The epidemiological and clinical presentation of syphilis in a venereal disease centre in Paris, France. A cohort study of 284

ARTICLE

Auteur(s) : David Farhi¹, Nada Zizi¹, Philippe Grange², Nadjet Benhaddou³, Philippe Gerhardt¹, Marie-Françoise Avril¹, Nicolas Dupin^1,2

¹Department of Dermatology and Venereology, Pavillon Tarnier, Hôpital Cochin, Université Paris 5-René Descartes, 89 rue d’Assas, 75006 Paris, France
²Centre National de Référence de la Syphilis, Laboratoire de Dermatologie, UPRES EA 1833, Université Paris 5-René Descartes, 89 rue d’Assas, 75006 Paris, France
³Department of Bacteriology, Pavillon Tarnier, Hôpital Cochin, Université Paris 5-René Descartes, 89 rue d’Assas, 75006 Paris, France

accepté le 30 Mars 2009

Following the advent of penicillin in the 1940s, the incidence of syphilis decreased sharply, jointly with a progressive shift toward a lower proportion of tertiary syphilis [1], and fluctuated at low rates [2]. During the mid-1990s, the incidence of syphilis reached an all-time low in developed countries [3-6]. In 2000, the primary and secondary syphilis rate in the United States (US) was the lowest since reporting began in 1941 [4, 7]. This incidence decrease in developed countries has been at least partly attributed to population-wide behavioural modification in response to the HIV epidemic [8]. As a consequence, many clinicians became unfamiliar with its clinical presentation and some have never been confronted with this disease. Moreover, since the turn of the millennium, a marked increase in the incidence of syphilis has been reported in several developed countries [3, 9, 10].

Syphilis is highly contagious in its early stages, and it has been estimated that 30-60% of sexual contacts of individuals with early syphilis will be infected [11]. Untreated syphilis may have a pervasive effect on health, including impact on the central nervous system and other internal organs [11, 12]. Furthermore, syphilis can result in miscarriage, stillbirth and congenital infection [13], facilitate the transmission of HIV infection [14], and in HIV-infected patients favors increases in HIV viral load and decreases in CD4 cell count [15]. Early diagnosis and treatment are essential to break the transmission chain and prevent congenital syphilis [16].

Our aim was to appraise the epidemiological and clinical presentation of syphilis in Paris, France. We conducted a descriptive study of all consecutive cases of syphilis diagnosed in our venereal disease centre over the 2000-2007 period.

Patients and methods

Study design

Our venereal diseases centre has two primary missions: (1) anonymous and free screening of asymptomatic STD in patients at risk or reporting unsafe sex; (2) diagnosis and treatment of STD in both asymptomatic and symptomatic patients. Over the study period, of 70,798 visits, 35,814 were motivated by clinical symptoms or signs (50.6%) and 34,984 corresponded to systematic screening in asymptomatic patients (49.4%). The 284 syphilis cases (0.4% of all visits) included in our study were diagnosed in both asymptomatic (systematic screening) and symptomatic patients (clinically-oriented screening).

Case definition

In patients with a previous history of syphilis, the diagnosis of a new syphilis infection required one of the following: (1) either a fourfold or greater increase of VDRL titers in an asymptomatic patient; or (2) – when previous VDRL titers were unknown – both positive serologic tests and a recent onset of syphilis clinical signs. Clinical staging of syphilis was based on sexual history, physical signs, dark-field examination and serologic tests.

Patients suspected of having non-primary syphilis were routinely evaluated for the presence of neurological and ophthalmic signs – including ocular fundoscopy. A lumbar puncture was performed in all patients with syphilis who presented either neurological or ophthalmic clinical abnormalities. Criteria for the diagnosis of neurosyphilis included a confirmed syphilis and at least one of the following cerebrospinal fluid features (CSF): (1) white blood cells > 10/mm³; (2) protein > 500 mg/L; (3) raised VDRL or TPHA index [3, 12, 17].

Laboratory testing

Data collection

Statistical analysis

Results

Epidemiological presentation

Clinical presentation

Clinical manifestations overall and by syphilis stages are summarized in table 3. Among sixteen patients who had a lumbar puncture, 10 (62.5%) were diagnosed with early neurosyphilis, including 8 with lymphocytic meningitis and 2 with radiculitis. All cases of neurosyphilis were associated with extra-neurological symptoms and signs of secondary syphilis, and were thus classified as having “early neurosyphilis”. An involvement of the eyes was diagnosed in 10/279 cases (3.6%), including 7 anterior uveitis and 3 papilledema and 1 retinitis (both anterior uveitis and papilloedema in 1 case). Seven patients had both neurological and ophthalmic involvements and 3 had an eye involvement without documented neurological abnormalities (two of them had a normal CSF and one declined the lumbar puncture). Recently acquired central hearing loss and tinnitus, which both receded after penicillin treatment, were diagnosed in one case.

A Jarisch-Herxheimer reaction occurred in 4 patients, all of whom were treated for secondary syphilis presenting with a diffuse roseola syphilitica. In all 4 cases, physical signs, which consisted of fever and exanthema exacerbation, developed within 24 hours of a first injection of penicillin G and faded within 48 hours of administration of oral prednisone (0.5 mg/kg, daily). The median baseline TPHA, VDRL and FTA-abs were higher among patients presenting a Jarisch-Herxheimer reaction (respectively 20480, 48 and 2400), than among the 121 other patients with secondary syphilis (respectively 10240, 32 and 1200), although this difference was not statistically significant due to the small number of occurrences.
Table 2 Reasons for clinical visits, stages, baseline VDRL titers and treatment of 284 consecutive cases of syphilis

Table 3 Clinical manifestations among 284 consecutive cases of syphilis, overall and according to clinical stages

^bDenominators below 284 indicate missing data.

^cIn most patients, the cutaneous eruption was made of oval pink discrete macules (roseola syphilitica).

^d2 neurosyphilis and 1 eye involvement occurred during primo-secondary syphilis.

Behavioural features and associated sexually transmitted disease

Previous sexually transmitted disease

Concomitant sexually transmitted disease

Syphilis in HIV-infected patients

^bAmong HIV-positive patients.

Discussion

In several recent reviews of the clinical presentation of syphilis, it is stated that 30 to 40% of syphilis cases are diagnosed at the primary stage [4, 24]. This low rate may result from numerous factors: (1) the absence of primary lesions; (2) the atypical semeiology or location of primary clinical signs; (3) the asymptomatic nature of most chancres and their possible location in internal mucosa, such as anus and vagina; (4) the patients’ inattention. The failure to diagnose syphilis at the primary stage maintains the transmission chain and exposes patients to extra-cutaneous complications, including neurosyphilis and ocular involvement. A raised degree of suspicion and an awareness of the actual epidemiological and clinical presentation of syphilis should help physicians in achieving the goal of early diagnosis.

The most striking epidemiological feature of patients diagnosed with syphilis over the past decade is the increasingly higher proportion of MSM and HIV-infected patients [25].

In our series, 83% and 50% of the cases occurred respectively in MSM and HIV patients. Similar trends have been reported in the US [7, 17] and in the UK [10]. In the US, 65% of syphilis occurred in MSM in 2005 [7]. In the US, among men infected with syphilis, 28% have HIV co-infection [26]. In the UK, 68% of 829 cases reported in 2005 occurred in MSM, and HIV co-infection was present in 45% of MSM versus 7% of heterosexual patients [10].

In the UK, the rates of syphilis were higher in the 25-34 year-old group (19/100,000) [10]. In our series, syphilis tended to occur even later in life (median age: 36 years, IQR: 30-44 years), as reported in the US [4].

Since the early years of the HIV epidemics, the numerous potential levels of interplay between HIV and syphilis have continuously fed controversies, and provided a rationale for intense clinical research [22]. Indeed, HIV and syphilis share common transmission routes and epidemiological risk factors, represent a heavy healthcare burden worldwide and have complex and multiple biological interactions. For instance, whether syphilis treatment and lumbar puncture indications should depend on the HIV status is still intensely debated [17, 18, 27]. Nevertheless, it is of note that studies from the 1980s and 1990s addressing the HIV – syphilis interaction were undertaken in an outdated epidemiological and biological context: since the advent of HAART in the mid-1990s, HIV infection has a markedly different clinical presentation and biological behaviour. In our series, almost nine patients out of 10 had over 200 CD4 cells/mm³ and the median RNA level was low (300 copies/mL). Clearly, when dealing with the medical literature on the issue of the syphilis – HIV interaction, one should always consider that there is a pre-HAART era and a post-HAART era. Thus, we need to re-think and re-appraise this point in further controlled studies.

We observed that most patients diagnosed with syphilis had a previous history of at least one STD. HIV infection was diagnosed – previously or concomitantly – in half of syphilis cases. Although it is universally recognised that having another STD is a risk factor for having syphilis, studies providing estimates of the rates of past or present STDs in patients with syphilis are scarce. In a recent survey, Dumortier et al. found that of 184 syphilis cases, 36 were concomitantly diagnosed with at least one other STD, including 15 HIV co-infections, 10 chlamydial infections, 6 gonococcal infections, 3 LGV and 3 human papillomavirus infections [28].

The anatomical location of primary lesions reflects the transmission route. Most extragenital chancres are located in the anal and oral areas [4, 29, 30]. In a retrospective study of homosexual men in London, primary lesions were located on the mouth in 13% of patients and on the anal margin in 20% [31]. In our series, the chancre was located in the mouth and the anal margin in 7.3% and 14.6% of primary syphilis cases, respectively. In 2005, in the UK, 45% of syphilis occurring in MSM were reported as acquired through oral sex [10]. In our series, condom was never used for oral sex in 83.2% of the cases and the chancre had an oral location in 7.3% of primary syphilis cases. Unprotected oral sex as the sole high risk sexual practice has been reported previously as a significant factor in sustaining the syphilis epidemic [32]. The idea that oral sex is “safer” is widespread and should be addressed by targeted educational campaigns [25, 33, 34].

Large studies of the clinical presentation of syphilis have been scarce over the past decade [28, 35]. Thus, knowledge of the clinical picture of syphilis is mainly based on textbooks [1] and older studies [36, 37]. In our series, most syphilis cases (77%) were symptomatic and nearly one third of the cases were diagnosed at the primary stage. In untreated patients, the average chancre healing time was 6 weeks and the lymphadenopathy usually persisted for longer [4]. Untreated, half of the patients subsequently develop symptoms of the second stage and half enter directly into the latency phase. The chancre persists at the onset of the second stage of syphilis in up to one-third of the cases overall and more often in HIV co-infected patients [35]. In our series, 10 of 217 (4.6%) early symptomatic syphilis presented with clinical signs of both primary and secondary stages. The dramatic late manifestations are increasingly rare in industrialized countries [23] and were not diagnosed in our series.

The most common extra-dermatological manifestations of syphilis in our series involved the nervous system and the eyes (present in respectively 6.4% and 7.2% of secondary syphilis). In all cases, these manifestations receded after penicillin treatment. In published studies, internal organ involvements have been reported in about 10% of syphilis [11]. In a recent American series of 231 consecutive syphilis in HIV co-infected patients, neurosyphilis was diagnosed in 41 cases (18%), and was significantly associated with CD4 cell count < 350/mm³, rapid plasma regain titre > 1/128, and male sex [38]. In a recent French series of 80 consecutive secondary syphilis, the rates of central nervous system and eye involvement were 7.5% and 8.8%, respectively [28]. In an older study, a cytolytic hepatitis was diagnosed in 17 of 175 cases of early syphilis (10%) [37]. Among 409 patients with syphilis who underwent fundoscopic examination, 13 patients presented abnormalities (3.2%), including chamber clouding, papilloedema, optic nerve atrophy and retinal lesions [35]. CSF abnormalities were significantly more frequent in HIV-infected patients [35].

In conclusion, since few clinicians have dealt with syphilis, the need for increased awareness of the actual presentation of the disease has recently been emphasized [4]. We have presented herein the epidemiological and clinical features in a large series of recently diagnosed syphilis in Paris, France. Among the most interesting findings, we have demonstrated a strong predominance in men, peculiarly MSM, a high rate of HIV co-infection, a scarce use of condoms, especially for oral sex, and a marked preponderance of early symptomatic syphilis. The likely absence of a syphilis vaccine in the foreseeable future implies that future syphilis control will essentially rely on safer behaviour and early treatment [11]. Our findings contribute to updating the current epidemiological and clinical picture of syphilis and could be incorporated in medical training and guide targeted sexual health promotion campaigns on STD prevention.

Ackonwledgement

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