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Syphilis• Named from poempublished by theItalian physicianand poet GirolamoFracastoro –shepherd fromHispaniola namedSyphilis whoangered Apollo andwas given thedisease aspunishment Dr.T.V.Rao MD 2
Syphilis"He who knowssyphilis, knowsmedicine"Sir William OslerDr.T.V.Rao MD 3
Treponema pallidum• Described in1905 bySchaudinn andHoffman,HamburgDr.T.V.Rao MD 4
SYPHILISINTRODUCTION• Caused byTreponema pallidum.• Transmission:sexual;maternal-fetal,bloodtransfusion andrarely by othermeans of bothtransmitting andgetting infected withHIV. Dr.T.V.Rao MD 5
Introduction to Spirochetes• Long, slender, helically tightly coiledbacteria• Gram-negative• Aerobic, microaerophilic or anaerobic .• Corkscrew motility• Can be free living or parasitic• Best-known are those which causedisease: Syphilis and Lyme’s diseaseDr.T.V.Rao MD 6
Other Related to Treponemes• Related Treponemescause the non-venerealtreponematosesbejel, or endemicsyphilis (T. pallidumendemicum), yaws(T. pallidumpertenue), and pinta(T. carateum).Dr.T.V.Rao MD 9
Treponema pallidum.• Spiral spirochete thatis mobile of spiralsvaries from 4 to 14Length 5 to 20microns and very thin0.1 to o.5 microns.Can be seen on freshprimary or secondarylesions by darkfieldmicroscopy orfluorescent antibodytechniquesDr.T.V.Rao MD 10
Morphology• Have axial filaments, which are otherwisesimilar to bacterial flagella• Filaments enable movement of bacterium byrotating in placeDr.T.V.Rao MD 11
Special Staining MethodsFontana’s Method• Levadati’s methodDr.T.V.Rao MD 12
TREPONEMA PALLIDUM SSP.PALLIDUM (T. PALLIDUM)• T. pallidum, the causative agent ofsyphilis, was first isolated fromsyphilitic lesions in 1905. Infection isusually acquired by sexual contactwith infected individuals and iscommonest in the most sexuallyactive age group of 15-30-year-olds.Dr.T.V.Rao MD 13
Congenital Syphilis• Congenital syphilisusually occurs followingvertical transmission ofT. pallidum from theinfected mother to thefetus in utero, butneonates may also beinfected during passagethrough the infectedbirth canal at delivery.Dr.T.V.Rao MD 14
Structure of Spirochetes• Spirochetes are slender unicellular helicalor spiral rods with a number ofdistinctive ultra structural features usedin the differentiation of the genera Thecytoplasm is surrounded by acytoplasmic membrane, and apeptidoglycan layer contributes to cellrigidity and shape.Dr.T.V.Rao MD 15
Structure of Spirochetes• Several flagella areattached at each pole ofthe cell and wraparound the bacterial cellbody. In contrast toother motile bacteria,these flagella do notprotrude into thesurrounding mediumbut are enclosed withinthe bacterial outermembrane.Dr.T.V.Rao MD 16
Treponema cannot be cultivated inCulture Media• The inability to growmost pathogenicTreponemes in vitro,coupled with thetransitory nature ofmany of the lesions,makes diagnosis ofTreponemal infectionimpossible by routinebacteriological methodsDr.T.V.Rao MD 17
Cultivation of .. ?• Although the Treponemesare distantly related toGram-negative bacteria,they do not stain byGrams method, andmodified stainingprocedures are used.Moreover, the pathogenicTreponemes cannot becultivated in laboratorymedia and aremaintained by subculturein susceptible animals.Dr.T.V.Rao MD 18
Pathology• Penetration:– T. pallidum enters the body via skin and mucousmembranes through abrasions during sexualcontact– Also transmitted transplacentally• Dissemination:– Travels via the lymphatic system to regional lymphnodes and then throughout the body via theblood stream– Invasion of the CNS can occur during any stage ofsyphilisDr.T.V.Rao MD 19
Pathology• The bacteria rapidly enter thelymphatics, are widely disseminatedvia the bloodstream and may lodgein any organ. The exact infectiousdose for man is not known, but inexperimental animals fewer than tenorganisms are sufficient to initiateinfection. Dr.T.V.Rao MD 20
Chancre• The bacteria multiplyat the initial entrysite forming achancre, a lesioncharacteristic ofprimary syphilis,after an averageincubation period of3 weeksDr.T.V.Rao MD 21
Basic lesion of syphilis• The chancre ispainless and mostfrequently on theexternal genitalia,but it may occuron the cervix,perianal area, inthe mouth or analcanal. Dr.T.V.Rao MD 22
Chancre• The chancre usually heals spontaneouslywithin 3-6 weeks, and 2-12 weeks laterthe symptoms of secondary syphilisdevelop. These are highly variable andwidespread but most commonly involvethe skin where macular or pustularlesions develop, particularly on thetrunk and extremities. The lesions ofsecondary syphilis are highly infectious.Dr.T.V.Rao MD 23
Progress of Disease• Relapse of the lesions of secondarysyphilis is common, and latent syphilis isclassified as early (high likelihood ofrelapse) or late (recurrence unlikely).Individuals with late latent syphilis arenot generally considered infectious, butmay still transmit infection to the fetusduring pregnancy and their blood mayremain infectious.Dr.T.V.Rao MD 24
Pathology• The chancre is painlessand most frequently onthe external genitalia,but it may occur on thecervix, peri-anal area, inthe mouth or analcanal. Chancres usuallyoccur singly, but inimmunocompromisedindividuals,Dr.T.V.Rao MD 25
What is Syphilis• Syphilis is a systemic, sexually transmitteddisease (STD) caused by the Treponemapallidum bacterium. The three means ofsyphilis transmission are:• Person to person via vaginal, anal, or oral sexthrough direct contact with a syphilischancre.• Person to person during foreplay, even whenthere is no penetrative sex (much lesscommon).• Pregnant mother with syphilis to fetus.Dr.T.V.Rao MD 26
STAGES OF SYPHILIS1. Primary2. Secondary3. Latent• Early latent• Late latent4. Late or tertiary• May involve any organ, but main parts are:– Neurosyphilis– Cardiovascular syphilis– Late benign (gumma)Dr.T.V.Rao MD 28
Stages of syphilis• Untreated syphilis maybe a progressive diseasewith primary, secondary,latent and tertiarystages. T. pallidumenters tissues bypenetration of intactmucosae or throughabraded skin.Dr.T.V.Rao MD 29
PRIMARY SYPHILIS(The Chancre)• Incubation period 9-90 days, usually ~21 days.• Develops at site of contact/inoculation.• Classically: single, painless, clean-based, induratedulcer, with firm, raised borders. Atypical presentationsmay occur.• Mostly anogenital, but may occur at any site (tongue,pharynx, lips, fingers, nipples, etc...)• Non-tender regional adenopathy• Very infectious.• May be darkfield positive but serologically negative.• Untreated, heals in several weeks, leaving a faint scar.Dr.T.V.Rao MD 31
Primary syphilis• (a) One or more painless chancres (induratedraise edges & clear bases) that erupt in thegenitalia, anus, nipples, tonsils or eyelids.• b) Starts as papule and then erode• c) Disappear after three to six weeks evenwithout treatment.• d) Lymphadenopathy that is either unilateralor bilateralDr.T.V.Rao MD 32
Secondary syphilis• a) The rash can be macular, popular, pustule, or nodular.• b) Lesions are of a uniform size, well-defined andgeneralized• c) Macules often erupt between rolls of fat on the trunkand on the arms, palms, soles, face and scalp• d) Lesions enlarged and erode in warm moist areas of thebody (condylomata lata).• e) Headache, anorexia, malaise, weight loss, nausea andvomiting, sore throat and slight fever.• f) Temporary alopecia may occur• g) Nails become brittle and pittedDr.T.V.Rao MD 39
Latent Syphilis• Latent syphilisa) Reactive serologic testb) Asymptomatic until death• Late syphilisThree subtypes of Late syphilis–Late, benign syphilis*Develops between 1 to 10 years after theinfection*Presence of gummaDr.T.V.Rao MD 47
Mother to Child Transmission• Infection in uteromay have seriousconsequences forthe fetus. Rarely,syphilis has beenacquired bytransfusion ofinfected freshhuman blood.Dr.T.V.Rao MD 48
Congenital Syphilis• Passed from mother to fetusduring pregnancy–Abnormally shaped teeth–Nasal septum collapses–Skeletal abnormalitiesDr.T.V.Rao MD 49
What Congenital Syphilis Means• If a pregnant woman has syphilis andis not treated quickly, these tinybacteria travel with her blood to thebaby’s body. Syphilis infection can be acause of fetal death and spontaneousabortion, or can result in the deliveryof the dead baby, or the baby can diewithin several days of life.Dr.T.V.Rao MD 50
Congenital Syphilis• If the baby survives, there is a high risk thatthis baby will have copious nasal discharge(snuffles) packed with Treponemes and severeinflammatory reaction as a consequence,destroying nasal cartilages and bones. Thebaby will likely suffer from liver and spleenenlargement and dysfunction, meningitis ormeningoencephalitis, and inflammatory skinrash—all of these are symptoms of earlycongenital syphilis.Dr.T.V.Rao MD 51
Some present in Differed Manner• Some babies will not develop signs of earlycongenital syphilis, but around eight years ofage or older they will demonstrate symptomsof late congenital syphilis: their vision willbecome deteriorated due to inflammatorychanges in eyes, some of their centralpermanent teeth will have unusual conicshape and notching, and they may becomedeaf with complaining of vertigo and ringing inthe ears. Their bones will be deformed,Dr.T.V.Rao MD 53
DIAGNOSIS OF SYPHILIS• 1. History and clinical examination.• 2. Dark-field microscopy: specialtechnique use to demonstrate thespirochete as shiny motile spiral structureswith a dark background.• The specimen includes oozing from thelesion or sometimes L.N. aspirate. It isusually positive in the primary andsecondary stages and it is most useful inthe primary stage when the serologicaltests are still negative.Dr.T.V.Rao MD 55
Diagnosis of Syphilis• Evaluation based on three factors:– Clinical findings.– Demonstration of spirochetes in clinical specimen.– Present of antibodies in blood or cerebrospinalfluid.• More than one test should be performed.• No serological test can distinguish betweenother Treponemal infections.Dr.T.V.Rao MD 56
Provisional Diagnosis of Syphilis• A presumptive diagnosisis possible withsequential serologic tests(e.g. VDRL, RPR), usingthe same testing methodeach time. A fourfoldchange in titer (e.g. from1:8 to 1:32) is usuallyconsidered to be clinicallysignificant. Confirmatorytests should beperformedDr.T.V.Rao MD 57
Other Diagnostic Tests• Serological tests ofsyphilis.• Biopsy rarelyneeded. It showsendarteritisobliterans withinflammatoryreaction containinga plenty of plasmacells. Granulomamay found intertiary syphilis.Dr.T.V.Rao MD 58
Laboratory Testing• Direct examination of clinical specimenby dark-field microscopy or fluorescentantibody testing of sample.• Non-specific or non-treponemalserological test to detect reagin, utilizedas screening test only.• Specific Treponemal antibody tests areused as a confirmatory test for a positivereagin test.Dr.T.V.Rao MD 59
SERLOGICAL TESTS OF SYPHILIS:STS• Non-specific or lipoidal tests• A. VDRL (venereal disease research laboratories)- It is useful for the screening, diagnosis andfollow up.- The results can be qualitative or qualitativeFalse positive results• 1. Acute type: usually low titre and don’t persist formore than 6 months• 2. Chronic type: usually last for more than 6months• B. Rapid plasma reagin test.• C. Wasserman test not used moreDr.T.V.Rao MD 60
Specific serological tests ofSyphilis• A. Reiter protein complement fixation test.• B. Fluorescent Treponemalantibody/absorption test, FTA/ABS. the mostspecific and most sensitive .• C. Treponema pallidumhaemagglutination test- TPHA- D.Treponema pallidum immobilization test- TPIDr.T.V.Rao MD 61
Venereal Disease Research Laboratory- VDRL• Flocculation test, antigen consists of very fine particles thatprecipitate out in the presence of reagin.• Utilizes an antigen which consists of cardiolipin, cholesteroland lecithin.– Antigen very technique dependent.– Must be made up fresh daily.• Serum must be heated to 56 C for 30 minutes to remove anti-complementary activity which may cause false positive, ifserum is not tested within 4 hours must be reheated for 10minutes.• Calibrated syringe utilized to dispense antigen must deliver 60drops/mL +/- 2drops.Dr.T.V.Rao MD 62
VDRL• Performing the test:– 0.05 mL of serum added to circle on ceramic slide and spread.– Add one calibrated drop of antigen to each circle.– Rotate at 180 rpms for 4 minutes.– Read microscopically at 100x and grade reaction if positive.– Perform titer on positive samples, report out titer.• Quality control:– Run three levels of control: Non-reactive, weakly reactive and reactive.– Glass syringe with 18g delivery needle must be checked daily to ensuredelivery of 60 drops/mL.– Rotator rpms must be checked to ensure 180 rpms.– Room temperature must be 23-29 C.• VDRL used primarily to screen cerebral spinal fluid.Dr.T.V.Rao MD 63
VDRL• Each preparation of antigen suspension should first be examined bytesting with known positive or negative serum controls.• The antigen particles appear as short rod forms at magnification of about100x. Aggregation of these particles into large or small clumps isinterpreted as degrees of positivity• Reactive on left, non-reactive on rightDr.T.V.Rao MD 64
Rapid Plasma Reagin Test - RPR• General screening test, can be adapted toautomation.• CANNOT be performed on CSF.• Antigen– VDRL cardiolipin antigen is modified with choline chlorideto make it more stable– attached to charcoal particles to allow macroscopicreading– antigen comes prepared and is very stable.• Serum or plasma may be used for testing, serum isnot heated.Dr.T.V.Rao MD 65
RPR• Test Procedure:– Serum or plasma added to circle on card and spread.– One drop of antigen from a needle capable of delivering 60 drops/mLis added.– Rotate at 100 rpms/minute for 8 minutes.– Results are read macroscopically.• Daily quality control:– 20 gauge needle checked for delivery of 60 drops/mL– Rotator checked for 100 rpms/minute– Room temperature must be 23-29 C.– Three levels of control must be run and give appropriate results.• RPR appears to be more sensitive than the VDRL.Dr.T.V.Rao MD 66
Treponema pallidum haemagglutination(TPHA)• Adapted to microtechniques (MHA-TP)• Tanned sheep RBCsare coated with T.pallidum antigen fromNichol’s strain.• Agglutination of theRBCs is a positiveresult.Dr.T.V.Rao MD 67
Treponema pallidum Haemagglutination (TPHA)• Based on the agglutination ofcolored gelatin particle carrierssensitized with T. pallidumantigen.• Patient sera incubated withsensitized particles inmicroliter wells and sensitizedgelatin particles in controlwells. Dr.T.V.Rao MD 68
Treponema pallidum Haemagglutination(TPHA)• Patient sera containing specific antibodies willreact only with the antigen to form a smooth matof agglutinated particles.• A compact button formed by the settling of thenon-agglutinated particles in the microtiter wellscontaining sensitized particles indicates lack ofspecific antibody in patient sera (-).• If agglutination is seen with both sensitized andunsensitized particles, nonspecific agglutinationis indicated.Dr.T.V.Rao MD 69
Fluorescent Treponemal AntibodyAbsorption Test (FTA-ABS)• Diluted, heat inactivated serumadded to Reiter’s strain of T.pallidum to remove crossreactivity due to otherTreponemes.• Slides are coated with Nichol’sstrain of T. pallidum and addabsorbed patient serum.Dr.T.V.Rao MD 70
Fluorescent Treponemal AntibodyAbsorption Test (FTA-ABS)• Slides are washed, and incubated withantibody bound to a fluorescent tag.• After washing the slides are examined forfluorescence.• Requires experienced personnel to read.• Highly sensitive and specific, but timeconsuming to perform.Dr.T.V.Rao MD 71
FTA-ABS Step 1• Teponema pallidum, the known antigen, is fixed toa microscope slide.Dr.T.V.Rao MD 72
FTA-ABS – Step 2• If there are antibodies against Treponema pallidumin the patients serum, they will bind to thespirochete.• All other antibodies are washed from the slide.Dr.T.V.Rao MD 73
FTA-ABS- Step 3• Fluorescent anti-human gamma globulin (anti-HGG) is addedto the well.• The anti-HGG will bind with human IgG antibodies bound tothe Treponema pallidum on the slide.• All unbound anti-HGG is washed from the slide.• Viewed with a fluorescent microscope, the spirochetes willfluoresceDr.T.V.Rao MD 74
Positive FTA Test for Syphilis Viewed with aFluorescent MicroscopeDr.T.V.Rao MD 75
ELISA• Microtitration wells coated with T.pallidumantigens are exposed to test specimens whichmay contain specific antibodies.• After an incubation period, unboundcomponents in the test sample are washedaway.• Specifically-bound IgG reacts with an anti-human IgG antibody bound with horseradishperoxidase during a second incubation period.Dr.T.V.Rao MD 76
ELISA ( cont )• Following a second wash cycle, specifically-bound enzyme conjugate is detected byreaction with hydrogen peroxide and thechromogen.• The colour reaction is measuredspectrophotometrically to indicate thepresence or absence of IgG treponemalantibodies.Dr.T.V.Rao MD 77
Enzyme Immunoassay for HIV Antibodies• Step 2 - The patients serum is added.• If the serum contains antibodies against the known HIVantigens, they will bind to those antigens.• All other antibodies are then washed from the well.Dr.T.V.Rao MD 78
Enzyme Immunoassay for HIV Antibodies• Step 3 - Enzyme-linked anti-human gamma globulin (anti-HGG) is added to the well.• The anti-HGG will with any human IgG antibodies bound tothe adsorbed HIV antigens.• All unbound anti-HGG is then washed from the well.Dr.T.V.Rao MD 79
Non Treponemal diseases tooReact• The nontreponemal tests, VDRL and rapidplasma reagent (RPR), are antilipoidalantibodies seen in other disease states,pregnancy, and occasionally after vaccination.They are nonspecific and cannot rule indisease. These tests have sensitivitiesapproaching 80% in patients withsymptomatic primary syphilis and virtually100% in patients with secondary syphilisDr.T.V.Rao MD 80
Every Pregnant women NeedsScreeningDr.T.V.Rao MD 81
Congenital Syphilis• Passed from mother to fetusduring pregnancy–Abnormally shaped teeth–Nasal septum collapses–Skeletal abnormalitiesDr.T.V.Rao MD 82
TREATMENT OF SYPHILIS:• Early syphilis:• benzathine penicillin 2.4 million units intramuscularlyonce• procaine penicillin 600,000 units intramuscularly dailyfor 10 days• if the patient is unable to take penicillin, then givetetracycline or erythromycin 500 mg 4 times a day bymouth – or doxycycline 100 mg x2- for 15 days.• Ceftriaxone, 2 gm qd IM/IV for 10-14 d is a new alternativetreatmentDr.T.V.Rao MD 83
Treatment of Late Syphilis• Late syphilis:• benzathine penicillin 2.4 million units intramuscularlyweekly for 3 weeks.• procaine penicillin 1.2 million units intramuscularlydaily for 21 days• Tetracycline or erythromycin 500 mg 4 times a day –or doxycycline 100 mg x2- by mouth for 30 days• Jarrisch-Herxheimer reaction• Follow-upDr.T.V.Rao MD 84
Other Treponemes• Three other pathogens in the group:Treponema which are morphologicallyand antigenically similar to T. Pallidum• Differences are in:–characteristics of lesions,–Amount of systemic involvement and–course of the disease.
T. pertenue• Found in tropics, causes disease Yaws.• Non-venereal transmission, transmitted by directcontact.• Disease of bone and skin, rarely viscera• Persistent lesions, wart-like, occur primarily inchildren, causes and ulcerative necrosis, scarformation, disfiguring.• Untreated disease not as severe as syphilis, butlesions are more persistent.• Treat with penicillin• Serologic syphilis test will be reactive.
T. pertenue• Occurs mainly in equatorial regions and can be foundin South America, Central America, the Caribbean,Africa, and Southeast Asia.• It is associated with high humidity and rainfall.• Fifty years ago, the WHO recognized that endemictreponematoses—yaws in particular—were a majorcause of disfigurement and disability and a significanteconomic burden in poor countries.
Infection with Treponema pallidum pertenue. Noticethe deformed tibiae, the so-called sabre tibiae.
T. endemicum• Causes non-venereal syphilis knownas bejel or endemic syphilis• Typically spread among children,most commonly in the Middle Eastand the southern Sahara desertregions.• Bejel is completely curable withpenicillin.• Serologic syphilis test will bereactive.
T. endemicum• Bejel affects the skin, bones, and mucousmembranes of the mouth.• Transmission is by direct contact, with broken skin orcontaminated hands, or indirectly by sharing drinkingvessels and eating utensils.• Symptoms begin with a slimy patch on the inside ofthe mouth followed by blisters on the trunk, arms,and legs.• Bone infection develops later, mainly in the legs.• Also in later stages, soft, gummy lumps may appearin the nose and on the roof of the mouth (softpalate).
T. carateum• Pinta (T carateum) occurs in Central and SouthAmerica and the Caribbean.• More common in young adults.• Non-venereal, direct contact, disease of skin.• Lesion is initially a scaly patch, becomes red-blue,later become depigmented and atrophy.• Treat with penicillin• Serologic syphilis test will be reactive.
Mode of Transmission• Organism is very fragile, destroyedrapidly by heat, cold and drying.• Sexual transmission most common,occurs when abraded skin or mucousmembranes come in contact with openlesion.• Can be transmitted to fetus.• Rare transmission from needle stick andblood transfusion.
• The Programme is created forMedical and ParamedicalStudents in the DevelopingWorld• Email• email@example.comDr.T.V.Rao MD 96