaction
leads to false negatives early in an inflammatory process.

Normalisation of an elevated erythrocyte sedimentation rate once an


immunoglobulin response has occurred may take weeks to months.

Compared to the erythrocyte sedimentation rate, C-reactive protein is a more


sensitive and specific marker of the acute phase reaction and is more responsive
to changes in the patients condition. There are only two circumstances where the
erythrocyte sedimentation rate is superior detecting low-grade bone and joint
infections, and monitoring disease activity in systemic lupus erythematosus.

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

IDENTIFICATION OF PATHOGEN

Microscopy
Culture
Serology
Specific Infection
UTI

URINE EXAMINATION

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 bacterial
infection at any site of urinary tracts.
Infection is usually confirmed with bacterial count and culture

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

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