The syphilis spirochete in the XXI century

Syedah Sarah Hussaini1, Fran Dominic Grubeša2


From the recognition of the disease during its European outbreak in the late XV century, to the identification of the spirochete itself four centuries later and the concentrated interest in the disease beyond that time, diverse attempts were employed to study its complex pathogenesis and versatile presentations in hope for complete eradication. Despite the emergence of penicillin in 1928 and novel methods for early recognition of syphilis, the centuries old pathogen, Treponema pallidum subspecies pallidum, still reminds us of its existence today (Figure 1). Ever since reaching a historic low in the early 2000s, syphilis cases continue to rise reaching 129,813 new reports of syphilis at all stages in 2019 as estimated by the Centers for Disease Control and Prevention (CDC) [1].

Syphilis’ great array of clinical manifestations is at the core of its complexity and consequently, poses significant diagnostic challenges for even the most experienced clinicians. In fact, many refer to the disease as “The Great Pretender'” due to its ability to mimic a plethora of dermatological diseases [1, 2]. Therefore, dividing syphilis into stages has been particularly important in the treatment and management of this infectious disease.

Staging of syphilis requires detailed patient history and careful anogenital and dermatologic inspection in order to correctly assume primary, secondary, latent or tertiary stages [3].

Despite the inherent challenges that accompany investigating this pathogen, namely the inability to generally culture or genetically manipulate T. pallidum, researchers have been successful in uncovering certain facets of its pathogenicity [4, 5]. It is known that the stealth organism is reliant on the human body as its only natural host and that it’s mode of transmission may be horizontal via sexual exposure or vertical resulting from haematogenous dissemination across the placenta. Despite effective diagnostic methods, difficulties in their interpretation are often encountered. In terms of treatment, long-acting penicillin preparations such as benzathine penicillin G are highly effective for all stages and the preferred therapy for most patients, leading to a serologic cure especially in its early stages [6]. All things considered, syphilis should be an ideal candidate for elimination and yet, the notably rising number of cases reported allows it to remain a global public health challenge during our time [1].

Epidemiology: transmission, occurrence

The transmission of syphilis occurs in large by direct person-to-person contact with a syphilitic sore, also known as a chancre. A chancre is usually a single ulcer on the site where the bacteria has entered the body. The genitals are the most common areas for further development of the ulcer, however these ulcers may also form around the anus or the mouth. Ulcers that developed from syphilis have a painless and firm characteristic and are filled with fluid containing the syphilis bacteria. During this stage of infection syphilis is highly contagious due to the oozing properties of these ulcers. It is important to understand the foundations of syphilis transmission in order to provide further insight into its prevalence and incidence rates. Transmission of syphilis is mostly promoted by sexual contact, this includes vaginal, orogenital and anogential contact. Furthermore, the spread may also be congenital. In this case the congenital spread is in utero but may, in a small number of cases, be spread during passage through the birth canal. Albeit rare, cases of transmission through blood products or organ donation have also been recorded [1]. A chancre of primary syphilis may heal after one to five weeks [1] or longer; individuals, however, remain infected. The burden of syphilis transmission and infection is soaring worldwide, with an approximate 10.6 million incident cases occurring annually [8].

The epidemiological development of syphilis throughout the XXI century is becoming increasingly more prevalent. It has become a general consensus that syphilis infection is easily identifiable and effectively treatable. However, data suggest that the rate of infection continues to rise in all varieties of socioeconomic and gender populations. The global transmission and occurrence rate are difficult to precisely analyze due to lack of adequate reporting and multifactorial hindrances in data collection. Estimates show that syphilis rates in Asia have increased through the 1990's and 2010’s (Figure 2).

Figure 2. Average number of eligible syphilis prevalence data points, recorded in the Spectrum STI syphilis database, grouped by WHO region. Lines represent linear trend lines fitted through the data points for each region. This graph originates from an article licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license (http://creativecommons.org/licenses/by/4.0/), and indicate if changes were made: Korenromp EL, Mahiané SG, Nagelkerke N, Taylor MM, Williams R, Chico RM, Pretorius C, Abu-Raddad LJ, Rowley J. Syphilis prevalence trends in adult women in 132 countries – estimations using the Spectrum Sexually Transmitted Infections model. Sci Rep 2018; 8:11503. DOI: 10.1038/s41598-018-29805-9 [12].
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In Europe, the rates of syphilis have been shown to be more prevalent in southern and eastern areas. These rates are considered to be around 6.0 per 100,000. Furthermore, similar to other reports, the incidence rate is substantially higher in men (Figure 3), especially men who have sex with men (MSM). General reports on infection vary throughout Europe.

Figure 3. Primary and secondary syphilis — distribution of cases by sex and sex of sex partners, United States, 2019. Chart originates from Centers for Disease Control and Prevention, National Overview – Sexually Transmitted Disease Surveillance, 2019 /online/. Access valid on 12 April 2022: https://www.cdc.gov/std/statistics/2019/overview.htm#Syphilis [16].
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The lowest recorded rate of infection was in Croatia, where 1 in 100,000 were affected and highest was Denmark where 13.7 in 100,000 were infected. The CDC have assessed that in the beginning of the XXI century, transmission and occurrence of syphilis plummeted to historical lows. It is only after the years 2000 and 2001 that syphilis rate of transmission and infection began to rise. According to the CDC, the increasing rates of primary and secondary syphilis are likely attributed to the growing population of MSM. In 2019 cases of syphilis related to MSM remained stable. However, estimates show that syphilis infection counts directly attributed to MSM are “disproportionately impacted” [9] and still account for the majority (56.7%) of all male cases in 2019 (Figure 4).

Figure 4. Map of syphilis prevalence estimates among men who have sex with men by country. Map originates from an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited: Tsuboi M, Evans J, Davies EP, Rowley J, Korenromp EL, Clayton T, Taylor MM, Mabey D, Chico RM. Prevalence of syphilis among men who have sex with men: a global systematic review and meta-analysis from 2000–20. The Lancet Global Health 2021; 9:E1110-8. DOI: 10.1016/S2214-109X(21)00221-7 [19].
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The rates of primary and secondary syphilis are lower in women than men, but still show a considerable increase in the recent time. Rates of infection have increased by an estimated 178.6% from 2015-2019 [9]. These data suggest that the syphilis epidemic is on the rise (Figure 5).

Figure 5. Syphilis — rates of reported cases by stage of infection, United States, 2010–2019. Graph originates from Centers for Disease Control and Prevention, National Overview – Sexually Transmitted Disease Surveillance, 2019 /online/. Access valid on 12 April 2022: https://www.cdc.gov/std/statistics/2019/overview.htm#Syphilis [20].
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According to WHO estimates, syphilis prevalence in key populations such as female sex workers (FSW) and MSM provide an additional index of data in regards to syphilis prevention and control. Data indicates that about one in five countries reported syphilis prevalence in these key populations [10] in 2016-2017. The median values of syphilis cases show a seroprevalence of 3.2% for FSW and 6.0% for MSM [10]. Syphilis among MSM was reported in more than half of the countries with a seroprevalence of more than 5%.

SARS-COV-2 co-infection. Precise numbers on the prevalence of syphilis in correlation with the rising number of SARS-CoV-2 infections since the beginning of the pandemic, remain unknown. Nonetheless, a retrospective review was performed on a number of patients screened for syphilis and found that the rate of presumed active infection increased from 1.2% to 1.8% in the span of one year and almost 20% of patients with presumed active infection presented for STI-related complaints [11]. Another study suggested that social measures introduced to help prevent the transmission of SARS-COV-2 may have influenced sexual risk behaviours and as a result, modified the incidence of syphilis [13]. Still, continued epidemiological surveillance for an extended period of time is required to more accurately draw conclusions from SARS-COV-2 and its coexistence with sexually transmitted infections (STIs).

Pathogenesis and clinical manifestations

The information regarding the pathogenesis of syphilis mainly derives from animals, simply due to the finite amount of conclusive evidence available through human study. It is generally accepted that the T. pallidum bacteria penetrates through breaks or tears in human skin [14]. Further inoculation of organisms, such as rabbits in the case of Magnuson et al. whose experiments yielded concrete evidence on the intracutaneous inoculation of syphilis and the appearance of a chancre in 50 to 7 days [15] provided great insight into our further understanding of syphilis.

Only years later, in 1932, the U.S Public Health Service (USPHS) conducted a study that aimed to record the natural history of syphilis. Working in part with the Tuskegee Institute, the study was originally called "Tuskegee Study of Untreated Syphilis in the Negro Male", but is now referred to as the "USPHS Syphilis Study at Tuskegee". The study involved the examination of healthy and infected individuals and in most cases informed consent was not collected [17]. Participants were being treated for “bad blood” a term which was used to describe a plethora of ailments including anaemia, fatigue, and syphilis. Even though penicillin was available and considered as the appropriate treatment for syphilis by 1943, it was not administered to affected individuals. Some 30 years later, the study was evaluated and deemed "ethically unjustified", thus forcing panels to advise the study be stopped. Approaching the XXI century the pathological findings of T. pallidum become abundant. The current research supports that T. pallidum is a helically shaped microaerophilic bacterium consisting of a central protoplasmic cylinder bounded by its membrane, a peptidoglycan layer, and an outer membrane [18].

It uses two to three flagella for locomotion, which originate at the ends of each organism. T. pallidum virtuosic properties are seen in its outer membrane structure, with only a few exposed transmembrane proteins. This lack of immune targets on the outer membrane has led to T. pallidum being labelled as a “stealth pathogen” [18]. Furthermore, the precise mechanisms involving T. pallidum’s ability to enter cells is still not known. However, it has shown in vitro attachments to mammalian cells, and in some cases attachment may have occurred in specific ligands [8]. T. pallidum’s most critical virulence factor demonstrates the ability to penetrate the endothelial cell monolayers and membranes.

The true origins of syphilis are still a matter of debate and its inception has been hypothesized for multiple centuries. As we stand today, two theories are proposed; the Old World and New World theory. The first assumes that syphilis origins are rooted in central Africa. The second assumes that syphilis was a localized endemic in modern day Haiti, and was later in the 1400's brought to Europe by Columbus. However, we now know that by 1495 syphilis spread throughout Europe, and shortly after spread to India and China in 1498 and 1505 respectively. Lues venereum, the Great Pox, morbus gallicus and German, Spanish, Polish, or Italian disease were all early names for the disease caused by T. pallidum. It was only in 1530 that Hieronymus Fracastorius coined the term syphilis. Syphilis was the name of a mythical shepherd and is now known to have derived from a character of one of his poems – Syphilis Sive Morbus Gallicus. Early investigations of syphilis supported the idea that gonorrhoea and syphilis were the same disease. This was due to experimental patients involved in the study developing symptoms of both diseases, but once lesions (chancre) and signs of what we now know as secondary syphilis appeared, researchers believed donors had both gonorrhoea and syphilis [21]. In later history, researchers such as Philippe Ricord were able to justify their conclusions in regards to the mechanisms and clinical manifestations of syphilis by conducting studies with over 2,500 human inoculations [21]. Due to Ricord’s intensive study, he became a pioneer in the clinical distinguishment of syphilis and proposed to classify syphilis into modern sub-categorical stages which we still use today; primary, secondary, tertiary stage (Table 1).

Table 1. Syphilitic stages and clinical manifestation throughout incubation periods.
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Primary syphilis is mainly characterized by chancre and lesion manifestation [9]. These lesions are painless, round, and singular in the affected areas. However, infected individuals may notice multiple sores if the bacteria has entered the body through multiple locations [3]. Common areas affected include: anus; vagina; penis; rectum; and/or the lips and mouth (Figure 6).

Figure 6. Individuals infected with syphilis. Manifestation of primary stage syphilitic chancre. Photos originate from the article published under a Creative Commons Attribution-NonCommercial 4.0 International License: Ramoni S, Cusini M, Gaiani F, Crosti C. Syphilitic Chancres of the Mouth: Three Cases. Acta Derm Venereol 2009; 89:648-9. DOI: 10.2340/00015555-0709. Access valid on 12 April 2022: https://www.medicaljournals.se/acta/content/html/10.2340/00015555-0709 [22].
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In most clinical cases, the painless nature of the sores causes patients to be unaware of their infection. Lesions and sores tend to last between 3-6 weeks [23]. These lesions generally heal regardless of whether patients have received treatment and individuals may disregard the fact that treatment is still necessary. Adequate treatment will stop the further progression of syphilis past the primary stage. Lymphadenopathy is another key clinical manifestation of primary stage syphilis. Similarly to the chancre of primary syphilis, clinical manifestations such as bilateral inguinal lymphadenopathy is also usually painless [1]. Regional or generalized lymphadenopathy is almost always present with primary and secondary syphilis. Distant affected areas most commonly involve the inguinal region and its corresponding lymph nodes. In this case most often associated with sores and lesions localized in the genital region of infected individuals.

After 2-12 weeks from the initial infection, the primary sores heal and the onset of secondary stage of syphilis ensues. During the secondary stage of syphilis, individuals develop rashes and sores in the mouth, anus, or vagina [3]. These rashes are usually localized on the palms of the hand or bottom of the feet and have rough, red to brown colour (Figure 7). Such rash can also show up when the primary sore is healing or several weeks after the sore has healed.

Figure 7. Atypical palmar (A) and plantar (B) manifestation, misdiagnosed as palmoplantar psoriasis, during the secondary stage of syphilis. Photos originate from the article distributed under the terms of the Creative Commons Attribution License: Martins CJ, Lima RB, de Araujo Eyer‑Silva W, Almenara CB, Carvalho-Rangel I, de Souza Carvalho R, Basílio-de-Oliveira RP, de Araujo LF, de Almeida Ferry FR, da Silva LR. Secondary syphilis presenting as Syphilide psoriasiforme: lessons from the older syphilology literature. Rev Inst Med Trop São Paulo 2020; 62:e21. DOI: 10.1590/S1678-9946202062021 [24].
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In most clinical cases the rash is not itchy or irritable. Sometimes patients do not notice its appearance. Further clinical manifestations include hair loss (alopecia), fever, headaches, sore throat, swollen lymph nodes and in some cases individuals may develop meningitis. Syphilitic meningitis is actually a form of neurosyphilis [25], and unlike previously mentioned symptoms, it is a life-threatening complication associated with secondary stage syphilis. Symptoms of secondary stage syphilis will begin to recede if treated. Without proper treatment the infection will progress to the latent and in some cases to the tertiary stage of syphilis [1].

Individuals whose syphilis infection remains untreated past the twelve week incubation period of secondary stage syphilis will almost always remain asymptomatic throughout the latent stage; showing no visible symptoms or signs of infection. The disease still, however, continues to inhabit the body. Luckily, clinical evidence and multiple studies show that a large proportion of untreated individuals do not develop tertiary syphilis [1]. In the chance of further development, the disease may continue to affect a wide array of organ systems. The possible affected areas include the cardiovascular system, brain, and thus the entire nervous system. Neurosyphilis is an example of such development. Without treatment, yphilis spreads to the brain and nervous system and can occur at any given syphilis stage [1]. The symptoms and side effects of ongoing tertiary syphilis are far more serious and could develop as far as 30 years after initial infection [18]. The development of the disease in this syphilitic stage could result in organ failure and death.

Diagnostic considerations

The varied and often subtle nature of syphilis' clinical presentations make it quite difficult to diagnose, leading to numerous infections remaining unrecognized. Nevertheless, the majority of syphilis cases are diagnosed through a combination of clinical findings, examination of lesion material for treponemes and serological testing that includes treponemal and nontreponemal tests [7, 18]. Although direct and indirect methods help provide a definitive diagnosis, some are not as readily available in many clinical settings.

A successful and sustained culture of the organism that causes the infectious disease is challenging and primarily used in research. Its infectious capability is lost within a few days of harvest outside its obligate mammalian host, but isolation of T. pallidum for the purpose of investigation has been achieved through rabbit inoculation [4, 7, 26]. Direct detection using dark-field microscopy when lesions are present is preferable. This method is most suitable when lesions are moist and if the examination can be done instantly after specimen retrieval [27]. Unfortunately, most clinical settings do not encompass the capacity to perform such visualization of this small organism. Alternatives for definitive diagnosis by direct detection of T. pallidum include fluorescent antibody staining, immunohisto-chemistry and nucleic acid amplification (PCR) [6, 27, 28]. Still, with the exception of PCR, these methods remain insensitive and require services of reference laboratories and clinical expertise [27].

There is no single optimal alternative test, but today the most common method for syphilis screening, diagnosis and monitoring is serological testing [28]. As previously stated, serological tests fall into two categories: nontreponemal and treponemal. The nontreponemal serological tests (NTTs) are classified as such due to their ability to assemble antibodies which act in response to an antigen that is not unique to T. pallidum. This particular antigen is decorated with lecithin, cholesterol and cardiolipin, molecules that are thought to be incorporated into the pathogen’s membrane and create an antigenic configuration capable of reacting with antibodies produced in response to infection [4, 28]. NTTs (e.g. a rapid plasma reagin [RPR], the Toluidine Red Unheated Serum Test [TRUST] or the Venereal Disease Research Laboratory [VDRL] tests) are useful in detecting active syphilis, but do not become positive until 10 to 15 days after the primary chancre appears. Due to this disadvantage, up to 30% of syphilis cases may remain undiagnosed (Table 2) [29]. IgG and IgM antibody titres correspond with the stage of the disease, increasing throughout the initial time of infection and reaching peak levels at the late secondary or early latent stage of the infection [27]. A rapid decline may be observed after treatment initiation with a slower rate of decline in the absence of treatment. In fact, without treatment the nontreponemal titres peak at around 1 to 2 years after infection, but may remain positive even at low titres throughout late stages. 20% of patients experience a persistently reactive low titre NTT that is a possible consequence of a weakened pro-inflammatory immune response [30].

Treponemal tests (TTs), on the other hand, detect antibodies directed against T. pallidum and are generally more sensitive than NTTs during early infection with syphilis [31]. One must keep in mind, however, that most patients suffering from syphilis have treponemal antibodies that persist throughout their entire life. Hence, TTs (e.g. T. pallidum particle agglutination test (TPPA), fluorescent treponemal antibody absorption or the T. pallidum haemagglutination tests) cannot be used as a method to distinguish a current infection from a previously treated infection and furthermore, cannot be used to monitor treatment effectiveness [6]. In contrast to NTTs, TTs can offer a positive result around 6-14 days after the onset of the primary lesion, which may aid early detection that may have been missed by the less sensitive NTTs [29]. Additionally, up to 24% of syphilis-infected patients have seroreversion even after years post-therapy (Table 2) [7]. These tests are more expensive than NTTs and also require trained personnel and specialized equipment that is not always readily available. Thus, limiting their use as confirmatory assays [32].

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Figure 1. This photomicrograph depicts a Treponema pallidum bacterium, a spirochete 5-15 µm in length, which is the causative agent of syphilis. This image and text are in the public domain and are courtesy of the Public Health Image Library, Susan Lindsley, and the National Centre for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention.
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In the standard testing algorithm, reactive NTTs are confirmed by TTs. Reverse algorithms where TTs are used initially are also an approved method of diagnosis, but are of questionable benefit in high prevalence populations and in patients with a history of syphilis, ue to the aforementioned persisting nature of treponemal antibodies. Furthermore, it is important to note that serologic results are nonreactive in up to 30% of patients and therefore, should be performed once more after 2 weeks if a nonreactive result is initially obtained (Table 2) [7].

Table 2. Standard and reverse testing algorithms with interpretation of serological results.
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Diagnostic considerations regarding referrals for lumbar puncture and cerebrospinal fluid (CSF) analysis are currently recommended for diagnosis of neurosyphilis in patients with corresponding clinical signs and symptoms, for individuals with suspected treatment failure and for some patients in latent or tertiary stages of the disease [28, 32]. Treatment and special circumstances

First syphilis treatments dating back to the early XVI century included preparations of guiacum or mercury as its alternative [33]. In fact, mercury’s seemingly higher efficacy led to its extensive use as an oral compound, a topical ointment, as an injection and was even administered through fumigation. Although the use of mercury had detrimental side effects, such as mouth ulcers, loss of teeth, kidney failure, neuropathy or mercury poisoning, it stayed in favour as treatment for many years to come. Things changed in 1910 after Paul Erlich received the Nobel Prize for the discovery of the antisyphilitic effects of arsenic and developed what can be considered the first modern antimicrobial agent: Salvarsan or “the magic bullet” [31, 34]. In spite of recorded drug efficacy, many cases progressed to the development of neurosyphilis. In response to this unsatisfactory result, a Nobel prize was awarded to Julius Wagner-Jauregg for his malariotherapy invention that was based on the observation that malaria inoculation and the subsequent febrile illness clearly reduced neurosyphilis-related symptoms [35]. Nowadays, such pyrotherapy experimentation, that is inoculating patients with a pathogen to help reduce symptoms caused by another pathogen, would be considered deeply unethical. Furthermore, Wagner-Jauregg’s honorary status sparked great controversy due to the discovery of his involvement in the Nazi party and his support of Hitler’s ideology of racial purity [35]. To this day, his role as an enthusiastic proponent of Nazi doctrines overshadows his medical achievements [36].

The real breakthrough and the pinnacle of syphilis therapy transformation occurred in 1943 when Mahoney et al. proved successful treatment of the early stage infection with penicillin [14]. With no reported cases of resistance, penicillin remains the drug of choice to date. A single dose of 2.4 million units of the long-acting benzathine penicillin G intramuscularly (IM) is currently recommended for primary, secondary and early latent syphilis. CDC further recommends the same dose of the drug once a week for three consecutive weeks for the treatment of late latent syphilis or latent syphilis of an unknown duration. Due to the inability to achieve measurable levels of benzathine penicillin G in the CSF, patients with tertiary syphilis suffering from neurosyphilis or ocular syphilis require treatment with intravenous (IV) aqueous crystalline penicillin G for 10-14 days [37]. Response to treatment is assessed both clinically and serologically [38].

Treatment reactions must be adequately disclosed with every patient receiving the recommended therapies. Syphilis is the leading spirochetal infection that gives rise to what is known as the Jarisch-Herxheimer reaction (JHR) manifesting as fever, chills, headache, myalgia and a possibly worsening rash. Often mistaken for an allergy and sometimes overlooked as signs of the underlying infection, JHR is hypothesized to be related to a massive destruction of the spirochete, leading to an inflammatory response as a result of a significant release of lipoproteins and cytokines [39]. It has been reported to occur in up to 70% of patients with early stage syphilis, and so should be presented as a likely risk for individuals receiving treatment [40]. For patients with confirmed penicillin allergy through patient history or a positive skin test, other effective antimicrobials should be used (e.g. doxycycline, tetracycline, ceftriaxone). Additionally, to cater to patients for whom the only option is penicillin (i.e. during pregnancy, patients with neurosyphilis) desensitization is recommended [41].

Human immunodeficiency virus (HIV) co-infection. Studies have indicated the correlation between individuals with a history of syphilis or other sexually transmitted infections and their risk for HIV acquisition. The dense infiltration of lymphocytes which are the primary target cells in HIV at sites of genital ulcerations create a focused route for HIV acquisition and transmission [7]. In the United States, almost 50% of MSM with primary and secondary syphilis have been found to also be living with HIV [1]. Most patients have shown similar clinical manifestations to those without the coexistent HIV infection, however some studies havedocumented instances of more apparent genital lesions and a faster rate of syphilis progression into neurosyphilis [42]. Due to this complication, patients may have an increased likelihood of inadequate serologic response to therapy. Case reports and retrospective studies have addressed whether outcomes of treatment in syphilis-infected patients with HIV and those without the concurrent infection differ. Although larger prospective studies are needed, there has been no evidence for more effective treatment regimens in preventing syphilis progression. Hence, benzathine penicillin G remains the treatment of choice for both groups of patients with further close follow-up for treatment failure and CSF analysis [32, 43]. It is important to note that unless neurologic signs are present, the CDC does not recommend CSF examination for persons with early syphilis, irrespective of HIV status [32]. Available data regarding enhanced penicillin regimens such as the additional administration of amoxicillin and probenecid, demonstrates no association with improved clinical outcomes and most persons with HIV and coexisting primary, secondary or early latent syphilis, still respond best to the single dose penicillin injection [43].

Pregnancy and congenital syphilis. Congenital syphilis occurs through vertical transmission when T. pallidum is passed from mother to foetus transplacentally. Such transmission may occur at any gestational age and transmission rates are highest in the primary and secondary stages of the infection (40-90%) compared to latent stages (10-40%) [44]. If mother-to-child transmission occurs within the first trimester of the pregnancy (early congenital syphilis), it may result in detrimental consequences such as spontaneous abortion, premature delivery, nonimmune hydrops, stillbirth or perinatal death [45]. On the other hand, most infants born to mothers with untreated syphilis that got infected during the second or third trimester (late congenital syphilis) have no clinical or serological evidence of the infection at birth. However, if the seemingly-healthy children are left untreated, they may develop clinical manifestations months or years later [8]. Many develop within the first 3 months of life, persistent rhinitis or “snuffles” being one of the earliest signs and occurring in up to 22% of infants. Such nasal discharge is highly contagious and may present itself as profuse and purulent or stained with blood [45]. Other main manifestations of congenital syphilis include hepatosplenomegaly, skin rash with desquamation, chorioretinitis, cataracts, glaucoma, periostitis, gastrointestinal malabsorption, nephrotic syndrome, anemia or thrombocytopenia [46]. All women who are seropositive for syphilis during pregnancy should be given benzathine penicillin G to prevent transmission [31]. Till date, there are no proven alternatives for treatment of syphilis in pregnant women. Similarly, there are no substitute regimens for congenital syphilis and benzathine penicillin G must be given to treat foetal infection as well [46]. Thus, in cases of penicillin allergy, desensitization is required by means of specific protocols or modified protocols performed by allergists that may require patient referral to specialized centres [31]. As recommended by the CDC, pregnant women should be treated with the advised penicillin regimen for their stage of infection and confirmed or highly probable congenital syphilis should be treated with aqueous crystalline penicillin, 100,000-150,000 units per kg per day, administered as 50,000 units per kg body weight per dose by IV every 12 hours during the first 7 days of life and every 8 hours thereafter for a total of 10 days or procaine penicillin G, 50,000 units per kg body weight per dose IM in a single daily dose for 10 days [46].

Neurosyphilis, ocular syphilis and otosyphilis. Syphilitic infection of the nervous system can occur at any stage of the disease and remains one of the most feared complications. First, the presence of the disease must be addressed through reactive serological tests and CSF abnormalities in order to further provide treatment [27]. When there is clinical evidence of neurologic involvement (e.g. motor or sensory deficits, cognitive dysfunction, cranial nerve palsies, signs of meningitis or stroke symptoms) a CSF examination must be performed prior to the start of therapy [25]. Ocular or otologic syphilis manifestations that might occur throughout the course of untreated syphilis may be isolated abnormalities or may be associated with the aforementioned complication of neurosyphilis. As opposed to neurosyphilis, isolated eye and ear involvement does not need prior CSF analysis, but immediate referral and collaboration with ophthalmologists or otolaryngologists is pivotal. Currently the recommended regimen for neurosyphilis, ocular syphilis and otosyphilis among adults by the CDC is aqueous crystalline penicillin G, 18-24 mU IV every 4 hours for 10-14 days or if compliance can be assured procaine penicillin, 2.4 mU IM daily plus probenecid, 500 mg orally 4 times a day for 10-14 days may be considered [25].

Screening and prevention

Screening and prevention are of utmost importance in the attempt to stay one step ahead in the battle against syphilis. Infected individuals are frequently asymptomatic and must address early symptoms and warning signs in order to prevent reinfection and spread of the disease. The U.S. Preventive Services Task Force (USPSTF) recommends early screenings for syphilis infection in persons who are at an increased risk for infection [47]. Their risk assessment has concluded that MSM and persons living with HIV are the highest risk populous for syphilis; factors which are directly associated with higher prevalence rates include: history of incarceration, FSW, ethnicity, geography, and males under 29 years of age [47]. Other external risk factors include general engagement in unprotected sex and/or having sex with multiple partners. Screening for syphilis has become highly accessible and many effective tests have been developed. The most common screening method is the use of nontreponemal and treponemal antibody tests.

The USPSTF concluded with a high certainty that non-pregnant individuals in the aforementioned risk categories benefit substantially from screening for syphilis. Furthermore, it has also recommended screening for syphilis in pregnant women and adults who are sexually active. The ability of a pregnant woman to pass syphilis onto an unborn baby is a critical factor. Congenital syphilis increases the rate of miscarriage dramatically. Health officials generally recommend that all pregnant women go through screening for syphilis [47].

Prevention also plays a critical role in public health in regards to the syphilis infection. The USPSTF believes that public health agencies are responsible for investigating reported syphilis cases and should attempt to identify further contacts who may require screening or treatment [47]. In the United States, primary care doctors are provided with several legal apparati responsible for reporting syphilis cases. Seeing that no vaccine for syphilis is currently available, it is important to mention the main prevention against syphilis is practicing safe sex [2].

Quality of life and future directions

Stigma associated with syphilis permeated social and cultural boundaries across centuries. Modern paleolithic examinations with skeletal remains dating back to the period of incurable syphilis and mercury toxicity, that is the XVII-XVIII century, show significant basis for severe physical stigmata with individuals having advanced skeletal changes that eventually led to complete destruction of the body [48]. Historical reports dating back from the XV century further indicate the disease caused by T. pallidum and its manifestations as being a source of public alarm resulting in many individuals hiding their symptoms in fear of social rejection [33]. Unfortunately, reductions in rates of tertiary disease and associated virulent complications we see today have not drastically improved quality of life in syphilis-infected patients. In the modern era, studies on the ethical responsibility of partner notification show permanent anxiety, fear of retaliation, domestic violence and often loss of relationships due to the diagnosis [21]. In fact, research further demonstrates hat syphilis is the source of more stigma than other STI diagnoses and patients assign the greatest amount of shame to it than to any other STIs, including HIV/AIDS and other disfiguring skin conditions [49,50].

Additionally, stigma and the aforementioned shame associated may be of key influence in the major public health challenge that is the underreporting of STIs. In fact, many patients with STIs in countries with a high number of cases seek to obtain medications directly from pharmacies, without first consulting a clinician. Avoidance of proper diagnosis by a professional (and consequently, proper treatment) may lead to diminished or completely absent reporting at a central level even in countries with increased STI prevalence. Special studies such as outbreak investigations, studies on public and private sector STI screening or evaluations of STI syndromic management algorithms may be helpful in estimating the extent of such underreporting [51]. Methods to improve reporting should focus on patient education through encouraging site visits, support groups, as well as providing access to educational courses and materials with up to date information on STI treatment, diagnosis and patient responsibility.

Today, one of the major aims of ongoing research is developing a vaccine for syphilis prevention. Rising numbers of HIV infections, congenital syphilis occurrence in developing nations and decreased quality of life of patients living with the infection provide a clear rationale for vaccine development efforts. At present, researchers are still trying to uncover more information about T. pallidum’s biology and host response to infection, all being crucial factors of vaccine development [52]. Although significant focus is given to vaccination, further studies are underway to establish more effective treatment options through better use of existing drugs [53]. In order to aid progression, associated risks such as antibiotic resistance, as well as alterations in the microbiome must be considered in these investigations to better our chances of eradicating the syphilis spirochete once and for all.


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Conflict of interest: none declared.

Authors’ affiliations:
1 Jagiellonian University Medical College, School of Medicine in English, Cracow, Poland
2 The Faculty of Medicine of the University of Rijeka, Rijeka, Croatia

Corresponding author:
Syedah Sarah Hussaini
Warszawska 200/60
05-520 Konstancin-Jeziorna
e-mail: sshussaini786@gmail.com

To cite this article: Hussaini SS, Grubeša FD. The syphilis spirochete in the XXI century. World J Med Images Videos Cases 2022; 8:e26-43.

Submitted for publication: 12 April 2022
Accepted for publication: 10 May 2022
Published on: 26 May 2022

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