clinical markers in infectious diseases

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 (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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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• Erythrocyte sedimentation rate


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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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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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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

clinical markers in infectious diseases

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