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Syphillis

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STRUCTURE AND PHYSIOLOGY OF TREPONEMES, Pathogenesis, Classification of Syphilis, PRIMARY SYPHILIS, SECONDARY SYPHILIS, TERTIARY SYPHILIS, Late benign syphilis, Cardiovascular syphilis, Neurosyphilis, …

STRUCTURE AND PHYSIOLOGY OF TREPONEMES, Pathogenesis, Classification of Syphilis, PRIMARY SYPHILIS, SECONDARY SYPHILIS, TERTIARY SYPHILIS, Late benign syphilis, Cardiovascular syphilis, Neurosyphilis, Lab diagnosis of syphilis


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  • microhemagglutination assay for antibody to T. pallidum [MHA-TP].
  • But they are difficult to visualize by routine light microscopy because their long and very thin dimensions
  • It had been suggested that surface of bacterium is covered by mucopolysaccharide “slime layer” Or by host-derived proteins, thus blocking the binding of specific antibodies to surface antigens Number of visible “particles” on the surface of T. pallidum was significantly lower (by 90%) compared to cultivable treponemes and other spirochetes In contrast, the inner membrane contains numerous visible particles
  • 1.Treponemal proteins specifically bind the extracellular matrix (ECM) components laminin and fibronectinTp0155 and Tp0483 bind to fibronectinTp0751 binds to lamininCork-screw motility help in the invasion of treponemesSerodiagnosis of syphilis is based upon antibodies to lipid antigens in the VDRL and RPR (so-called “nontreponemal”) tests And to predominantly protein antigens in the FTA-ABS, TPPA, and TPHA (“treponemal”) tests
  • The edge and base of the ulcer have a cartilaginous (buttonlike) consistency on palpation. Although classic chancres are not painful, they can become so if suprainfected with bacteria. Atypical primary lesions are common and may manifest as a papular lesion without subsequent ulceration or induration.
  • involving the skin, bones, central nervous system, or viscera, particularly the heart and great vessels
  • from pinhead to pea size
  • Merritt and colleagues
  • T refringens and T denticola , T phagedenis
  • Four non treponemal tests are currently considered standard testsCholine chloride is added to eliminate the need to heat inactivate the serum & It also enhances the reactivity of the antigen
  • However, plasma samples may be used in RPR card test and TRUST
  • Antilipoidal antibodies are antibodies that not only are produced as a consequence of syphilis and other treponemal diseasesAcute: < 6 month durationassociated with hepatitis, infectious mononucleosis, viral pneumonia, chicken pox, measles, other viral infections, malaria, immunizations, pregnancy, and laboratory or technical errorChronic :>6 month duration associated with connective tissue diseases such as SLE or diseases associated with immunoglobulin abnormalitiesOther conditions are narcotic addiction, aging, leprosy and malignancyBut also may be produced in response to non treponemal diseases of an acute and chronic nature in which tissue damage occur
  • For 85% of persons successfully treated, test results remain reactive for years, if not lifetimeHowever, a reactive treponemal test result on a sample that is also reactive in a nontreponemal test is highly specific
  • Unexplained reactive serologic results also may occur, particularly in elderly patients
  • Great importance of TPI has been its specificity, making it possible to distinguish BFP reaginic reactions from genuine positivesWith early treatment of syphilis, the TPI may become negativeHowever, if disease has been untreated for more than 5–6 months, reaction is likely to remain positive for rest of patient’s life, despite any later treatmentStudies in 1970s found that TPI was less sensitive & specific than other treponemal test
  • Two PCR-based techniques were described almost simultaneously in 1991
  • When a patient is treated for neuro syphilis CSF cell count should return to normal firstthen CSF protein concentration finally, the results of the VDRL-CSF test
  • Transcript

    • 1. SEMINAR PRESENTATION SYPHILIS MODERATOR DR.C.M. KULDEEP
    • 2. INTRODUCTION • Syphilis - infectious treponematoses caused by Treponema pallidum transmitted usually by sexual intercourse • Discovered by Schaudinn and Hoffmann(1905) • Affects most of the organs – Marked by florid manifestations on the one hand – And years of asymptomatic latency on the other hand • Affects both man & women in age group of 20-40 years
    • 3. STRUCTURE AND PHYSIOLOGY OF TREPONEMES • motile spiral-shaped gram –ve bacteria • Size – approx 10–14 μm in length and 0.1–0.2 μm in diameter,10 regular spirals at interval of about 1 μm. • Outer membrane of T. pallidum differs from most gram-negative bacteria in major respects:  lacks lipopolysaccharide  has a dearth of integral membrane proteins  has less cytoplasm  And has 9 cytoplasmic fibrils
    • 4. • T. pallidum - stealth pathogen(antigenic inertness) MOTILITY • T. pallidum is actively motile, moving with a corkscrew motion, with bending and flexing, but with little translational movement CHEMOTAXIS • Chemotaxis machinery is thought to assist T. pallidum as it navigates throughout the body during dissemination • Recent microarray studies indicate that a number of chemotaxis genes are upregulated during early active syphilis infection Two strains – Nichol’s and Reiter strains
    • 5. METABOLISM AND SURVIVAL IN VITRO • Lacks genes for – Krebs cycle Haem proteins involved in electron transport To synthesize most amino acids purines, pyrimidines and lipids • This suggests that T. pallidum is able to generate only two molecules of ATP per glucose molecule through glycolysis • Accounting for its significantly lower growth rate (generation time of ~30–33 hours). • Survives better in microaerophilic rather than anaerobic conditions • So far it had not been cultured in artificial media
    • 6. Range 9- 90days 2-12 WEEKS
    • 7. Pathogenesis Mode of transmission 1. 2. 3. 4. 5. Sexual intercourse Blood transfusion Contaminated needles Vertical transmission To hospital personnel indiscriminate handling infected lesions by of 1.ATTACHMENT, INVASION AND DISSEMINATION 2. INNATE HOST RESPONSE – TLR2 3. ACQUIRED IMMUNITY - clinical manifestations caused by inflammatory and immune responses rather than by any direct cytotoxic effect of T. pallidum 4. BACTERIAL CLEARANCE- phagocytosis of treponemes by macrophages • Predominant cytokine –Th1 • Predominant mediator- IFN-γ 5. ANTIBODIES IN SYPHILIS 6. INVASION OF HOST IMMUNITY AND ESTABLISHMENT OF LATENT INFECTION 7. PROTECTIVE AND LONG-LASTING IMMUNITY
    • 8. • Of these, only relative lack of surface proteins is currently considered to be major factor in persistence. • One of most intriguing discoveries in syphilis pathogenesis is recent description of antigenic variation • The gene encoding TprK, a putative target of opsonic antibody, was demonstrated to have seven sequence variable regions (V regions) • Thus, changing the amino acid sequence of antibody epitope even slightly permits bacterium to escape activities of anti-TprK antibodies that are induced during infection. • This antigenic variation mechanism likely permits some treponemes to escape local bacterial clearance during resolution of early lesions • And contributes to the long-term survival of T. pallidum during latent syphilis and chronic infection • Study demonstrate that immunity to syphilis is very slow to develop, is often incomplete except in untreated syphilis, and may be strain specific
    • 9. Classification of Syphilis 1. 2. Clinical course of acquired syphilis is divided in to early &late syphilis. Early-duration is 1 yrs. – Includes primary and secondary stage and early latent syphilis Late-after 1 yrs. – Include late latent & tertiary syphilis Congenital Syphilis • COLLES’S LAW(1837) Syphilitic infants could transmit the disease to previously healthy wet nurses but never to their own mother • KASSOWITZ’S LAW(1876) Untreated syphilitic mother tends to improve on her past performance
    • 10. PRIMARY SYPHILIS • Starts as painless, erythematous indurated papule – ulcer • Lymphadenopathy • Usually single , painless, clean, well defined, Nontender & markedly indurated • Inguinal lymph node invariably involved • Site - genital, perineal or anal area; however, any part of the body may be affected • Multiple, non tender, discrete, rubbery , Usually Bilateral • Syphilis d emblee- when primary chancre may be overlooked or concealed • Phagedena – invasion of ulcer with Vincent organisms may result in gangrenous changes • Heal spontaneously leaving behind tissue paper scar Regardless of stage of disease and location of lesions, histopathologic hallmarks of syphilis include endarteritis (which in some instances may be obliterative in nature) and a plasma cell–rich infiltrate.
    • 11. SECONDARY SYPHILIS • 2-12 weeks of development of primary syphilis – pt manifests with symptoms of secondary syphilis • Characterized by low-grade fever, malaise, sore throat, headache, adenopathy and cutaneous or mucosal rash. • Manifest as- Evanesent copper-colored macular rash • A few days later, symmetric papular eruption appears, involving entire trunk and the extremities, palm and soles • Papules - reddish brown,scaly,discrete,0.5–2 cm in diameter. • Variats - pustular,combination of these , lichenoid , acneiform nodular ,circinate,corymbose,annular • 25% of pts have abnormal CSF
    • 12. Fig.Secondary syphilis,macular rashes
    • 13. FIGURE . Secondary syphilitic rash on palm and sole.
    • 14. Syphilitic alopecia scalp has moth-eaten appearance eyebrow hair is absent there is rash on the cheek Mucus patches involving the tongue in secondary syphilis.
    • 15. • • • • • • Mucosal lesions small, superficial, ulcerated areas with grayish borders that resemble painless aphthous ulcers or larger gray plaques Condyloma lata is a term used to describe large, raised, whitish or gray lesions found in warm, moist areas,intertriginous area Generalised LN enlargement present in majority of pts Periosteal inflammation – 25% cases Subclinical hepatitis - 20% Iritis , glomerulonephritis or nephrotic syndrome - Deposition of immune complexes
    • 16. LATENCY • Definition-persons with historical or serological evidence for syphilis who have never received treatment for this disease and who have no clinical manifestations (Symptoms/Sign) • Requires exam of CSF to rule out asymptomatic neurosyphilis • In Oslo study of untreated syphilis ,secondary relapses occurred in 25% of patients whose infection had become latent, with most relapses occurring in the first year. • U.S. Public Health Service therefore defines early (potentially infectious) latency 1 year from onset of infection
    • 17. TERTIARY SYPHILIS • Morbidity and mortality of syphilis in adults in past years were due to late manifestations of illness • There may be an interval of 1 - 20 yrs from acute infection to clinical onset of late or tertiary stages of disease •    Tertiary syphilis conveniently divided into three main groups Late benign syphilis Cardiovascular syphilis Neurosyphilis
    • 18. BENIGN TERTIARY SYPHILIS - Characterized by gumma & appear 3-10 yrs after infection - proliferative granulomatous inflammatory process causing destructive of affected tissues - Most lesions occur in skin and bones, with lesser frequency in mucosa and of viscera muscles and ocular structures Theory: 1. Best evidence in support of hypersensitivity was provided by Magnuson et al. who inoculated volunteers in Sing Sing Prison with the Nichols strain of T. Pallidum 2. Gummas developed only in persons with a history of previous syphilis .They concluded that superinfection in sensitized patient may explain gumma formation
    • 19. Clinical manifestations Skin- Two forms may appear: nodular or noduloulcerative and solitary lesion. • 1.Nodular and noduloulcerative lesions deep indurated nodule reddish brown in colour that varies in size • Multiple nodules - distributed in arciform pattern • Site - face,scapular,interscapular areas and extremities • May remain for weeks or mths and may heal without breaking down but - show scarring • If nodular lesions break down to noduloulcerative form, they heal leaving atrophic noncontractile scar 2.The solitary gumma Subcutaneous process that involves the skin secondarily • Site thighs, buttocks, shoulders, foreh ead and scalp. • As it becomes necrotic it has characteristics of “cold abscess” • These lesions resolve promptly with effective treatment
    • 20. • Skeleton- periostitis, gummatous osteitis and sclerosing osteitis. • C/Fs- pain (especially nocturnal), tenderness, swelling, bony tumor, stiffness and limited motion • Upper respiratory tract, mouth, and tongue- Gummatous osteitis of the nasal bones, hard palate and nasal septum(perichondritis) • Digestive system-can involve any part • Gumma of the liver was the most common • Myocardium-gummas especially of the left ventricle and commonly asymptomatic have been reported
    • 21. A. Nodular syphilid on inferior side of the penis. B. Nodular syphilid of the pubic area and solitary gumma on dorsum of the penis. C. Nodular syphilid of the knee. There were signs of aortic incompetency.
    • 22. FIGURE Ulcerating solitary gumma of skin of 12 months’ duration. Note scarring from spontaneous healing. Accompanying solitary ulcers on each shoulder and on the leg, 4–8 cm in diameter, began as pimples 7 months previously.
    • 23. FIGURE . Osteitis of hard palate with perforation
    • 24. CARDIOVASCULAR SYPHILIS • Clinically manifest after latent period of 15–30 years Pathology • Spirochetes appear to have predilection for vasa vasorum of aorta particularly the proximal aorta • Produce transmural inflammatory lesions - endarteritis of these vessels • Obliteration of lumen of vasa vasorum the aortic media develops patchy necrosis with subsequent focal scarring
    • 25. Aortic aneurysm • MC manifestations • • Virtually involve ascending thoracic aorta Syphilitic aneurysms do not dissect probably because of the medial scarring and wall thickening • Symptom - develop when aneurysm encroaches on surrounding structures or ruptures • Radiograph may be N or show a mediastinal mass with typical eggshell calcification outlining aneurysm Coronary artery disease • Only the ostia or most proximal few mm of coronary arteries are affected • May lead to IHD including angina pectoris or sudden death Aortic regurgitation • Pure AR without stenosis formerly was common cardiovascular manifestation • Occurring in roughly 30% of pts
    • 26. NEUROSYPHILIS • Abnormalities in CSF have been noted in  13% of pts with untreated primary syphilis  25–40% of pts with untreated secondary syphilis • After initial invasion of CNS during early syphilis, untreated infection     may resolve spontaneously persist as asymptomatic syphilitic meningitis progress to symptomatic acute syphilitic meningitis progression of early asymptomatic or symptomatic meningeal infection may lead to meningovascular syphilis (usually 5–12 yrs after primary infection) or parenchymatous forms of neurosyphilis such as tabes or paresis (usually 18–25 yrs)
    • 27. Table. Classification of Neurosyphilis Asymptomatic 31a Early Late Meningeal 20 Acute syphilitic meningitis 6 Meningovascular 11b Cerebral Spinal form 3 Parenchymatous 48 General paresis 12 Tabes dorsalis 30 Taboparesis (mixed) 3 Optic atrophy 3c Gummatous 1 Cerebral form Spinal form Total 100 aDistinction between early and late asymptomatic syphilis could not be made. b”Deafness,” comprising 1% of cases in Merritt et al.26, was included in this category. c“Optic neuritis,” comprising 3% of cases in HH Merritt et al.26, was included in this category.
    • 28. Lab diagnosis of syphilis Tests are divided in four categories – – – – (i) direct microscopic exam - used when lesions are present (ii) non treponemal tests - used for screening (iii) treponemal tests - are confirmatory (iv) direct antigen detection tests - used in research settings and as gold standards for test evaluation
    • 29. Direct detection methods 1.Animal inoculation • Oldest method • Most sensitive method • Used as gold standard for measuring sensitivity of methods such as PCR 2.Dark-field microscopy • When lesions are present, most specific and easiest means of diagnosing syphilis is by direct detection of organism • Since treponeme are viabile organisms examination must be accomplished immediately after specimen is obtained • Most productive during primary, secondary, infectious relapsing and early congenital syphilis
    • 30. • Enlarged regional lymph nodes can also serve as a specimen source • Lesion should be cleansed only if encrusted or obviously contaminated • Normal saline (without antibacterial additives) should be used • After cleansing lesion, gently abrade it and apply gentle pressure until only clear serum exudes • Place a drop of serum on surface of cover slip or slide • Positive findings on dark-field examination permit specific and immediate diagnosis of syphilis • Sensitivity of this test is not more than 50% hence it should be done on 3 consecutive days
    • 31. 3.DFA-TP 4.DFAT-TP test • Detects and differentiates pathogenic treponemes from nonpathogenic treponemes • Hence Organism is not required to be motile in DFA-TP • Drawback-cannot distinguish between the pathogenic strains of Treponema spp. • Use of DFA-TP test has been extended to include staining of tissue sections • Used to diagnose late-stage or congenital syphilis or to distinguish skin lesions of secondary or late syphilis from those of Lyme disease
    • 32. Non treponemal Tests 1. 2. 3. 4. VDRL( veneral disease research laboratory test) USR(unheated serum reagin) RPR(rapid plasma reagin) TRUST(toludine red unheated serum test) • USR test antigen is VDRL antigen stabilized by the addition of EDTA • So Need for daily preparation of an antigen suspension is eliminated • TRUST and RPR card test antigens differ only in the visualization agent added to antigen For RPR card test - sized charcoal particles are added to antigen For TRUST - paint pigment particles are added
    • 33. • Particles of both tests become entrapped in antigen-antibody lattice formed with a reactive serum • Based on an antigen composed of : alcoholic solution containing measured amts of cardiolipin , cholesterol and sufficient purified lecithin to produce standard reactivity • Serum - specimen of choice for both non treponemal and treponemal tests • VDRL only test that can be used for testing CSF (NEUROSYPHILIS) • In screening for congenital syphilis, CDC recommends the testing of mother’s serum followed by neonatal serum - with cord blood being least reactive
    • 34. • Done in two ways : qualitative and quantative • Quantitative tests - establish baseline of reactivity from which change can be measured • Recent infection can be demonstrated by fourfold rise in titer • Reinfection / relapse can be detected among persons with a persistently reactive (serofast) test for syphilis • All non treponemal tests have approx same sensitivity and specificity • Advantage : - widely available - inexpensive - convenient to perform on large numbers of specimens - necessary for determining efficacy of treatment • Limitations - lack of sensitivity in early dark field- positive primary cases and in late syphilis - possibility of prozone reaction(false-negative) or falsepositive results
    • 35. • Non treponemal (reagin) tests measure IgM and IgG antibodies to lipoidal & lipoprotein-like material released from damaged host cells as well as to cardiolipin released from treponemes • Without some other evidence for the diagnosis of syphilis, a reactive non treponemal test does not confirm T. pallidum infection • Causes of False-positive reactions  Acute: < 6 month duration  Chronic :>6 month duration
    • 36. Treponemal Tests • FTA-ABS, FTA-ABS double staining, MHA-TP and TPI • Use - T. pallidum as antigen • Confirmatory test - Used when non treponemal test is NR but there is evidence of syphilis, such as might occur in late syphilis • Technically more difficult and costly to perform and cannot be used to monitor treatment • 1% of the general population will have false-positive results(cause is unknown) • A definite association has been made between false-positive FTAABS test results and the diagnosis of systemic, discoid, and druginduced varieties of LE • Patients with SLE can have false-positive FTA-ABS tests that exhibit an ‘‘atypical beading’’ fluorescence pattern
    • 37. • To resolve these types of false positive reactions, absorption with calf thymus DNA can be used to remove the anti-DNA antibodies in the serum • Some false-positive reactions may be due to failure of sorbent used in the tests to remove all cross-reacting group, genus, or family antibodies, e.g. in Lyme disease • In these instances, absorption with Reiter treponeme or the use of hemagglutination test may be only means of differentiating between syphilis and a falsepositive reaction • MHA-TP is more sensitive and specific than FTA-ABS except In 3rd to 4th wk of infection
    • 38. 1.FTA-ABS test: • Indirect fluorescentantibody technique • Patient’s serum is first diluted in sorbent (an extract from cultures of nonpathogenic Reiter treponeme) • To remove group treponemal antibodies that are produced in some persons in response to nonpathogenic treponemes 2.FTA-ABS test double staining method: • Employs tetramethylrhodamine isothiocyanate-labeled anti-human IgG and counterstain with FITClabeled anti-T. pallidum conjugate • Counterstaining organism ensures that nonreactive result is due to absence of antibodies and not to absence of treponemes on slide
    • 39. 3.T. pallidum immobilization (TPI) test: • • • • • • In 1949, Nelson and Mayer proved that serum from syphilitic patients contains an antibody which in presence of complement inhibits normal movements of virulent T. pallidum Reaction of treponemes in presence of patient’s serum is observed by dark-field microscopy Positive - 50% or more are immobilized test Negative - if less than 20% In 99% of cases, result is very clear-cut and certainly very specific, probably nearly 100% Test is time consuming and expensive
    • 40. Table :Sensitivity and Specificity of Serologic Tests for Syphilis
    • 41. MOLECULAR BIOLOGY-BASED METHODS FOR THE DIAGNOSIS OF SYPHILIS • Shortcomings of standard tests for syphilis for diagnosis of early primary, congenital and neuro syphilis have made techniques based on detection of treponemal DNA or antigens 1. DNA Probes • Assay gave a positive result when approx - 2,500 treponemes were present in sample • LIMITATION: Only rarely that many numbers of treponemes seen in clinical samples
    • 42. 2.PCR: • Extremely valuable in diag– congenital syphilis – neurosyphilis (serologic test available presently is only 50% sensitive) – early primary syphilis – distinguishing new infections from old infections 3.RT PCR: • Targeting the polA gene of treponeme • Assay is fast and has high sensitivity(94%) & specificity(100%)
    • 43. ENZYME IMMUNOASSAY • A number of treponemal EIA tests are commercially available , including Captia Syphilis G , Captia Syphilis M and Captia select Syph-G (Trinity Biotech, Ireland), SpiroTek syphilis test (Organon Teknika, USA), Enzygnost Syphilis (Dade Behring, Germany) and Bio-Rad Syphilis G (Bio-Rad Laboratories, USA) • Captia Syphilis G test detects IgG antibodies • May be used both as screening test and confirmatory test and is an appropriate substitute for the MHA-TP test • Captia Syphilis M test - designed to detect IgM antibodies in congenital syphilis - may be more sensitive than FTA-ABS 19S IgM • Considered to be suitable for detection of early syphilis • SpiroTek syphilis test has highest sensitivity of all treponemal tests (especially in untreated primary syphilis) and is recommended as confirmatory test by CDC
    • 44. • EIA tests have been shown to be equal to or better than FTA-ABS and TPHA tests in overall sensitivity and specificity and are more useful in HIV coinfected individuals • While a number of laboratories have switched over to treponemal EIAs for screening • Drawback is that treponemal tests generally remain reactive for life in most patients • CDC is currently recommending that, if EIA is used for screening, then an RPR test should be performed on all EIA reactives, and a second treponemal test such as TPHA or FTA-ABS should be used for confirmation if the RPR test is reactive
    • 45. Laboratory diagnosis for different stages for syphilis Primary syphilis • Serous fluids from lesion contain numerous treponemes, detectable by either dark-field microscopy or the DFA-TP • Humoral antibodies appear 2 to 3 weeks after chancre • App. 30% of those with early primary syphilis will have NR nontreponemal test results on First visit • Definitive diagnosis of primary syphilis requires direct microscopic identification of T. pallidum in lesion material, lymph node aspirate, or biopsy section • For persons with a h/o syphilis fourfold increase in titer on quantitative non treponemal test when results of past tests are compared with most recent test results • MHA-TP is less sensitive than FTA-ABS test and non treponemal tests • Suggestive diagnosis based on presence of lesion and sexual contact within preceding 90 days with person in whom syphilis has been diagnosed
    • 46. Secondary syphilis • In secondary stage, with few if any exceptions, all serologic tests for syphilis are reactive • And treponemes may be found in lesions by direct microscopic examination • As with primary syphilis Definitive diagnosis based on observation of T. pallidum by direct microscopic examination • Presumptive diagnosis is based on presence of typical lesions and a reactive non treponemal test titer of 8 or more and no previous history of syphilis or, • For persons with history of syphilis fourfold increase in most recent titer compared with past test results
    • 47. • For patients with atypical lesions and/or non treponemal test titers of <8, non treponemal tests should be repeated and a confirmatory treponemal test should be performed before a presumptive diagnosis is made. • Sensitivity of MHA-TP is equal to sensitivity of FTA-ABS tests • Suggestive diagnosis is made only when serologic tests are not available and is based on both presence of clinical manifestations and sexual exposure within past 6 months to a person with syphilis
    • 48. Latent syphilis • Since lesions are not present, a definitive diagnosis is not possible • Presumptive diagnosis of latent syphilis is based on combination of serologic results and a history of a nonreactive non treponemal test the prior year • Or fourfold increase in titer compared with the most recent test for persons with a history of syphilis, or a history of symptoms compatible with those of earlier stages of syphilis
    • 49. Tertiary syphilis. • Because results for approx 30% of pts with late syphilis will be nonreactive in the non treponemal tests • Treponemal test results should be obtained if syphilis in these stages is suspected and non treponemal tests are non reactive • Treponemal tests are almost always reactive and may be only basis for diagnosis
    • 50. • For neurosyphilis CSF examinations should be done • Diagnosis of neuro syphilis requires – a reactive treponemal test result with a serum sample – a CSF cell count of >5 mononuclear cells per cubic centimeter – CSF total protein >40 mg/dl • A definitive diagnosis is made on the basis of – a reactive serum treponemal test – a reactive VDRL-CSF on a spinal fluid sample – identification of T. pallidum in tissue by microscopic examination of tissue stained with silver stain or fluorescent antibody
    • 51. Management of Syphilis • Parenteral penicillin is DOC for all stages of syphilis • Parenteral penicillin is only treatment with documented efficacy in neurosyphilis, HIV infection and pregnancy • Tetracyclines, erythromycin, and third-generation cephalosporins have strong anti treponemal activity in experimental and clinicai trials but are less effective than penicillin • HIV serology is recommended for all patients with syphilis and should be repeated in 3 months in patients living in areas with high HIV prevalence
    • 52. Treatment of primary, secondary and early latent syphilis First line • Inj Benzathine penicillin G 2.4 MU i.m. single dose Penicillin allergy • Cap Doxycycline 100 mg twice daily orally for 14 days • Tab Erythromycin 500 mg four times daily orally for 14 days • Inj Ceftriaxone 1g daily i.m. for 10 days (if no anaphylaxis to penicillin) CHILDRENS • A single intramuscular injection of benzathine penicillin 50,000 units/kg up to 2.4 million units
    • 53. HUMAN IMMUNODEFICIENY VIRUS INFECTl0N • Treatment same, but follow- up is closer • Some experts recommend CSF examination in patients with CD4 counts <350 cells/mm3 and nontreponemal titers equal or above 1:32 • No evidence to support administration of three weekly injections of benzathine penicillin G • Or enhanced therapy with ampicillin and probenecid after a course of benzathine penicillin injections F0LLOW-UP • Patients should be reexamined clinically and serologically at 6 and 12 months (if HlV- seropositive then 3, 6,9, 12 and 24 mths)
    • 54. Late Latent Syphilis • Inj Benzathine penicillin G, 2.4 million units intramuscularly week apart for three doses • If patient misses a dose, treatment may be resumed as long as the interval between injections has not exceeded 2 weeks with exception of pregnant women CHILDREN • Three weekly intramuscular injection of Inj benzathine penicillin G 50,000 units/kg up to 2.4 million units
    • 55. CSF examination: • Asymptomatic individuals ,yield of positive findings in lumbar puncture is low, but CSF examination is clearly indicated in certain cases: – Cardiovascular, neurologic, eye, or auditory symptoms or in late benign syphilis – HIV infection – RPR titer> 1:32 – Treatment failure – Treatment other than penicillin • If the CSF examination demonstrates abnormalities patient should be treated for neurosyphilis
    • 56. Tertiary syphilis ( Cardiovascular, Late Benign syphilis) • Inj Benzathine penicillin G 2.4 million units 1 week apart for three doses is recommended treatment Penicillin allergy • Cap Doxycycline 100 mg twice daily orally for 30 days • If the patient is not HIV infected and CSF is negative
    • 57. Neurosyphilis • Inj Aqueous crystalline penicillin G 18 to 24 mu administered daily as 3 to 4.0 million units iv every 4 hours for 10 to 14 days • Alternatively, treatment with procaine penicillin G, 2.4 mu i.m. daily, and probenecid 500 mg orally every 6 hours for 10 to 14 days • Treatment with ceftriaxone ( 1 g i.v. daily for 14 days)is not as effective as penicillin
    • 58. PENICILLIN ALLERGY • Desensitize and treat with penicillin F0LL0W-UP • Re -examination CSF every 6 months until normal • Cell counts should decrease by 6 months and CSF VDRL and protein levels by 2 year • If not, retreat with i.v. penicillin
    • 59. Treatment in pregnancy • Penicillin regimen appropriate for stage of infection should be used PENICILLIN ALLERGY • Desensitize and treat with penicillin • Erythromycin's ability to cross placenta is fair to poor • Infants born to mothers who received erythromycin for syphilis during pregnancy should be thoroughly evaluated for active disease
    • 60. Syphilis in HIV infected patients • A penicillin regimen should be instituted according to the stage of disease PENICILLIN ALLERGY • Desensitize and treat with penicillin CSF EXAMINATION: • Some experts recommend CSF examination before treatment of early syphilis as well as 6 months after treatment • but there is no evidence of improved outcomes FOLL0W-UP • Closer follow-up with clinical and serological tests required at 3 month interval • CSF examination is indicated if there is serologic evidence of treatment failure at any time, or if the serofast response continues after 12 months
    • 61. Recommended treatment and follow-up for syphilis in HIV-infected patients. Zetola N M , and Klausner J D Clin Infect Dis. 2007;44:1222-1228 © 2007 by the Infectious Diseases Society of America
    • 62. TABLE Stages of Syphilitic Infection Stage Clinical manifestations Diagnosis (sensitivity) Treatment Primary syphilis Chancre Dark-field microscopy of skin lesion Penicillin G benzathine, 2.4 million units IM (80%)Nontreponemal tests (78% to (single dose)Alternatives in nonpregnant 86%)Treponemal-specific tests (76% to 84%) patients with penicillin allergy: doxycycline (Vibramycin), 100 mg orally twice daily for 2 weeks; tetracycline, 500 mg orally four times daily for 2 weeks; ceftriaxone (Rocephin), 1 g once daily IM or IV for 8 to 10 days; or azithromycin (Zithromax), 2 g orally (single dose) Secondary syphilis Skin and mucous membranes: diffuse rash, Dark-field microscopy of skin lesion condyloma latum, other lesionsRenal system: (80%)Nontreponemal tests glomerulonephritis, nephrotic syndromeLiver: hepatitisCentral nervous system: headache, meningismus, cranial neuropathy, iritis and uveitisConstitutional symptoms: fever, malaise, generalized lymphadenopathy, arthralgias, weight loss, others (100%)Treponemal-specific tests (100%) Same treatments as for primary syphilis
    • 63. Latent syphilis None Nontreponemal tests (95% to Early latent syphilis: same treatments as for 100%)Treponemal-specific tests (97% to primary and secondary syphilisLate latent 100%) syphilis: penicillin G benzathine, 2.4 million units IM once weekly for 3 weeksAlternatives in nonpregnant patients with penicillin allergy: doxycycline, 100 mg orally twice daily for 4 weeks; or tetracycline, 500 mg orally four times daily for 4 weeks Tertiary (late) syphilis Gummatous disease, cardiovascular disease Nontreponemal tests (71% to Same treatment as for late latent syphilis 73%)Treponemal-specific tests (94% to 96%) Neurosyphilis Seizures, ataxia, aphasia, paresis, Cerebrospinal fluid examination Aqueous crystalline penicillin G, 3 to 4 million hyperreflexia, personality changes, cognitive units IV every 4 hours for 10 to 14 days; or disturbance, visual changes, hearing loss, penicillin G procaine, 2.4 million units IM neuropathy, loss of bowel or bladder function, once daily, plus probenecid, 500 mg orally others four times daily, with both drugs given for 10 to 14 days
    • 64. Penicillin reactions • Accidental deaths following treatment are very rare and mainly due to anaphylactic shock reactions to penicillin • If penicillin is used in patients with a history of allergy, it is advisable to keep the patient under observation for 15–20 min after injection • An emergency kit should always be available • In addition to early and late allergic reactions and the Jarisch– Herxheimer reaction • Hoigne reactions (acute psychotic symptoms due to inadvertent iv injection of procaine in procaine penicillin) are recognized
    • 65. Jarisch–Herxheimer reaction • An acute febrile reaction that occurs in many patients within 24 hr of commencing treatment • Mediated by cytokines • Headache, myalgia, bone pains and an exacerbation of skin lesions may accompany the fever • Must be differentiated from penicillin allergy • Patients should be advised that it might occur • Symptoms may be controlled by antipyretics • Fever (38–40°C) rarely persists more than 8 h
    • 66. • In pregnant women reaction may induce early labour or cause fetal distress • In late neurosyphilis and cardiovascular syphilis, reaction can be more serious and may be associated with life-threatening sequelae • Many clinicians advocate a short course of corticosteroids to lessen its effects in these patients • One such regimen is to prescribe oral prednisolone 30–60 mg daily for 3 days, beginning syphilis treatment 24 h after first dose
    • 67. Management of sexual contacts • It is recommended that attempts be made to identify, trace and offer further investigation to at-risk sexual contacts • In early syphilis, these are those contacts occurring within 3 months plus the duration of symptoms for primary syphilis • Within 6 months plus the duration of symptoms for secondary syphilis and within 1 year for early latent disease • All long-term partners of patients with late syphilis should be offered investigation • Many clinicians recommend presumptive treatment of all sexual contacts within 90-day period preceding patient presentation of early syphilis • if serological test results are not immediately available and if follow-up cannot be assured
    • 68. Efficacy of azithromycin on the treatment of syphilis • Penicillin therapy is associated with low cost and also inexistence of problems with adherence to treatment • Although, the injection is painful and nearly 10% of the population has allergic reactions to penicillin Results • We selected three clinical trials comparing azithromycin with benzathine penicillin, totaling 499 patients in the study group and 471 patients in the control group • One study examined two dosages of azithromycin (2g and 4g) whereas the other two used the dosage of 2g • Penicillin G benzathine was administered at its conventional dose (2.4 million units) in all studies
    • 69. • Healing in three months: Three studies have compared azithromycin with benzathine penicillin in the period of three months. One hundred and ninety-five patients in the study group and 190 patients in the control group didn't heal in this period. There was no statistically significant difference between groups (p=0.88, I2=0%). • Healing in six months: Three studies have compared azithromycin with benzathine penicillin in a follow-up of six months. One hundred and fiftysix patients in the study group and 165 patients in the control group didn't heal in this period. There was no statistically significant difference between groups (p=0.39, I2=44%). • Healing in nine months: Two studies have compared azithromycin with benzathine penicillin in a follow-up of nine months. Thirty two patients in the study group and 44 in the control group had no cure in this period. Azithromycin has increased the chance of cure in 8% (95%CI 0,01 to 0,15; p=0.02 and I2=21%) when compared with benzathine penicillin, needing to treat 13 patients to obtain this benefit
    • 70. Conclusion • This review showed clearly that a single dose of azithromycin, orally, is as effective as the 2.4 million units of benzathine penicillin for treating syphilis
    • 71. Antibiotic Desensitization Therapy in Secondary Syphilis and Listeria Infection: Case Reports and Review of Desensitization Therapy • • • • A 45-year-old male presented with a two month history of an erythematous, pruritic, maculo-papular rash initially involving the truncal area and then spreading to the genital area and extremities, including both palmar and plantar surfaces. The lesions varied in size from 0.5 to 2.5 cm and gradually became hyperpigmented with superficial desquamation. Secondary syphilis was suspected and confirmed with Rapid Plasma Reagin (RPR) positivity (1:64) and Fluorescent Treponemal Antibody (FTA) reactivity. The patient admitted to having two recent sexual contacts, one casual contact and another with a commercial sex worker. Past medical history was significant for reaction to penicillin with hives, dyspnea, loss of consciousness, and hypotension requiring hospitalization at age fourteen. He also had a remote history of treated gonococcal and chlamydial genital infections. Due to his previous severe reaction to penicillin, the patient was initially started on alternative therapy with a fourteen day course of doxycycline with no resolution of his disseminated rash. The infectious disease consultant recommended that the patient undergo penicillin desensitization for optimal therapy. He was admitted to the hospital for antibiotic desensitization followed by penicillin therapy under unit-level observation He tolerated the procedure well with no hypersensitivity reaction and was discharged the following day. The patient subsequently had complete resolution of his rash and negative RPR testing at follow-up.
    • 72. THANK YOU

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