serological diagnosis of syphilis
DESCRIPTION
Serological diagnosis of syphilisTRANSCRIPT
Dr.T.V.Rao MD
Dr.T.V.Rao MD 1
Syphilis
"He who knows syphilis, knows
medicine"
Sir William Osler Dr.T.V.Rao MD 2
Syphilis was a Taboo
Poster for testing of syphilis, showing a man and a woman bowing their heads in shame (ca. 1936).
Dr.T.V.Rao MD 3
SYPHILIS
INTRODUCTIONCaused by Treponema pallidum.Transmission: sexual; maternal-fetal, and rarely
by other means. Primary and secondary syphilis in the US dropped
by ~ 90 %t from 1990 to 2000, the number of cases have gone up since then.
A dramatic increase in cases in men from 2000 to 2002 reflected syphilis in MSM.
Syphilis increases the risk of both transmitting and getting infected with HIV. Perform HIV testing in all patients with syphilis.
Dr.T.V.Rao MD 4
Introduction to Syphilis
Syphilis is one of a group of diseases caused by spirochete organisms of the genus Treponema. Sexually acquired syphilis occurs worldwide and is caused by T. pallidum subspecies pallidum.
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Other Related to Treponemes
Related Treponemes cause the non-venereal treponematosesbejel, or endemic syphilis (T. pallidum endemicum), yaws (T. pallidum pertenue), and pinta (T. carateum).
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STAGES OF SYPHILIS
1. Primary
2. Secondary
3. Latent Early latent
Late latent
4. Late or tertiary May involve any organ, but main parts are:
Neurosyphilis
Cardiovascular syphilis
Late benign (gumma)
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The nontreponemal tests, VDRL and rapid plasma reagent (RPR),
are antilipoidal antibodies seen in other disease states, pregnancy, and occasionally after vaccination. They are nonspecific and cannot rule in disease. These tests have sensitivities approaching 80% in patients with symptomatic primary syphilis and virtually 100% in patients with secondary syphilis.
– A positive VDRL/RPR should be quantified and titers followed at regular intervals after treatment. As such, its value is in response to treatment. However, it does not correlate with symptom resolution.
– Most patients have nonreactive nontreponemal tests within several years after successful treatment for syphilis, but a significant number have persistently positive tests, the so-called serofast reaction. Dr.T.V.Rao MD 8
Diagnosis of Syphilis
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Laboratory Diagnosis
Identification of Treponema pallidum in lesionsDarkfield microscopy
Direct fluorescent antibody - T. pallidum(DFA-TP)
Serologic testsNontreponemal tests
Treponemal tests
Diagnosis
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Nontreponemal Serologic Tests (continued)
Advantages: Rapid and inexpensive
Easy to perform and can be done in clinic or office
Quantitative
Used to follow response to therapy
Can be used to evaluate possible reinfection
Disadvantages:May be insensitive
in certain stagesFalse-positive
reactions may occur
Prozone effect may cause a false-negative reaction (rare)
Diagnosis
Patients with a reactive VDRL or RPR should have the
result confirmed by specific treponemal testing. FTA-ABS and or EIA.
• Tertiary syphilis Serology is used in the diagnosis. Evaluation of neurosyphilis requires a lumbar puncture (LP) and evaluation of the CSF.
– The CDC currently recommends LP only if the patient is seroreactive and HIV positive, has symptoms of neurosyphilis
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Diagnosis
Syphilis may be confirmed either via blood tests or direct
visualization using microscopy. Typical diagnosis is with blood tests using nontreponemal and/or treponemal tests. Nontreponemal test are used initially and include venereal
disease research laboratory (VDRL) and rapid plasma regain however as these test occasionally are falsely positive
confirmation is required with a treponemal test such as treponemal pallidum particle agglutination (TPHA) or fluorescent treponemal antibody absorption test (FTA-Abs)
Tests to Confirm
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VDRL - Background
The Venereal Disease Research Laboratory (VDRL) test is one of two variations of flocculation procedures used for serological testing of syphilis, the other being the Rapid Plasma Reagin (RPR). Flocculation testing is based on antibody detection with the interaction of soluble antigen with an antibody that results in a precipitate formation of fine particles.
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VDRL Test Basics
The VDRL is a confirmatory serological micro flocculation slide test used for the detection of syphilis antibodies. In a VDRL procedure, the patient’s serum is heat-inactivated and mixed with a buffered saline suspension of VDRL Antigen containing cardiolipin, lecithin and cholesterol that binds with Reagin, an antibody-like protein. A combination of Reagin and VDRL Antigen form microscopic clumping called flocculation.
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VDRL – A Standard Test for Syphilis
The VDRL can be used for qualitative and quantitative measurements and is recommended when a patient suspected of having syphilis has a negative dark field microscopy result or when atypical lesions are present.
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VDRL Serological Procedure Principles
VDRL Antigen is a nontreponemal antigen composed of cardiolipin cholesterol and lecithin. The nontreponemal tests measures anti-lipid antibodies, which are formed by the host in response to lipids released from damaged host cells early in infection with T. pallidum, and lipid-like material form the treponemal cell surface. During syphilis infection, an antibody-like substance called reagin can be detected in the patient’s serum or CSF.
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Preparation of Antigen
Prepare a fresh antigen suspension each testing day. Once prepared, it should be used within 8 hours.
Store prepared suspension at 23-29)C.
Test antigen suspension reactivity with control sera (Reactive, Weakly reactive and Nonreactive). Test serum dilutions within 1 hour after heat inactivation.
Use antigen suspension only if it produces the expected reactivity with the control sera comparable to results obtained with the reference antigen.
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Required MaterialsVDRL Antigen with buffered saline solution
containing 1% sodium chloride, pH 6.0+/-0.1 with 0.05% formaldehyde preservative
Reactive, weakly reactive and nonreactive serum
0.9% saline, non-disposable 1cc glass syringe and calibrated needles without bevel-18 gauge(serum) or 21-22 gauge(CSF), slide cards(serum) or concavity slides(CSF)
Stirrers
RotatorDr.T.V.Rao MD 19
Specimen Collection and Preparation for Serum
Collect 5-8 ml of blood by aseptic venipuncture in a red top tube.
Allow blood to clot at room temperature then centrifuge to obtain serum.
Heat the test sera at 560C for 30 minutes. Specimen must be at 23-290C when tested. Specimen must be clear of hemolysis and show no
visible evidence of bacteria contamination. Store at room temperature for 4 hours, after which
store at 2-80C, maybe refrigerated up to 5 days, then frozen at <-200C.
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Specimen Collection and Preparation for CSF
Centrifuge and decant the specimen
Specimens do not require heat inactivation before testing.
Spinal fluids that are visibly contaminated or that contain gross blood are unsatisfactory
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Antigen Suspension Preparation
Pipette 0.4ml of VDRL buffered saline to the bottom of a round 30 ml glass stoppered bottle with a flat inner-bottom surface. Gently tilt bottle so that VDRL buffered saline will cover the entire inner-bottom surface of the bottle.
Add 0.5 ml of VDRL Antigen directly into the saline while continuously but gently rotating the bottle on a flat surface from the lower half of a 1.0 ml pipette graduated cylinder to the tip. Add antigen drop by drop at a rate that allows about 6 sec for 0.5 ml of antigen. Keep pipette tip in the upper third of the bottle and do not splash saline unto the pipette.
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Antigen Suspension Preparation
Expel the last drop of antigen without touching pipette to the saline and continue rotation of the bottle for 10 sec.
Add 4.1 ml of buffered saline from a 5 ml pipette. Do not drop saline directly on antigen; allow it to flow down the side of the bottle.
Cap the bottle and mix by gentle inversion. Allow to stand for 5 minutes but no more than 2 hours. The suspension is ready for use.
Remix suspension by swirling only
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Antigen Suspension
Cap the bottle and mix by gentle inversion. Allow to stand for 5 minutes but no more than 2 hours. The suspension is ready for use.
Remix suspension by swirling only
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Procedure: Step 1Wells should be labeled as reactive ®, weakly reactive (WR), and nonreactive (NR),
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Procedure: Step 3
Add one drop (.01 ml) of sensitized antigen suspension to each specimen with a 21 or 22 gauge needle.
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Procedure: Step 4
Rotate slides for 8 minutes on a mechanical rotator at 180 rpm. Note: when the tests are performed in a dry climate, the slides may be covered with a box lid to prevent evaporation.
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Results for Serum Specimen
Qualitative Testing -Medium to large clumps (Reactive); Small clumps (Weakly Reactive); No clumping or very slight roughness (Nonreactive).
Verify control sera results for expectation. If reactions are not as expected, the test is invalid and results can not be reported.
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Reporting the Results
Perform a quantitative test to endpoint on all serum samples that produce reactive, weakly reactive or “rough” nonreactive results in the qualitative slide test.
Quantitative Testing -Report the titer as the highest dilution that produces a Reactive (not weakly reactive) results
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Diagnosis of CNS Infection with Syphilis
No test can be used alone to diagnose neurosyphilis.
VDRL-CSF: highly specific but insensitive
Diagnosis usually depends on the following factors: Reactive serologic test results, Abnormalities of CSF cell count or protein, or A reactive VDRL-CSF with or without clinical manifestations.
CSF leukocyte count usually is elevated (>5 WBCs/mm3) in patients with Neurosyphilis.
The VDRL-CSF is the standard serologic test for CSF, and when reactive in the absence of contamination of the CSF with blood, it is considered diagnostic of Neurosyphilis.
Diagnosis
Specimen Collection and Preparation for CSF
Centrifuge and decant the specimen
Specimens do not require heat inactivation before testing.
Spinal fluids that are visibly contaminated or that contain gross blood are unsatisfactory Dr.T.V.Rao MD 32
Testing CSF Samples Quantitative tests are run on all spinal fluids found to be reactive in the qualitative test. Prepare fluid as follows:
A. Pipette 0.2 ml of 0.9% saline into each of 5 or more tubes.
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Testing of CSF Samples
Add 0.2ml of unheated spinal fluid to tube 1, mix well and transfer 0.2 ml to tube 2 .
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Testing of CSF Samples
Continue mixing and transferring 0.2 ml from one tube to the next until the last tube is reached. The respective dilutions are 1:2, 1:4, 1:8, 1:16.
Etc.,
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Reporting CSF Samples
2. Test each spinal fluid dilution and undiluted spinal fluid as described under “VDRL slide qualitative on spinal fluid.”
3. Report results in terms of the greatest spinal fluid dilution (dils) that produces a reactive result.
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All Positive Samples tested by Quantitative Method
In Quantitative Testing - Report the titer in terms of the highest dilution that produces a reactive (not weakly reactive) result.
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Quantitative Testing and Reporting
In Quantitative Testing - Report the titer in terms of the highest dilution that produces a reactive (not weakly reactive) result.
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Interpretation
Nonreactive VDRL - with clinical evidence may indicate early primary syphilis, a prozone reaction in secondary or late syphilis.
Nonreactive VDRL - with no clinical evidence may indicate no current infection or an effectively treated infection.
Quantitative VDRL - detects changes in reagin titer. Serum samples displaying a fourfold increase in titer on a repeated sample may indicate an infection, reinfection or treatment failure. A fourfold decrease during treatment indicates adequate therapy.
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Sources of Error
False positive reactions - occur in 10% to 30% of positive serological tests for syphilis and consist of nonsyphilitic positive VDRL. reactions with cardiolipin type antigens.
False negative reactions - consist of conditions and a variety of situations.
Weakly reactive - caused by very early infection, lessening of the activity of the disease after treatment and improper technique or questionable reagents.
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False Positive ReactionsLupus
erythematosus
Rheumatic fever
Vaccinia and virus pneumonia
Pneumococcal pneumonia
Infectious mononucleosis
Infectious hepatitis
Leprosy
Malaria
Rheumatoid arthritis
Pregnancy
Aging individualsDr.T.V.Rao MD 41
False Negative Reactions
Technical error -unsatisfactory antigen or technique.
Low antibody titers
Presence of inhibitors in the patient’s serum
Reduced ambient temperature (below 230
to 290)
Prozone reaction
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The RPR test is a nontreponemal testing procedure for the serologic detection of
syphilis.
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Principle of RPR Test The RPR Card antigen
suspension is a carbon particle cardiolipin antigen that detects reagin.
Reagin is an antibody like substance present in serum or plasma from individuals with syphilis.
The reagin binds to the test antigen which consists of cardiolipin-lecithin coatedparticles that cause macroscopic flocculation.
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Principle of RPRWhen a specimen such
as serum or plasma contains antibody, flocculation occurs with the resulting aggregation of the carbon particles.
The flocculation appears as black clumps against the white background of the plastic coated card.
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Principle of RPR Antibodies associated
with syphilis begin to appear in the blood 4 to 6 weeks after infection. Nontreponemal tests determine the presence of reagin. Reagin is a nontreponemal autoantibody directed against cardiolipin antigens.
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Materials for RPR
RPR Test Cards
RPR Control Cards
RPR Antigen
Distilled Water
Dispenstirs
Rotator Dr.T.V.Rao MD 47
RPR Test Background The RPR test uses a
white plastic coated card that consist of several circles that are 18 mm in diameter.
The controls which are strongly reactive, moderately reactive, and non-reactive are contained on the control card in a dried form.
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Specimen Collection
Unheated Plasma -specimen should be collected with an anticoagulant such as EDTA or heparin, plasma must be stored at 2 C to 8 C. Plasma must be tested within in 24 hrs. of collection
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Specimen Processing
*The addition of choline chloride, which inactivates complement enables the serum to be tested without prior heating.
Unheated serum-centrifuge for sedimentation of cellular elements, serum may be frozen until time of testing.
Heated Serum- transfer serum to clean tube and place in 56 C water bath for 30 minutes
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Prepare the Card Label rings on test card
with numbers of samples to be tested
Use Dispenstir to draw up serum sample.
Hold Dispenstir in a perpendicular position directly over the test circle to which the specimen is to be delivered.
Squeeze Dispenstir to allow 1 drop to fall on to each circle
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Performing the Test Invert Dispenstir,and
using the sealed end spread the specimen in the confines of the circle.
Reconstitute the antigen bottle, by shaking. Holding the bottle in a straight vertical position drop one or two drops in the upper corner of each test circle, then place one “free falling” drop on each test area.
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Rotate card at Regulated Speed
Rotate card for 8 minutes on a mechanical rotator at 100 rpm. The test card she also be covered with a humidifier cover.
After rotating mechanically, the test card should be rotated manually by hand 3 to four rotations and then read immediately macroscopically in the “wet” state under a high intensity lamp.
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Procedure for Controls A. Use Dispensator to draw
up distilled water
B. Drop 1 drop on the card test circle for each patient sample.
C. Invert Dispensator and spread the water in the circle until the dried control is completely reconstituted.
D. Add antigen as described for the patients
E. Rotate for 8 minutes at
100 rpm
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Reactions of ControlsThe following reactions
should be observed to compare against the test results:
Reactive control -characteristic strong clumping.
Reactive moderate control - moderate clumping.
Non-reactive control -smooth, grayish appearance of unclumped particles
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Observe for Reactivity
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A non reactive RPR sample
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Repeat all Positive Samples after Dilutions
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Explanation of Results
A negative RPR test may indicate one of the following:
1. The patient does not have syphilis.
2. The infection is too recent for antibodies to be produced. (Repeated tests should be administered at 1 week, 1 month, and 3 month intervals to establish presence or absence of disease).
3. The syphilis is latent or inactive
4. Faulty immunodefense mechanism
5. Faulty lab techniques
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Explanation of Results
A positive reaction is not conclusive for syphilis. Several conditions produce biologic false positive results for syphilis. (False positive means that the test revealed a positive reaction when it was actually negative).
False positives may reveal the presence of other serious diseases.
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Nontreponemal positive Tests Need Confirmation
Nontreponemal antigen tests are not entirely specific for syphilis and do not have satisfactory sensitivity in all stages of syphilis. Whenever the results of a nontreponemal antigen test disagree with the clinical impression, a treponemal antigen test such as the FTA-ABS should be performed.
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Non-syphilitic Conditions Giving Biologic False-Positive Results
Malaria
Leprosy
Relapsing fever
Infectious Mononucleosis
Atypical pneumonia
Viral pneumonia
Lupus erythematous
Measles
pregnancy
drug abuse
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Resolving False Positive RPR Tests
False positive RPR tests may be resolved by testing the patient’s serum with a specific treponemal antigen tests.
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Treponemal tests are used to confirm
reactive non –treponemal procedures.
TPHA testing is now routinely done
A positive FTA-ABS test almost always remains positive and therefore is not recommended for monitoring therapy.
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Confirmatory Tests for Syphilis
TREPONEMAL TESTS
FTA-ABS Used as a confirmatory tests. Sensitivity and specificity high.
85% of patients with primary syphilis are reactive 99% with secondary syphilis > 95% with late syphilis (It may be the only test with a positive result for
patients with cardiovascular or neurologic syphilis).
Remains reactive for life in most, despite adequate therapy. Only 15-25 % of those treated for primary syphilis may turn negative by 2-3 yrs.
False positive in other treponemal diseases (pinta, yaws..) and other spirochete diseases (Lyme, leptospirosis…)
MHA-TP test (microhemagglutination assay for T. pallidum; agglutination of RBCs to which T. pallidum antigens have been fixed is the basis).
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TPHA and FTA-ABS Testing are commonly used Confirmatory Tests
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For Routine Testing a Combination of VDRL or RPR and TPHA is highly preferred
TPHA Test is a sensitive passive haemagglutination test, that detects specific Treponema pallidumantibodies in serum within one hour. Used in combination, the VDRL or RPR and TPHA Tests provide accurate and reliable confirmation of active syphilis infection. No specialized equipment is required and results are clearly visible and easily interpreted.
The MHA-TP was the earlier iteration of the TPHA. Occasionally, these tests are simply referred to as an indirect hemagglutination assay (IHA). The hemagglutination tests generally are simpler to perform than the fluorescent antibody tests and lend themselves to automation. The MHA-TP and TPHA tests are very rarely used currently. Both tests are quickly being replaced by newer and easier TP-PA and EIA-based tests (see below), including lateral flow strip test
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Microhemagglutination assay (MHA-TP)and TPHA (T. pallidum hemagglutination assay)
The MHA-TP and TPHA are used to confirm a syphilis infection after another method tests positive for the syphilis bacteria. The MHA-TP and TPHA tests detect antibodies to the bacteria that cause syphilis and can be used to detect syphilis in all stages, except during the first 3 to 4 weeks when antibody levels are too low. These tests are also suitable for use as a screening procedure. Neither of these tests is suitable for use on cerebrospinal fluid (CSF).
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Microhemagglutination assay
TPHA (Treponema Pallidum
Hemagglutination) is an indirect hemagglutination assay carried out on micro plates for the qualitative and semi-qualitative detection of anti- Treponema pallidum specific antibodies in human serum. Avian blood cells stabilized and sensitized with a solution of T. pallidum antigen agglutinate in the presence of anti-T Pallidum antibodies, exhibiting a typical agglutination pattern.
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Principles of TPHA Test
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Reading TPHA Results
The upper, left-hand well contains a positive control test. The red cells have had treponemal antigens attached and antibodies in the serum have caused these cells to agglutinate and form a mat across the bottom of the well. These antibodies can be presumed to be specific for Treponemes, since otherwise identical red cells that have not had the treponemal antigens attached do not cause haemagglutination, as seen in the bottom, left-hand well. A negative serum test is shown in the center and a patient's test is on the right. This result supports a diagnosis of syphilis.
Enzyme immunoassay (EIA), also known as an enzyme
linked immunosorbent assay (ELISA), for syphilis is a relatively new invention first appearing on the market in the mid-1990s. There are numerous benefits to the EIA platform over earlier technologies. Firstly, the majority of diseases that are considered to be of clinical and public health importance already exist in an EIA format, which is highly standardized even across international boundaries. This familiarity allows new EIAs to be readily accepted by clinicians and technicians with minimal difficulty. It also limits the need to purchase new capital equipment since most labs will already be equipped to handle EIAs.
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EIA tests for Syphilis
EIA tests Syphilis Gaining Importance
There have been several developments in particularly the advent of enzyme immunoassays(EIAs) and, lately, the commercial availability of recombinant antigen-based tests Dr.T.V.Rao MD 74
The FTA-abs test detects antibodies to T.
pallidum and can be used to detect syphilis infection at any stage except during the first 3 to 4 weeks after exposure (which is about the same time frame that the VDRL/RPR tests become effective) and in tertiary stages of the disease. In the secondary stage of syphilis, the FTA-abs test is most reliable and is reportedly positive in 100 percent of cases. It can be adapted to detect either IgG or IgM antibody. Dr.T.V.Rao MD 75
Fluorescent Treponemal Antibody Absorption (FTA-abs)
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Gold Standard Confirmatory test
The FTA-abs is still generally regarded as the ‘gold standard’, but it has a number of limitations. It is a subjective test and difficult to standardize. It is sensitive, but the TPHA is more sensitive, except in the third and fourth weeks of infection; the TPHA is also more specific2.
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Sensitivity of Serological Tests in
Untreated SyphilisStage of Disease (Percent Positive [Range])
Test Primary Secondary Latent Tertiary
VDRL 78 (74-87) 100 95 (88-100) 71 (37-94)
RPR 86 (77-99) 100 98 (95-100) 73
FTA-ABS* 84 (70-100) 100 100 96
Treponemal
Agglutination*76 (69-90) 100 97 (97-100) 94
EIA 93 100 100
*FTA-ABS and TP-PA are generally considered equally sensitive in the primary stage of disease.
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Causes of False-Positive Reactions in Serologic Tests for Syphilis
Disease RPR/VDRL FTA-ABS TP-PA
Age Yes
Autoimmune Diseases Yes Yes
Cardiovascular Disease Yes Yes
Dermatologic Diseases Yes Yes --
Drug Abuse Yes Yes
Febrile Illness Yes
Glucosamine/chondroitin sulfate Possibly
Leprosy Yes No --
Lyme disease Yes
Malaria Yes No
Pinta, Yaws Yes Yes Yes
Pregnancy Yes*
Recent Immunizations Yes -- --
STD other than Syphilis Yes
Source: Syphilis Reference Guide, CDC/National Center for Infectious Diseases, 2002
*May cause increase in titer in women previously successfully treated for syphilis
Diagnosis
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AIDS and Syphilis
The Serological Tests in AIDS and HIV related infections should be interpreted with caution and expertise, need a better understanding of the progress of the Disease.
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Nontreponemal Serologic TestsPrinciples
Measure antibody directed against a cardiolipin-lecithin-
cholesterol antigen
Not specific for T. pallidum
Titers usually correlate with disease activity and results
are reported quantitatively
May be reactive for life
Nontreponemal tests include VDRL, RPR,
TRUST,
Thomas B. Wiggers, Associate Professor Clinical Laboratory Sciences, UMMC
Additional photos:www.Kumc.EDU
Center for disease control (1999). Guidelines for evaluation and acceptance of new syphilis serology tests for routine use. US department of health, education and welfare publication, Atlanta.
Wasley G.D. (1988). Syphilis serology. Oxford press, New York.
Abbot laboratories, Abbott Park, IL 60064.
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References
Created / Designed by Dr.T.V.Rao MD for ‘e’ Learning Resources for
Medical and Paramedical Students in the Developing World
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