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1058 Academy DOI: 10.1111/j.1610-0387.2006.06072.x

CME

Diagnosis of : Clinical and laboratory problems Syphilisdiagnostik: Klinische und labormedizinische Problematik

Stephan Lautenschlager Department of Dermatology, City Hospital Triemli, Zurich, Switzerland

Section Editor Prof. Dr. Michael Landthaler, Regensburg

Introduction Due to HIV prevention campaigns there was a sharp decline in the incidence of classical sexually transmitted diseases in many Western European nations at the end of the 1980s and beginning of the 1990s. Also, the initially high mortality of AIDS contributed to the reduction of syphilis cases. After a dramatic increase of syphilis in the countries of the former Soviet Union since 1994, outbreaks have been registered in Great Britain, Ireland, France, Holland and Norway [1]. Similar trends can be observed in Germany and Switzerland [2–4]. The increase in syphilis observed for years continued in 2004 [2, 4] with 3,345 newly diagnosed cases being reported in Germany, an incidence rate of 4.1 cases per 100,000 population, a 14 % increase compared to 2003 [2]. Syphilis in Europe is observed mainly in large cities among young adults. Homosexual males in particular are affected, many of whom have known HIV [5]. The HIV co- rate varies greatly depending on country but ranges up to 50 %. Most recent trends also show a rise in syphilis among heterosexual men [2]. Particularly worrisome is that the rise in syphilis correlates with the renewed increase of sexually acquired HIV infection, which has risen by 20 % between 1995 and 2000 [1]. The return of syphilis presents a diagnostic challenge for young physicians who are often not familiar with the clinical presentation, diagnostic approach or treatment. We must re-familiarize ourselves with the diverse clinical features of syphilis [6] and the complex diagnostic approach to this disease [7, 8]. It is especially crucial to recognize the diverse clinical symptoms of each individual stage and to keep them in mind in considering differential diagnoses. The key to diagnosis is examination of the entire skin surface and its appendages, the anogenital region, the oral mucosa and regional lymph nodes while considering possible general and neurologic symptoms. The peculiarities in simultaneous HIV To stop the current spread of syphilis, co-infection must especially be considered. To stop the current spread of syphilis, we we must once more become familiar must once more become familiar with the complex clinical presentation and diagnostic with the complex clinical presenta- approach. Rapid diagnosis and treatment are essential to prevent further spread, late tion and diagnostic approach. complications, transfer to the newborn and may represent a key to reducing new sexually acquired HIV infections. Definition of the stages of syphilis The course of syphilis – caused by pallidum – is characterized by stages, where symptomatic periods are interrupted by sometimes very long phases (latent syphilis). Early syphilis comprises primary and secondary syphilis as well as early latent syphilis with a latency of < 1 year (definition of the Centers for Disease Control (CDC), Atlanta) or < 2 years (definition of the WHO) after infection. Late syphilis consists of late latent, tertiary and – depending on nomenclature – qua- ternary syphilis or metalues (Table 1). This classification in stages is a simplification which is not always applicable to the diverse clinical presentation.

JDDG |12˙2006 (Band 4) © The Authors • Journal compilation © Blackwell Verlag, Berlin • JDDG • 1610-0379/2006/0412-1058 Academy 1059

Table 1: Definition of the stages of syphilis.

Stage Duration Manifestations 3 weeks (9–90 days) Ulcer at the site of Primary syphilis 6 weeks inoculation, regional infection , general symptoms, Secondary syphilis Months further organ manifestations, hematogenous dissemination Early latency: < 1 year (CDC) < 2 years (WHO) Seropositivity, no clinical Latent syphilis Late latency: symptoms, spontaneous > 1 year (CDC) healing (two-thirds) > 2 years (WHO) Tuberoserpiginous syphilids, gummas in multiple organs, Tertiary syphilis Years cellular reaction in face of few Metasyphilis, quaternary syphilis Years , general paresis Meningovascular syphilis (symptomatic/asymptomatic), Years, possible in stage basilar meningitis, acute Neurosyphilis II-IV transverse dorsal myelitis, cerebral gummas, general paresis, tabes dorsalis

Early latent syphilis is defined as < 1 year according to the CDC and < 2 years Early latent syphilis is defined as according to the WHO. < 1 year according to the CDC and < 2 years according to the WHO. Clinical problems in syphilis diagnosis Primary syphilis The incubation period is 3 weeks, but can be as long as 3 months. After an average The incubation period is 3 weeks, but incubation period of 3 weeks (9–90 days) a dark red macule or papule develops at the can be as long as 3 months. site of inoculation and rapidly progresses to an erosion (Figure 1). Size and depth of the defect increase over the course of one to two weeks until a typical, indolent, well-circumscribed, flat ulcer with a yellow coated base and an indurated, non-undermined wall results [9]. This is followed by edema and bilateral asymptomatic . Classically, the is located in the coronal sulcus in males and on the labia minora in females. Principally, primary syphilis may present with atypical morphology, symptoms and locations causing diagnostic difficulties, so that only 30 to 40 % of patients in the primary stage are diagnosed [4, 10]. Only 30 to 40 % of cases are Only 30 to 40 % of cases are diagnosed in the primary stage of syphilis. diagnosed in the primary stage of syphilis. a) Atypical morphology and symptoms The clinical diagnosis of syphilis in its primary stage is unreliable because of possible The clinical diagnosis of syphilis in its atypical presentations. DiCarlo and Martin [11] demonstrated that in 446 males with primary stage is unreliable because the classical, indurated and indolent syphilitic chancre was present in of possible atypical presentations. only 31% and that clinical features in the majority could not be differentiated from herpetic ulcers or from [11]. In a recent outbreak in Manchester, many

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Figure 1: Early eroded papule in primary syphilis.

In industrialized lands, differentiation patients exhibited multiple, painful genital ulcers resembling [12]. In from genital herpes is most important. industrialized lands, differentiation from genital herpes is important. Sometimes the chancre is totally absent or multiple ulcers occur or simply a nodular lesion is present. Examination of lymph nodes does not always aid clinical diagnosis, as the lympha- denopathy may be painful as in other infections [11]. The most important differen- tial diagnoses of genital ulcers are listed in Table 2.

b) Atypical location Just as clinical presentation can be non-specific, so can the location of the chancre cause it to be overlooked. This is especially true for anal or rectal ulcers in homosexual Atypical locations as well as hidden males and vaginal or cervical ulcers in females. Atypical locations as well as hidden (cervical or rectal forms) chancres (cervical or rectal forms) complicate diagnosis in primary syphilis. In rectal complicate diagnosis in primary ulcers, lymphadenopathy occurs in para-aortal and not in inguinal nodes, so that it is syphilis. not noticed. In a recent study in England, 20 % of homosexual patients with syphilis had an anal chancre [13]. The anal chancre tended to be located towards the peri- neum. Sometimes only swelling, induration (edema indurativum) (Figure 2) or fissu- res are present, making differentiation from , anal fissures and other infections, e.g. herpes simple, necessary [14]. Examination of the anal canal – preferably with a proctoscope – should be part of the work-up for sexually transmit- Proctoscopy should be a routine part ted infections. Extragenital chancres are most frequent at anal or oral sites, but can of the work-up for sexually transmitted principally occur at any muco-cutaneous site coming into contact with an infectious infections. lesion. The incidence of extragenital chancres is reported at 5–14 % [6, 15–17]. Ab- out two-thirds occur in or around the mouth after unprotected . Among ho- mosexual syphilis patients, 12.5 % of chancres are oral [13]. Due to the increasing popularity of oral sex in recent years – in part because it supposedly is a safer-sex prac- Two-thirds of extragenital chancres tice – an increase of oral chancres has been observed. Case reports describe syphilitic are oral or perioral. chancres of fingers, mammillae, eyelid, arm, toe or presternal region (Figure 3) [6, 15, 18–20]. Decades ago extragenital chancres were no rarity; Fournier describes 642 from head to toe in his textbook [21]. Any indurated ulcer with regional lymphadenopathy An ulcer with lymphadenopathy should lead one to consider syphilis. An ulcer with lymphadenopathy should, regard- should, regardless of site, make one less of site, make one think of syphilis. Differential diagnosis of extragenital lesions think of syphilis. includes , cat scratch disease, sporotrichosis, mycobacteriosis, leishmaniosis, staphylococcal and neoplasia. A clinical diagnosis in primary syphilis is not reliable due to the clinical variability [11], which is why identification of the In primary syphilis an attempt should should occur. In primary syphilis an attempt should be made at detecting be made at detecting the pathogen. the pathogen.

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Table 2: Differential diagnosis of genital ulcers.

Infectious Disease Pathogen (sexually transmitted and non-sexually transmitted) 1. Bacterial Syphilis Chancroid Lymphogranuloma trachomatis venereum Serovar L1–L3 inguinale Calymmatobacterium (donovanosis) granulomatis Chancriform Streptococci, among others Genital Mycobacteria diphtheriae (very rare) Typhoid Salmonella typhi (very rare) 2. Viral Genital herpes Human herpesvirus 1 and 2 Acute HIV infection HIV Genital ulcers such as Epstein-Barr , ulcus vulvae acutum cytomegalovirus 3. Parasitic Amebiasis Leishmaniasis Inflammatory Lichen planus Lichen sclerosus et atrophicus Reiter syndrome Behçet syndrome Aphthosis Crohn’s disease Iatrogenic Fixed drug eruption multiforme Toxic Neoplastic Malignancies Traumatic Artefacts

Secondary syphilis The classical dilemma in secondary syphilis is the variability of the exanthems and as- sociated symptoms. Around 75 % of patients with secondary syphilis develop skin ma- nifestations. Most often the chancre has already healed but in 15 % it is still present [22, 23]. A frequent first manifestation of dissemination is an asymptomatic, discrete, pink macular eruption favoring the flanks and disappearing after about 2 weeks (syphilitic roseola). In the further course a characteristic maculopapular or papulos- Syphilitic roseola is the first clinical quamous, well-circumscribed, somewhat more darkly colored exanthema spreads to sites of manifestation of secondary syphilis.

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Figure 2: Edema indurativum of the anal area.

predisposition such as palms and soles, trunk, face and extremities. Pustular, papular, lichenoid, nodular, ulcerative, plaque-like, annular and even urticarial and granulo- matous forms (Figure 4) can occur [6, 10, 22, 24, 25]. Classical palmoplantar syphi- lids can be scattered and discrete (Figure 5). Contrary to the view presented in many textbooks, the exanthema can itch, especially in dark-skinned patients [26]. Various oral manifestations can be of diagnostic importance [27] and are present in one-third Oral manifestations play an to one-half of patients. Mucous plaques (Figure 6) and syphilitic angina are the most important diagnostic as well as frequent. Localized enanthems or perlèche-like lesions are possible. Expansive, epidemiologic role. smooth lesions (plaques lisses) and grey-white plaques (plaques opalines) are rarer [28]. Similar erythematous, moist plaques can occur in intertriginous regions and de- velop into broad-based condyloma-like vegetations (condylomata lata). Papules of the scalp can lead to “moth-eaten” alopecia. This hair loss can occasionally also affect eyebrows, eyelashes and beard. General symptoms such as fatigue, malaise, sore throat, fever, generalized micro-lym- phadenopathy as well as muscular and joint pain with a noticeable nocturnal pattern A wide variety of systemic manifesta- occur in varying intensities. Other organ involvement may include hepatitis, periosti- tions can result from hematogenous tis, arthritis, uveitis, gastritis or meningitis [26]. Diagnosis in secondary syphilis is spread of the pathogens. based on serology. Unclear or suggestive exanthems require serological exclusion or

Figure 3: Presternal syphilitic chancre.

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Figure 5: Discrete secondary syphilis lesions on the palm. Figure 4: Granulomatous eruption in secondary syphilis. confirmation of syphilis. At times the diagnosis is made histologically, with highly variable finding again being possible [29]. The pathogens may be seen on special stains (e.g. Warthin-Starry or Steiner) either in the epidermis or dermis [30]. A typical histological feature in all active lesions is an obliterating endangiitis with a plasma-- rich perivascular inflammatory infiltrate. Nodular lesions may exhibit granulomatous, sarcoidosis-like features with mixed cellular infiltrates and multinuclear giant cells [25].

Special features of syphilis in patients with HIV co-infection HIV usually does not influence the course of syphilis. Several clinical differences have been described in many case reports of patients with HIV co-infection [10, 31]. In particular the disease tends to present in the secondary rather than the primary stage, Usually, the clinical picture is not disease progression is more rapid and atypical features must be expected. Case reports altered by HIV co-infection. mention the appearance of multiple ulcers, deep ulcers and rare perforations in pri- mary syphilis as well as frequent overlap of stages [32, 33]. In secondary syphilis ul- cero-nodular forms and malignant syphilis are more frequent [22, 34, 35]. In Ger- many, HIV-infected patients develop malignant syphilis 60 times more often than do patient collectives without HIV infection [36]. Differences have also been documented for CNS, joint and bone as well as ocular involvement [10]. Atypical presentations, Atypical presentations, especially especially malignant syphilis, should lead to considering HIV co-infection. malignant syphilis, should lead to Problems in laboratory diagnosis of syphilis considering HIV co-infection. As culture of Treponema pallidum is not possible, diagnosis of syphilis depends on di- rect identification of the pathogen on the one hand and characteristic serology on the other. Serology is of prime importance in laboratory diagnosis of syphilis (Table 3) [7, 37–39], but must be viewed in context of the clinical presentation and history. Serology should always be viewed together with clinical presentation Detection of the pathogen and history. As the chancre can appear one to three weeks before a serological response, direct de- tection of the pathogen is vital in this phase of the disease [38]. This is usually achieved through darkfield microscopy of of the lesions free of blood at first with the 40x objective and following isolation of an organism with the 100x objective and oil immersion. Darkfield microscopy is the only laboratory test that allows immediate diagnosis and therapy. A reliable evaluation requires much experience. Microscopy Darkfield microscopy is the only lab- must be done immediately, as these corkscrew-shaped organisms are identified by oratory test that allows immediate their characteristic movements (bending movements and rotation on its own long diagnosis and therapy. A reliable axis). As about 105 organisms/ml are required for visualization, a negative darkfield evaluation requires much experience. examination does not rule out syphilis. Non-pathogenic, commensal spirochetes, e.g.

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Figure 6: Mucous patches of secondary syphilis.

of the oral flora, can be confused with Treponema pallidum even by experienced The presence of many examiners. Darkfield microscopy of oral lesions should not be performed for this non-pathogenic spirochetes limits reason. The presence of many non-pathogenic spirochetes limits the use of darkfield the use of darkfield examination for examination for oral syphilitic lesions. For experienced examiners the sensitivity of oral syphilitic lesions. darkfield microscopy ranges from 79–97 %, specificity from 77–100 % [40, 41]. False-negative results are usually due to use of topical or taking of even Even small amounts of systemic or small amounts of systemic antibiotics. Darkfield microscopy also provides for the topical antibiotics lead to false-nega- quickest therapy of sexual partners and prevents further spread [42]. Due to the tive results. renaissance of syphilis, all dermatologic clinics should provide for special training of young physicians in darkfield examination. In Great Britain, a recent study showed that one-third of hospitals (genitourinary medicine clinics) had problems in providing Training in darkfield microscopy darkfield examination [43]. A rarely employed alternative is direct immunofluores- should again receive greater cence using specific FITC-labeled monoclonal which allow differentiation emphasis. from non-pathogenic treponemes [7]. Secretions for darkfield examination can also be extracted from lesions of secondary syphilis. Tests based on polymerase chain reaction (PCR) to identify treponemal DNA in cli- nical material are quite promising [41, 44]. Many different methods using various targets are available primarily in private laboratories. Specificity is reported at 95–97 %, sensitivity at 91–95 % [41, 44]. Most tests are not validated and very expensive, making routine use impossible. In special scenarios, e.g. oral or rectal PCR appears quite promising; routine chancres, direct use on slides when histology is non-definitive or in chancres pretreated use cannot yet be recommended. with antibiotics, PCR may be a valuable addition [41]. Serology In serological diagnosis specific and non-specific tests are distinguished [7, 37, 45, 46].

Non-specific (nontreponemal) tests Serology can identify IgM and IgG antibodies reacting with cardiolipin (as well as lecithin and ) one to three weeks after the appearance of the chancre. These antibodies can be detected by the VDRL (Venereal Disease Research Laboratory) and RPR (Rapid Plasma Reagin) tests. Non-specific tests are better suited for monitoring treatment than for . Non-specific tests are quick and cheap. A positive Non-specific tests are better suited test does not prove treponemal infection but indicates destruction. The titer for monitoring treatment than for denotes the highest serum dilution at which precipitation still occurs. For example, a screening. test serum with a high titer can require many dilution steps (1:2). The ratio of serum to diluent decreases with each step (1:2, 1:4, 1:8, 1:16, 1:32, etc.). The titer of a patient serum requiring three such dilution steps is reported as 1:8. When the titer before therapy is 1:64 and after therapy 1:16 it is termed a fourfold decrease of the titer due to decreased antibody. A fourfold or greater decrease of the antibody

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Table 3: Indications for different serologic tests.

Screening test TPHA/TPPA (perhaps with VDRL) RPR (no longer recommended) EIA Confirmatory test FTA-ABS EIA (IgG/IgM immunoblot) Evaluation of disease activity VDRL IgM (19S-IgM-FTA-ABS test, IgM-FTA-ABS test, Captia-IgM) TPHA Treponema Pallidum Hemagglutination Assay TPPA Treponema Pallidum Particle Agglutination Assay VDRL Venereal Disease Research Laboratory RPR Rapid Plasma Reagin EIA Immunoassay FTA-ABS Fluorescent Treponemal Antibody Absorption

titer after 6 months correlates with decreased antibody levels and a high probability of An at least fourfold decrease of titer successful therapy of primary and secondary syphilis [7, 47]. The longer syphilis has 6 months after treatment correlates existed, the slower normalization of the reactions occurs [45, 48]. In later latency this with successful therapy of early can be expected after one year [48]. In less than 5 % of patients the reactions do not syphilis. revert despite adequate therapy, a condition termed “sero-fast”. VDRL and RPR are ti- tratable precipitation tests, but the height of the titers of the two tests are not compa- rable. To follow titer levels, the same test should be performed in the same laboratory. The sensitivity of the non-specific tests depends on the stage of syphilis (Table 4) [10, 49], which is why they are of only limited use as screening tests. The tests become positive 4 to 8 weeks after acquiring the infection (sensitivity 59–87 %). Sensitivity approaches 100 % in secondary syphilis due to the high antibody titers. With the Non-specific tests display varying drop of antibody levels in late syphilis, sensitivity also sinks. In up to one-quarter of sensitivities depending on disease patients the VDRL test can become negative in late syphilis even without therapy. stage. Generally, the time required to become negative after treatment correlates to duration of syphilis, height of titer and severity of the disease. A persistent positive titer in an immunocompetent patient despite adequate treatment suggests treatment failure, reinfection or a biological false-positive reaction. Sometimes persistent low titers (un- der 1:16) can be found after adequate treatment without signs of an active infection.

False-positive Non-specific tests Reactive non-specific tests with titers < 1:8 and negative confirmatory test are consi- dered biological false-positive results [38, 50]. Such false-positive tests are reported with a frequency of 1–20 % and are classified as either acute (< 6 months) or chronic biological false-positive results. Acute false-positive reactions can be associated with False-positive reactions in infections (mononucleosis, varicella, measles, malaria, , mumps, lympho- non-specific tests can be classified as granuloma venereum among others). Chronic false-positive reactions are often asso- acute or chronic forms, each having ciated with autoimmune diseases and chronic inflammatory processes (e.g. systemic different causes. lupus erythematosus, polyarteritis nodosa, antiphospholipid syndrome, chronic liver disease). Old age, and drug abuse can also cause false-positive results [38, 50]. Among HIV positive patients 10–30 % demonstrate false-positive non-specific reactions [51].

False-negative Non-specific tests False-negative tests are frequently found in early or late phases of the infection with low antibody titers. Occasionally, false-negative results can be found in secondary sy- philis with very high antibody titers [52, 53]. This prozone phenomenon occurs in up

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to 2 % of patients and is due to an inappropriate ratio of antibody versus The prozone phenomenon is preventing agglutination [53]. This prozone phenomenon is frequently found in frequently found in pregnancy and pregnancy and HIV infection. To prevent this phenomenon the patient’s serum HIV infection. should be diluted up to 1:16 if syphilis is strongly suspected.

Specific (antitreponemal) tests Specific antitreponemal antibodies can be determined with the FTA-ABS (Fluores- cent Treponemal Antibody Absorption), the TPHA (Treponema Pallidum Hemag- glutination Assay), TPPA (Treponema Pallidum Particle Agglutination Assay), Captia® Syphilis G/ Syphilis M and other tests. Specific tests are used for confirma- Specific tests are used as confirmation tion of a positive non-specific test, and in the case of TPHA/TPPA also for screening of infection (especially FTA-ABS and [37, 54]. EIA) or for screening (especially The most frequently employed confirmatory test is FTA-ABS, which is still consid- TPHA/TPPA and EIA). ered the golden standard. Specific antitreponemal antibodies do not correlate with disease activity and usually persist for life despite adequate therapy. The antitreponemal reactions are unable to differentiate between the nonvenereal endemic treponemato- ses (, , frambesia, bejel) and syphilis [55], which can cause difficulties in in- terpreting positive tests in patients from developing countries. due to T. denticola does not seem to influence serology [56]. FTA-ABS possesses the greatest sensitivity, especially in early syphilis. Due to the high specificity, FTA-ABS is almost never negative when non-specific tests are reactive. Very rare cases of false-negative FTA-ABS can occur [57]. False-positive results are rare (0.35 %) and can be found in HIV infection, autoimmune diseases and pregnancy [51]. Laboratory mistakes must also be taken into consideration. Generally, FTA-ABS can be considered very sensi- tive in all stages of syphilis, but evaluation of fluorescence is subjective and sometimes difficult and complex, making it unsuitable for screening, but suitable as confirma- tory test. Due to the need for a reliable, specific, rapid and automated screening and confirmatory test for syphilis, enzyme immunoassays (EIA) have been developed in The complex but sensitive FTA-ABS recent years [58, 59]. Various modifications allow the simultaneous detection of IgG test is increasingly being replaced by and IgM antibodies or their separate quantitative determination. Studies suggest com- the simple to perform enzyme parable results in screening compared with the combination VDRL/TPHA. EIA can immunoassay (EIA). also be utilized to confirm a positive TPHA screening test [7, 39]. The role of Western blot technique as confirmation is not yet precisely defined, but appears meaningful in dubious situations such as co-existing autoimmune disease. Specificity is 99 %. The role of an IgM blot cannot yet be assessed, as it is a purely qualitative antibody deter- mination limiting its capability to monitor treatment success [7].

Evaluation of disease stage A quantitative non-specific test (VDRL) and a test for specific IgM antitreponemal antibodies are helpful in evaluating the disease stage and serve as a basis for monito- ring treatment effects. Usually, IgM antibodies are present for up to 3–9 months af- ter adequate treatment, but can persist for up to 12–18 months following treatment of late syphilis. Through modifications of the FTA-ABS test IgM antibodies can dif- ferentially be measured. The IgM-FTA-ABS test can deliver false-positive and false-

Table 4: Sensitivity and specificity of different serologic tests ac- cording to the stage of the disease.

Test Sensitivity Sensitivity Sensitivity Specificity (%) (%) (%) (%) Stage I Stage II Stage III Non-specific RPR 75–86 99–100 70–73 98 VDRL 59–87 99–100 37–75 98 Specific TPHA 80 99–100 95 99 FTA-abs 81–100 99–100 95–98 98

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negative results, so that this test is only partly suitable [7]. The 19S-IgM-FTA-ABS test delivers almost 100 % specificity. The Captia-IgM test can quantitatively mea- sure 19S-IgM antibodies. The demonstration of specific IgM antibodies in patients who have not recently been treated is evidence for an active infection requiring treat- ment. The evaluation of therapy success is the of the therapy guiding reac- The demonstration of specific IgM tions (VDRL/RPR). It is impossible on a serological basis to distinguish reinfection antibodies is helpful in evaluating from reactivation. In the event of a second infection, there is a strong rise in the stage of the disease. TPHA/TPPA and lipoid antibody titers, while IgM antibody kinetics can be highly variable [7].

Serology in patients with HIV infections Case reports and small case series describe atypical serological reaction in HIV co-in- fection [10]. Frequent false-negative serology in primary and secondary syphilis [60, 61], prozone phenomenon [62], “sero-fast” reactions [63] and specific antibodies be- coming negative after therapy [64] have all been reported. False-positive Non-speci- fic reactions are observed in up to 11 % of patients [65]. Usually, HIV infection does Usually, HIV infection does not alter not alter serology, but atypical results must be expected. Sometimes there is a false-ne- serology, but atypical results must be gative FTA-ABS test. A delayed fall in titer can occur and appears to be of no clinical expected. relevance. Despite such varying serological responses, work-up of HIV-infected patients is not different to that of HIV negative cases. A large prospective study showed no effect of HIV infection on serology [61], but the possibility of negative serology in early syphilis must be considered and detection of the pathogen be attempted in such cases [10].

Serology in congenital syphilis Maternal IgG antibodies can pass through the placenta and thus be found in the new- born’s serum. Passive maternal antibodies are eliminated with a half-time of 21 days. Finding specific IgM antitreponemal antibodies is helpful in diagnosing congenital infection. As a negative result does not rule out congenital syphilis, a control exami- nation together with a quantitative non-specific test to demonstrate the decline of passive maternal antibodies are required [47]. Even in face of negative IgM antibo- Even in face of negative IgM antibodies, dies, the decline of passive maternal antibodies must be documented to rule out con- the decline of passive maternal genital syphilis. Depending on the initial titer, they should become negative within antibodies must be documented to one year. Higher antibody titers in the newborn compared with the mother could rule out congenital syphilis. likewise indicate congenital syphilis [8].

Diagnostic approach to neurosyphilis Diagnosis of neurosyphilis is based on clinical findings, serology and analysis of cere- brospinal fluid (CSF) [7]. CNS involvement is never an isolated event; serology is al- ways positive. To confirm the diagnosis of CNS involvement, parallel testing of serum and CSF obtained on the same day is mandatory. A rule of thumb is that a positive VDRL in CSF together with signs of (leukocytes in CSF > 5c/l and CSF > 0.4g/l) is sign of neurosyphilis if there has been no contamination of CSF with blood. A negative FTA-ABS in CSF appears to rule out CNS involvement. Because of possible false-positive and false-negative results, often further tests are per- formed and indices calculated [7]. The key diagnostic criterion is the demonstration The complex diagnostics of of specific local antibody synthesis in the CNS. Well suited for this is the neurosyphilis takes clinical findings, TPHA/TPPA titer determination in serum and CSF followed by calculation of simultaneous specific and the pathogen-specific CSF/serum-antibody quotient ((ITpA index, intrathecal non-specific antibody tests in serum T. pallidum antibody index [TPHA titer in CSF : total IgG in CSF] x [total IgG and CSF,cells and protein in CSF as in serum : TPHA titer in serum]). A value > 2.0 suggests specific antibody production well as CSF/serum pathogen-specific in the CNS, a value > 3.0 proves it with high reliability. antibody quotients into consideration. Intrathecal specific antibody synthesis does not automatically mean active neurosy- philis, as this phenomenon can persist over years, perhaps even lifelong. In evaluating disease activity other parameters such as pleocytosis, raised CSF protein and function of the blood-brain barrier must be considered [7].

Conclusions With the resurgence of syphilis we are again faced with quite diverse clinical features and demanding diagnostics. This renaissance confronts young physicians often

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The complex clinical and serological unfamiliar with the clinical picture and diagnostic approach. The complex clinical and diagnosis of syphilis must once again serological diagnosis of syphilis must once again be emphasized in training and con- be emphasized in training and tinuing education. Further spread can only be prevented by the quickest possible diag- continuing education. nosis and immediate institution of adequate treatment of patients and their sexual partners. This requires knowledge of typical and atypical clinical presentations and disease courses as well as knowledge of the pitfalls of laboratory diagnosis especially in the context of HIV co-infection. During work-up the following principles should be observed: 1 Patients with negative serology but suspected syphilis infection should have a control test 2–3 weeks later due to the possible seronegative phase in early pri- mary syphilis. Detection of the pathogen – preferably by darkfield microscopy – should be attempted. 2 In Europe, TPHA/TPPA, perhaps in combination with VDRL, has become estab- lished as screening test. EIA is an alternative. Screening with an non-specific test alone can no longer be recommended due to possible false-negative results. 3 Positive screening tests require a specific confirmatory test, usually FTA-ABS, possibly treponemal EIA (in special cases Western blot). 4 Discrepant results in specific tests require an additional specific test. 5 In proven infection a quantitative Non-specific test (VDRL) and a specific IgM antitreponemal antibody test (Captia®-Syphilis-M/(19S-)IgM-FTA-ABS) should be performed to evaluate disease stage and monitor treatment. 6 In monitoring the titer, the same test should be performed in the same laboratory.

Summary After a distinct decline in the number of syphilis cases within the context of AIDS prevention campaigns, a significant increase has been observed in states of the former Soviet Union since 1994. As of 1999 outbreaks also have been registered in several European countries. Since a misdiagnosis of syphilis can have serious effects for the patient or even for a newborn child, we should be aware of the many difficulties in the diagnosis of this disease. Many younger physicians are no longer familiar with the diverse clinical symptoms and the complex diagnostic approach to syphilis. Often diagnosis is missed in the primary stage. On the one hand, this is due to the atypical locations of the lesions (anal, oral, cervical) and an occasionally atypical mor- phology (multiple or soft ulcers or only nodular indurations) as well as, on the other hand, to the difficulty of detecting the pathogen. Since seroreactions become positive after 3 weeks at a minimum and the pathogen cannot be cultured easily, the early diagnosis is based on direct examination. This requires a great deal of experience to perform. False-negative results may occur, as a consequence of using topical antibio- tics or taking only small quantities of systemic antibiotics. Additionally, the dark field examination of the anal area and oral cavity is made more difficult by many non- pathogenic treponema. Testing procedures based on the polymerase chain reaction (PCR) are not yet routinely available. In the clinically extremely diverse secondary stage, the diagnosis can always be con- firmed serologically, but a bewildering array of tests are available, both specific and non-specific. When clinical symptoms are lacking and a low titer or inconsistent test results are present, a diagnosis can be difficult or even impossible. Endemic trepone- matoses cannot be differentiated. Rarely specific tests may also give false-positive re- sults, caused by cirrhosis of the liver, vascular diseases, pregnancy, and infec- tions. Occasional patients co-infected with HIV may present with atypical clinical manifestations and laboratory results. <<<

Correspondence to PD Dr. St. Lautenschlager Department of Dermatology, City Hospital Triemli Herman-Greulich-Strasse 70 CH-8004 Zurich, Switzerland Tel.: +41-1-2 98-89 20 Fax: +41-1-2 98-89 89 E-mail: [email protected]

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References 1 Nicoll A, Hamers FF. Are trends in HIV, gonorrhoea, and syphilis worsening in western Europe? BMJ 2002; 324: 1324–1327. 2 RKI. Syphilis: Zur Situation in Deutschland 2004. Epidemiol Bull 2005; 26: 221–225. 3 Hamouda O, Marcus U. Syphilis auf dem Vormarsch. Neues Meldeverfahren nach dem Infektionsschutzgesetz. Hautarzt 2005; 56: 124–132. 4 Lautenschlager S. Sexually transmitted infections in Switzerland: return of the classics. Dermatology 2005; 210: 134–142. 5 Fenton KA, Lowndes CM. Recent trends in the epidemiology of sexually transmitted infections in the European Union. Sex Transm Infect 2004; 80: 255–263. 6 Schöfer H. Syphilis. Klinik der Treponema-pallidum-Infektion. Hautarzt 2004; 55: 112–119. 7 Schöfer H, Brockmeyer NH, Hagedorn H-J, Hamouda O, Handrick W, Krause W, Marcus U, Münstermann D, Petry KU, Prange H, Potthoff A, Gross G. Syphilis. Leit- linie der Deutschen STD Gesellschaft zur Diagnostik und Therapie der Syphilis. J Dtsch Dermatol Ges 2006; 2: 160–177. 8 CDC. Sexually transmitted diseases treatment guidelines 2002. Centers for Disease Control and Prevention. MMWR 2002; 51: 1–78. 9 Musher DM. Early syphilis. In: Holmes KK, Sparling PF, Mardh P, Lemon SM, Stamm WE, Piot P, Wasserheit JN. Editors. Sexually Transmitted Diseases. New York: McGraw-Hill, 1999: 479–485. 10 Lynn WA, Lightman S. Syphilis and HIV: a dangerous combination. Lancet Infect Dis 2004; 4: 456–466. 11 DiCarlo RP, Martin DH. The clinical diagnosis of genital ulcer disease in men. Clin In- fect Dis 1997; 25: 292–298. 12 Lacey HB, Higgins SP, Graham D. An outbreak of early syphilis: cases from North Manchester General Hospital. Sex Transm Infect 2001; 77: 311–313. 13 Hourihan M, Wheeler H, Houghton R, Goh BT. Lessons from the syphilis outbreak in homosexual men in east London. Sex Transm Infect 2004; 80: 509–511. 14 Lautenschlager S, Eichmann A. The heterogeneous clinical spectrum of genital herpes. Dermatology 2001; 202: 211–219. 15 Chapel TA, Prasad P, Chapel J, Lekas N. Extragenital syphilitic chancres. J Am Acad Dermatol 1985; 13: 582–584. 16 Haustein UF, Pfeil B, Zschiesche A. Analyse der von 1983–1991 an der Universitäts- Hautklinik Leipzig beobachteten Syphilisfälle. Hautarzt 1993; 44: 23–29. 17 Alam F, Argiriadou AS, Hodgson TA, Kumar N, Porter SR. Primary syphilis remains a cause of oral ulceration. Br Dent J 2000; 189: 352–354. 18 Donofrio P. Unusual location of syphilitic chancre: case report. Genitourin Med 1986; 62: 59–60. 19 Weber B. Ein Fall von syphilitischem Primäraffekt am Lid. Klin Monatsbl Augenheilkd 1982; 180: 565–566. 20 Lautenschlager S, Schwarzkopf S, Borelli S. Presternal indurated ulceration: primary syphilis. Dermatology 2006; 212: 200–202. 21 Fournier A. Treatment and prophylaxis of syphilis. London: Rebman Limited, 1906. 22 Kumar B, Gupta S, Muralidhar S. Mucocutaneous manifestations of secondary syphi- lis in north Indian patients: a changing scenario? J Dermatol 2001; 28: 137–144. 23 Martin DH, Mroczkowski TF. Dermatologic manifestations of sexually transmitted diseases other than HIV. Infect Dis Clin North Am 1994; 8: 533–582. 24 Carbia SG, Lagodin C, Abbruzzese M, Sevinsky L, Casco R, Casas J, Woscoff A. Liche- noid secondary syphilis. Int J Dermatol 1999; 38: 53–55. 25 Papini M, Bettacchi A, Guiducci A. Nodular secondary syphilis. Br J Dermatol 1998; 138: 704–705. 26 Chapel TA. The of secondary syphilis. Sex Transm Dis 1980; 7: 161–164. 27 Little JW. Syphilis: an update. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005; 100: 3–9. 28 Stepanova A, Marsch WC. Plaques opalines. Eine seltene Manifestation der Sekundär- syphilis an der Mundschleimhaut. Hautarzt. In press.

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29 Pandhi RK, Singh N, Ramam M. Secondary syphilis: a clinicopathologic study. Int J Dermatol 1995; 34: 240–243. 30 Engelkens HJ, ten Kate FJ, Vuzevski VD, van der Sluis JJ, Stolz E. Primary and second- ary syphilis: a histopathological study. Int J STD AIDS 1991; 2: 280–284. 31 Körber A, Dissemond J, Lehnen M, Franckson T, Grabbe S, Esser S. Syphilis bei HIV- Koinfektion. J Dtsch Dermatol Ges 2004; 2: 833–840. 32 Rompalo AM, Joesoef MR, O’Donnell JA, Augenbraun M, Brady W, Radolf JD, John- son R, Rolfs RT. Clinical manifestations of early syphilis by HIV status and gender: results of the syphilis and HIV study. Sex Transm Dis 2001; 28: 158–165. 33 Inamadar AC, Palit A. Perforating chancre: any cause-effect relation with HIV infec- tion? Sex Transm Infect 2003; 79: 262. 34 Wappner D, Carbia S, Gioseffi L, Schroh R, Losso MH. Diagnosis: malignant syphi- lis. Clin Infect Dis 1997; 25: 1343, 1447. 35 Don PC, Rubinstein R, Christie S. Malignant syphilis (lues maligna) and concurrent infection with HIV. Int J Dermatol 1995; 34: 403–407. 36 Schöfer H, Imhof M, Thoma-Greber E, Brockmeyer NH, Hartmann M, Gerken G, Pees HW, Rasokat H, Hartmann H, Sadri I, Emminger C, Stellbrink HJ, Baumgarten R, Plettenberg A. Active syphilis in HIV infection: a multicentre retrospective survey. The German AIDS Study Group (GASG). Genitourin Med 1996; 72: 176–181. 37 Egglestone SI, Turner AJ. Serological diagnosis of syphilis. PHLS Syphilis Serology Working Group. Commun Dis Public Health 2000; 3: 158–162. 38. Larsen SA, Steiner BM, Rudolph AH. Laboratory diagnosis and interpretation of tests for syphilis. Clin Microbiol Rev 1995; 8: 1–21. 39 Goh BT, Voorst Vader PC. European guideline for the management of syphilis. Int J STD AIDS 2001; 12 Suppl 3: 14–26. 40 Cummings MC, Lukehart SA, Marra C, Smith BL, Shaffer J, Demeo LR, Castro C, McCormack WM. Comparison of methods for the detection of treponema pallidum in lesions of early syphilis. Sex Transm Dis 1996; 23: 366–369. 41 Palmer HM, Higgins SP, Herring AJ, Kingston MA. Use of PCR in the diagnosis of early syphilis in the United . Sex Transm Infect 2003; 79: 479–483. 42 Wheeler HL, Agarwal S, Goh BT. Dark ground microscopy and treponemal serologi- cal tests in the diagnosis of early syphilis. Sex Transm Infect 2004; 80: 411–414. 43 Rogstad KE, Simms I, Fenton KA, Edwards S, Fisher M, Carne CA. Screening, diagnosis and management of early syphilis in genitourinary medicine clinics in the UK. Int J STD AIDS 2005; 16: 348–352. 44 Liu H, Rodes B, Chen CY, Steiner B. New tests for syphilis: rational design of a PCR method for detection of Treponema pallidum in clinical specimens using unique regions of the DNA polymerase I . J Clin Microbiol 2001; 39: 1941–1946. 45 Brockmeyer, N.H. Syphilis. In: Petzoldt D, Gross G, editors. Diagnostik und Therapie sexuell übertragbarer Krankheiten. Berlin: Springer Verlag, 2001: 101–111. 46 Wicher K, Horowitz HW, Wicher V. Laboratory methods of diagnosis of syphilis for the beginning of the third millennium. Microbes Infect 1999; 1: 1035–1049. 47 Young H. Syphilis. Serology. Dermatol Clin 1998; 16: 691–698. 48 Heise H. Aktuelles zur Syphilistherapie und zur serologischen Kontrolle. Hautarzt 2004; 55: 1087–1089. 49 Hook EW, III, Marra CM. Acquired syphilis in adults. N Engl J Med 1992; 326: 1060–1069. 50 Nandwani R, Evans DT. Are you sure it’s syphilis? A review of false positive serology. Int J STD AIDS 1995; 6: 241–248. 51 Kuznetsov AV, Burgdorf WH, Prinz JC. Latent syphilis confirmed by polymerase chain reaction in 2 HIV-positive patients with inconclusive serologic test results. Arch Der- matol 2005; 141: 1169–1170. 52 Smith G, Holman RP. The prozone phenomenon with syphilis and HIV-1 co-infec- tion. South Med J 2004; 97: 379–382. 53 Taniguchi S, Osato K, Hamada T. The prozone phenomenon in secondary syphilis. Acta Derm Venereol 1995; 75: 153–154. 54 Young H. Guidelines for serological testing for syphilis. Sex Transm Infect 2000; 76: 403–405. 55 Koff AB, Rosen T. Nonvenereal treponematoses: yaws, endemic syphilis, and pinta. J Am Acad Dermatol 1993; 29: 519–535.

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56 Marangoni A, Sambri V, Cavrini F, Frabetti A, Storni E, Accardo S, Servidio D, Foschi F, Montebugnoli L, Prati C, Cevenini R. infection is not a cause of false positive Treponema pallidum serology. New Microbiol 2005; 28: 215–221. 57 Erbelding EJ, Vlahov D, Nelson KE, Rompalo AM, Cohn S, Sanchez P, Quinn TC, Brathwaite W, Thomas DL. Syphilis serology in human virus infec- tion: evidence for false-negative fluorescent treponemal testing. J Infect Dis 1997; 176: 1397–1400. 58 Schmidt BL. Evaluation of a new particle gel immunoassay for determination of anti- bodies against Treponema pallidum. J Clin Microbiol 2004; 42: 2833–2835. 59 Schmidt BL, Edjlalipour M, Luger A. Comparative evaluation of nine different en- zyme-linked immunosorbent assays for determination of antibodies against Treponema pallidum in patients with primary syphilis. J Clin Microbiol 2000; 38: 1279–1282. 60 Hicks CB, Benson PM, Lupton GP, Tramont EC. Seronegative secondary syphilis in a patient infected with the human immunodeficiency virus (HIV) with Kaposi sarcoma. A diagnostic dilemma. Ann Intern Med 1987; 107: 492–495. 61 Augenbraun M, Rolfs R, Johnson R, Joesoef R, Pope V. Treponemal specific tests for the serodiagnosis of syphilis. Syphilis and HIV Study Group. Sex Transm Dis 1998; 25: 549–552. 62 Haslett P, Laverty M. The prozone phenomenon in syphilis associated with HIV infec- tion. Arch Intern Med 1994; 154: 1643–1644. 63 Malone JL, Wallace MR, Hendrick BB, LaRocco A, Jr., Tonon E, Brodine SK, Bowler WA, Lavin BS, Hawkins RE, Oldfield EC, III. Syphilis and neurosyphilis in a human immunodeficiency virus type-1 seropositive population: evidence for frequent serolo- gic relapse after therapy. Am J Med 1995; 99: 55–63. 64 Janier M, Chastang C, Spindler E, Strazzi S, Rabian C, Marcelli A, Morel P. A prospec- tive study of the influence of HIV status on the seroreversion of serological tests for syphilis. Dermatology 1999; 198: 362–369. 65 Rompalo AM, Cannon RO, Quinn TC, Hook EW. III. Association of biologic false- positive reactions for syphilis with human immunodeficiency virus infection. J Infect Dis 1992; 165: 1124–1126.

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Fragen zur Zertifizierung durch die DDA

1. Welche Aussagen zum 3. Welche Aussagen zum 5. Zum Stadium II der Syphilis syphilitischen Primäraffekt sind Erregernachweis in der können folgende Symptome korrekt? Syphilisdiagnostik treffen zu: gehören ... 1. Weniger als die Hälfte der 1. Eine negative Dunkelfeldunter- 1. in bis zu 80 % der Patienten Syphilispatienten werden im suchung schließt eine Syphilis besteht eine Hautsymptomatik. Primärstadium diagnostiziert. aus. 2. schmerzlose v. a. inguinal 2. Das syphilitische Ulkus ist immer 2. Histologisch können Spirochäten lokalisierte Gummata. induriert und schmerzlos. mittels Spezialfärbungen 3. palmoplantare Syphilide. 3. Die durchschnittliche Inkubati- visualisiert werden. 4. Plaques muqueuses v. a. am onszeit beträgt 21 Tage. 3. In vitro lassen sich Treponemen Gaumen. 4. Die Inspektion des Analkanals nicht kultivieren. 5. schmerzhafte Periostitis. sollte bei Verdacht auf Syphilis 4. Der PCR-Nachweis von trepone- a) 1 und 3 treffen zu immer erfolgen. maler DNS hat eine hohe Spezi- b) 1, 3, 4 und 5 treffen zu 5. Klassischerweise kommt es zu fität und Sensitivität, weshalb sie c) 1, 3 und 5 treffen zu einer unilateralen schmerzlosen routinemäßig eingesetzt wird. d) 3, 4 und 5 treffen zu Lymphknotenschwellung. 5. Falsch negative Resultate der e) Alle sind richtig a) 1, 3 und 4 sind richtig Dunkelfeldmikroskopie können b) 1, 4 und 5 sind richtig infolge Anwendung topischer 6. Welche Aussagen zur c) 1, 2 und 3 sind richtig Antibiotika oder Einnahme serologischen Syphilisdiagnostik d) 1, 2, 3 und 4 sind richtig systemischer Antibiotika treffen zu? e) Alle Aussagen sind richtig auftreten. 1. Unspezifische Tests (z. B.VDRL) a) alle sind falsch eignen sich für ein Screening, da b) 1, 2 und 4 sind falsch 2. Die Dunkelfelduntersuchung ... sie sehr kostengünstig und c) 1, 2, 3 sind richtig 1. ermöglicht die sofortige schnell in der Durchführung sind. d) 2, 3 und 5 sind richtig Diagnosestellung und 2. Eine 4-fache Titer-Veränderung e) 1 und 5 sind falsch unmittelbare Therapie. des VDRL (von 1:64 vor der 2. ist heutzutage überflüssig, da Behandlung auf 1:16 sechs die moderne Serodiagnostik je- 4. Welche Aussage zur Klinik der Monate nach Behandlung) des Krankheitsstadium erfasst. Syphilis trifft zu? spricht für eine hohe 3. von enoralen Läsionen sollte auf 1. Die Inkubationszeit der Lues Wahrscheinlichkeit einer Grund von Abgrenzungsschwie- kann bis zu 90 Tage betragen. erfolgreichen Therapie bei Lues II. rigkeiten von Treponema 2. Der Primäraffekt ist extragenital 3. Biologisch falsch positive pallidum gegenüber kommensalen am häufigsten im Handbereich unspezifische Tests sind häufig Spirochäten nicht durchgeführt lokalisiert. (> 40 %), weil falsch positive werden. 3. Das syphilitische Ulcus liegt Reaktionen bei Infektionen, 4. kann auch mit Reizsekret aus beim Mann klassischerweise im chronisch entzündlichen Prozes- Effloreszenzen des Sekundärsta- Sulcus coronarius, bei der Frau sen, Schwangerschaft, im fortge- diums durchgeführt werden. an den kleinen Labien. schrittenen Alter sowie bei HIV 5. wird heutzutage infolge hohem 4. Beim rektalen Primäraffekt ist vorkommen. materiellem Aufwand selten die Lymphknotenschwellung 4. Der TPPA/TPHA wird für die durchgeführt. inguinal lokalisiert. Screening-Diagnostik a) 1, 3 und 4 sind richtig 5. Die Inzidenz der extragenitalen verwendet und der am häufig- b) 1, 4 und 5 sind richtig Primäraffekte beträgt etwa sten verwendete Bestätigungstest c) 1, 2 und 3 sind richtig 5–14 %. ist der FTA-abs., welcher immer d) 1, 2, 3 und 4 sind richtig a) 1, 2 und 5 sind richtig noch als Goldstandard gilt. e) Keine der Aussagen sind richtig b) 2, 3, und 4 sind richtig 5. Falsch positive FTA-abs. sind sehr c) 1, 3, 4 und 5 sind richtig selten, können jedoch in der d) 1, 3 und 5 sind richtig Schwangerschaft sowie bei e) Alle sind richtig HIV-Patienten vorkommen. a) 1, 2, 4 sind richtig b) 2, 4, 5 sind richtig c) 1, 2, 3 sind falsch d) Alle sind richtig e) 2, 3, 4 und 5 sind richtig

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7. Die unspezifischen Tests in der 9. Grundsätze in der 10. Welche der folgenden Syphilis- Serodiagnostik ... Syphilisdiagnostik umfassen: Aussagen sind richtig? 1. umfassen v. a. den VDRL und RPR. 1. Nach einem positiven 1. Bei einer HIV-Koinfektion können 2. sind beweisend für eine Screening-Test hat umgehend die Seroreaktionen im Stadium I Treponematose. eine Therapie inklusive und II gelegentlich negativ 3. sind als Screening- Tests nur Partnerbehandlung zu erfolgen. ausfallen. bedingt einsetzbar. 2. Bei diskrepanten spezifischen 2. Fehlende IgM-Antitreponemen- 4. haben je nach Syphilis-Stadium Tests kann die Abklärung mittels Antikörper im Blut von eine unterschiedliche Sensitivität. Western-Blot hilfreich sein. Neugeborenen schließen eine 5. erlauben keine Aussage bezüglich 3. Bei fehlender Titerreduktion 6 Lues connata nicht aus. Therapieansprechen. Monate nach adäquater Behand- 3. Beim Nachweis von IgG-Antitre- a) 1, 3 und 4 sind richtig lung lohnt sich eine Bestimmung ponemen-Antikörpern im Blut b) 1, 4 und 5 sind richtig der Werte in einem andern des Neugeborenen muss eine c) 1, 2 und 3 sind richtig Labor. kongenitale Infektion d) 1, 2, 3 und 4 sind richtig 4. Spezifische Tests können angenommen werden. e) nur 5 ist richtig zwischen nicht-venerischen 4. Zur Sicherung einer Neurolues Treponematosen differenzieren. ist die parallele Untersuchung 8. Welche der folgenden Aussagen 5. Der FTA-abs weist speziell in der von gleichentags gewonnenen zur Syphilisdiagnostik sind richtig? Frühsyphilis die größte Liquor- und Serumproben 1. Spezifische IgM-Antikörper Sensitivität auf. erforderlich. gegen Treponemen sind a) 1, 2 und 5 sind richtig 5. Der Nachweis eines positiven mindestens 18 Monate nach b) 2, 4 und 5 sind richtig TPHA im Liquor beweist eine adäquater Behandlung noch c) 2, 3 und 5 sind richtig aktive Neurolues. nachweisbar. d) 2 und 5 sind richtig a) 1, 2, 3, 4 sind richtig 2. Unspezifische Tests (z. B.VDRL) e) nur 2 ist richtig b) 1, 3, 4 sind richtig und spezifische c) 1, 2, 4 sind richtig IgM-Antitreponemen- d) 1, 2, 5 sind richtig Antikörpertests sind hilfreich zur e) 2, 4, 5 sind richtig Überwachung der Therapieeffekte und des Krankheitsstadiums. 3. Die Unterscheidung zwischen Reinfektion und Reaktivierung kann serologisch einfach gestellt werden. 4. Als Screening-Test hat sich in Europa der TPHA/TPPA etabliert. 5. Enzym-Immuno-Assays (EIA) werden zunehmend für das Screening und die Bestätigung verwendet. a) 1, 2, 3, 4, 5 sind richtig b) 2, 3, 4 sind richtig c) 2, 4, 5 sind richtig d) nur 4 ist richtig e) 2, 3, 5 sind richtig

Liebe Leserinnen und Leser, Der Einsendeschluss an die DDA für diese Ausgabe ist der 19. Januar 2007. Die richtige Lösung zum Thema „Zosterneuralgien“ in Heft 10 (Oktober 2006) ist: 1d, 2d, 3c, 4d, 5b, 6a, 7c, 8e, 9d, 10f. Bitte verwenden Sie für Ihre Einsendung das aktuelle Formblatt auf der folgenden Seite oder aber geben Sie Ihre Lösung online unter http://jddg.akademie-dda.de ein.

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