Resurgence of syphilis, the great imitator

Abstract

Syphilis, one of the earliest diseases to be discovered in humans, still remains an enigma when it comes to its myriad manifestations and changing epidemiological profiles. There has been a surge in cases in the last few decades due to various factors. The human immunodeficiency virus (HIV) epidemics, global travel, increased incidence of male to male sexually transmitted diseases, online relationships culminating in casual sex are few of the important factors. Increased awareness could also be a factor for increased diagnosis. The multitude of clinical features especially when it comes to secondary syphilis and the rare tertiary manifestations, which can mimic various systemic disorders still pose a diagnostic challenge to the best of venereologists and physicians. This review aims to discuss the causes of resurgence in syphilis and few recent developments in pathogenesis, which could have led to this resurgence.

Introduction

Syphilis, also known as ‘the great imitator’ has fascinated dermatologists since time immemorial with its ever-changing behaviour. Syphilis is a multisystem, sexually transmitted disease but can occasionally be acquired via blood transfusion and vertical transmission resulting in congenital syphilis. The disease consists of multiple overlapping stages and initially manifests as a painless indurated primary syphilitic chancre. Secondary syphilis is primarily responsible for the ‘great imitator’ phrase associated with the disease owing to most versatile manifestations in this stage. Tertiary syphilis is rare in present times but manifests as cardiovascular, central nervous system (CNS), and gummatous syphilis. In the late 1980s, when there was surge in syphilis cases, apparently the contact tracing was negative in most cases. This led to the discovery of a stage where clinical features in the source were absent, otherwise termed as latent syphilis or syphilis incognito.^1,2

Over the years, there have been numerous changes in manifestations, diagnosis, and management of syphilis. Latency of disease, drug resistance, and human immunodeficiency virus (HIV) infection have played a key role in altered approach towards the disease. Seroprevalence has rather been tumultuous owing to latent syphilis primarily. Supported by various Indian and Western studies, it is now believed that although there has been a decline in the prevalence of primary syphilis, relentless usage of antibiotics for common ailments (leading to accidental temporary remission) has led to the increasing presentation of secondary syphilis mimicking various other dermatoses and subsequent under-diagnosis. Even though multiple anti-microbials have been employed in treatment, penicillin remains the most effective drug since its first usage since its discovery almost a century ago. Since the mid-1980s, human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV-AIDS) has snowballed as probably the longest-running pandemic and is still a major concern. Co-infection with HIV has resulted in alteration in semiology as well as patterns of manifestations of syphilis.³ The Centre for Disease Control (CDC) devised a ‘call to action’ strategy to emphasise the rising trend of all sexually transmitted infections (STIs) and strongly urging ways and means to combat a resurgence of syphilis.⁴ The review focuses on changing trends in various aspects related to syphilis, possible reasons for the same and the way forward in controlling this disease.

History

The first mention of syphilis was in 1530 by Italian physician and poet Girolamo Francastaro in his poem Syphilis sive morbus gallicus. It was previously known as the French disease owing to its explosive occurrence post return of French troops from the invasion of Naples, Italy in 1495. But it was not until 1905 that Fritz Schaundinn and Erich Hoffmann discovered the causative organism to be Treponema pallidum var pallidum.^4,5

Epidemiological trends

Studies conducted on syphilis date back to the 1920s where the prevalence of the disease was rampantly increasing courtesy of the two world wars from 1914 to 1918 and 1939 to 1945, respectively. During this millennium, the Oslo and infamous Tuskegee study were conducted. Since the end of the Second World War in 1945, the incidence and prevalence of syphilis has had a gradually declining trend till 1985 when a short upsurge occurred lasting for five years. There was a contemplation of eliminating syphilis by the CDC in 1999 to be accomplished by the year 2000 owing to the lowest ever incidence since 1941 to 2.1 cases per 100,000 population in the United States and Europe.^6,7 However, there was a very gradual but a definite increase in the number of cases of primary, secondary, and latent syphilis from 2001 to 2009, a slight dip in 2010 and 2011, then increased by 22% from 2011 to 2015 where the prevalence was 5.2 cases per 100,000 population. The total number of syphilis cases (all stages) reported to the CDC increased 13% during 2012–2013 to 56, 471 cases for a rate of 18 cases per 100,000 population. In a study conducted by Tsachouridou et al in Western Europe in 2016, the incidence of various stages of syphilis co-infected with HIV was 26% primary syphilis, 33% secondary syphilis, 37% latent syphilis, and 4% neurosyphilis.⁸ The most resounding rise had been documented by numerous western and Indian studies to be in the years 2015–2017 to be ranging from 7.5% to 10% prevalence.

South, Southeast, and East Asian regions including India and China have observed the most dramatic change in the epidemiology of syphilis. Syphilis was considered on the verge of elimination in the 1960s in China, Japan, and the Indonesian archipelago but cases began to rise in the 1980s. From 1991 to 2005, caseload increased almost 16-fold to 16% of the total cases of STIs. By 2008, they had doubled, accounting for almost 38% of the total cases of STIs. In 2013, 444,952 cases of syphilis were reported with a rate of almost 33 cases per 100,000 population.⁹

The so-called epidemic has been largely driven by economic and social factors, including large scale migration, and evolving unorthodox sexual practices. Co-infection with HIV formed the key factor in the driving force for the epidemic. Men having sex with men (MSM), female sex workers, migrants, and intravenous drug users (IDU) are the groups at highest risk for syphilis with increasing vulnerability with concurrent HIV pandemic. Rapid economic development has led to an unprecedented number of migrants moving from less developed rural communities to more affluent urban centres. This trend is expected to continue over the next two decades to come. Many of the migrants are younger, without a formal education who are daily wagers living a hardened life. They lack adequate health insurance, seldom use medical facilities due in part to economic reasons and cannot access social welfare benefits that are available to urban residents. This demography poses a major public health challenge concerning STIs because studies suggest that migrants are more likely to engage in STI-associated risk factors including avoidance of condom use, multiple sexual partners, and illicit drug/substance use simultaneously with sexual activities.¹⁰

Reasons for resurgence

HIV and syphilis

Since the beginning of the HIV pandemic in the 1980s, there has been a paradigm shift in syphilis in all its aspects as they tend to have a multi-faceted synergistic association. Syphilis augments the rate of HIV acquisition by four-fold and the risk for HIV transmission by up to nine-fold. Various reasons have been hypothesised in facilitating HIV transmission by syphilis, Firstly, genital ulceration in primary syphilis results in recruiting of helper T cells, regulated upon activated T cells expressed and secreted (RANTES), CCR5 and CXCR4 receptor carrying macrophages to the ulcer site increasing availability of attachment sites for HIV virions. Secondly, a systemic immunosuppressive induced by syphilis results in transient alteration in the immune system in the form of a fall in CD4 count and rise in viral load of HIV.¹¹

The epidemiology of syphilis has been heavily influenced by that of HIV. A notable peak in the number of syphilis cases co-infected with HIV first came into light in between the years 1984–1990 owing to the first HIV surge. In the early 1990s, the awareness of HIV and strict measures imposed by health authorities to curb transmission and promote treatment led to a gradual decline in syphilis cases from a point prevalence of 8% to 1.2% from 1987 to 2000 in India.¹² Since then, STIs co-occurring with HIV has been on the ascendancy, especially viral STIs compared to bacterial STIs. Herpes genitalis initially considered under ‘other minor sexually transmitted infections’, has had the maximum prevalence. The World Health Organization (WHO) targets to reduce incidence of syphilis and gonorrhoea by 90% till 2030. India contributes heftily to the syphilis burden in the South East Asian region (SEAR) where the elimination strategy has been stringently implemented along with Sri Lanka, Myanmar and Thailand. Cornerstone of the strategy is promotion of condom usage amongst sex workers and increase in HIV testing that has resulted in fall in incidence of most STIs. Nonetheless, syphilis has shown a variable trend since the 2000s but overall, there has been a rise in the incidence of syphilis in SEAR mostly attributed to MSM and concurrent HIV infection.¹² The clinical manifestations of syphilis are quite different when associated with HIV. Early appearance of the primary chancre, overlapping of primary and secondary syphilis, telescoping of the disease to later stages quickly, increasing incidence of asymptomatic neurosyphilis.¹³

MSM and syphilis

In the 1960s, the terminology MSM came into being that described men involved with anal and oral sexual intercourse in a penetrative and receptive manner. These practices were initially considered punishable offences with remanding up to life imprisonment till the 1980s, but thereafter it ceased to occur, and laws were revised gradually across the globe. In India, on 20 August 2017, section 377 of Indian Penal Code (IPC), which governs such activities, was decriminalised. The laws pertaining to MSM go hand in hand with the trend of STIs including syphilis. From the 1960s to 1980s, because of stigma and the fear of prosecution, many individuals seldom reported the disease even though harbouring syphilis and this resulted in a fall in the incidence of syphilis. Leeway in regulations started happening in the 1980s, which unfortunately coincided with the beginning of the HIV pandemic. The incidence of syphilis showed an exponential rise with HIV to the extent of three-fold in the mid-1980s. Thereafter, awareness about HIV and curbing strategies resulted in a gradual decrease in incidence till the 2000s. Ironically, certain measures employed in preventing transmission of HIV contributed largely to increasing incidence for the next two decades which persists even now.

Methamphetamine and recreational drugs like amyl nitrate usage to facilitate painless anal intercourse amongst MSM resulted in increased transmission of syphilis.

Individuals meeting each other through social networking sites has increased resulting in unprotected high-risk sexual practices.

The introduction of pre-exposure prophylaxis (PrEP) in 2010 through which MSM use Truvada (tenofovir and emtricitabine) regularly, providing safety from HIV has indeed reduced transmission of HIV, but conversely as it provides no protection against syphilis transmission, there has been a surge in syphilis cases.¹⁴ Kojima et al have found that MSM populations taking PrEP for HIV prevention are up to 44.6 times more likely to contract syphilis infection than MSM populations who are not on PrEP.¹⁵

There has also been a disproportionate increase in the number of cases of syphilis amongst Black and Latino men in the US. Racial disparity resulted from higher reporting rates to STI clinics by these men and more judicious monitoring of such population as compared to white MSM community as inferred by the study conducted by Solomen and Meyer in 2015. In India, the incidence of syphilis corresponded to high prevalence regions of HIV, which included the North-Eastern states, Goa, urban areas of Tamil Nadu and Karnataka and metro cities compared to rural regions of the country.¹⁶

Miscellaneous factors

Intravenous drug use (IDU) and illicit drug usage have a long-standing relationship with the transmission of STIs. Studies directly correlating transmission of syphilis and IDU are still lacking but extensive studies have been conducted across the globe delineating risk for HIV transmission. The study conducted by Coffin et al regarding syphilis incidence in IDU in lower- and middle-income countries including India suggest a median incidence of 4% of syphilis, which is almost three times than the annual incidence of previous years and 67% of cases were also retropositive in this study population.¹⁷

A study conducted by Kumar et al suggests the prevalence of syphilis among blood donors was in rising trends especially among replacement donors. The most common co-infections in the study were syphilis with hepatitis B infection, followed by syphilis with HIV infection. The increasing prevalence of syphilis among the donors underscores the concern about the growing incidence of this disease in the community as these blood donors represent a highly selective community.¹⁸

Congenital syphilis remains an important cause of adverse outcomes of pregnancy in the form of premature abortions, Intra-uterine deaths (IUD) and birth defects. Predominant cases of mother to child transmission (MTCT) of syphilis are seen in low income developing countries constituting a whopping 68% of the total incidence. The study conducted by Stamm et al suggests that in 2014, out of 1.4 million pregnancies associated with syphilis, 50% of cases resulted in adverse outcomes including 215,000 stillbirths, 90,000 neonatal deaths, 65,000 pre-term or low birth-weight infants and 150,000 infants with congenital infection. Such alarming statistics are because of lack of proper screening process, antenatal monitoring and stigma associated with symptomatic cases resulting in non-reporting to either obstetrics or STI clinics.

Elimination of parent to child transmission (E-PTCT) of syphilis was proposed in 2015 launched by STI/RTI control and prevention programme under the aegis of the National AIDS Control Programme (NACO) in collaboration with Reproductive, Maternal, Newborn and Child Health and Adolescents (RMNCH + A) Programme under the National Health Mission (NHM). It will contribute to achieving three Millennium Development Goals (MDG) namely MDG 4 (reduce child mortality), MDG 5 (improve maternal health) and MDG 6 (Combat HIV/AIDS, Malaria and other diseases). The strategies to be employed include sustained high-level commitment towards screening pregnant women for syphilis, treating seropositive patients and their partners and the newborn. Also an integral part of the programme is strict surveillance, monitoring and evaluation.^19,20

Newer insights on the pathogenesis of syphilis

T. pallidum is a subtly motile spirochaete that has eluded microbiologists in deciphering exact pathogenesis and the reason for long latency. Obliterative endarteritis and plasma cell-induced immune response form the core of pathogenesis and resultant syphilitic stigmata in all stages. Recently, a study conducted by Cruz et al in South America has suggested certain novel concepts about the pathogenesis of the disease and may be pivotal in the development of a vaccine and most likely also plays a key role in the resurgence of the disease in the past two decades.²¹ Tp DNA and polA protein are detected in the lesions of secondary syphilis and exhibit robust cellular and humoral adaptive immune response. Unlike other gram-negative bacteria, Tp does not possess pro-inflammatory lipopolysaccharides (LPS) responsible for a sub-optimal immune response against the spirochaete. The highly antigenic T. pallidum outer membrane protein (TROMP) primarily responsible for antibody stimulation, is tethered by covalently bonded N-terminal lipids to the periplasmic leaflet of the cytoplasmic membrane. Mechanism of resistance against macrolide antibiotics is via A2058G mutation as reported by studies conducted by United States and Australia, first reported in 2004. Moreover, sequence variation of the Tp repeat (Tpr) family of polymorphic multi-copy repeat proteins has been postulated as an additional mechanism of immune evasion and persistent infection by the spirochete. Other outer membrane proteins like TprK and Tp92 are being extensively studied using micro-freezing and PCR techniques to bring into light the exact role of these proteins in immune evasion and possibly responsible for a resurgence.²²

Recent trends in clinical manifestations

Primary, secondary, tertiary, and latent syphilis tend to have considerable overlap in their occurrence throughout the course of the disease. Their prevalence has also been topsy–turvy in the past five decades. Primary syphilis conventionally manifesting as painless chancre is the first real clinical manifestation of syphilis. HIV co-infection and rampant usage of over the counter (OTC) antibiotics have resulted in either an indolent course of the ulcers or non-appearance of the clinical manifestations thus causing a decline in the incidence of chancre manifestation.²³

The study conducted by Shah et al, in 2016 suggests an early appearance of chancre leading to the terminology early primary syphilis, especially in individuals co-infected by HIV. However, the same study has inferred that latent and secondary syphilis occupy the highest prevalence rates stage-wise with or without the presence of other STIs including HIV. The resurgence of syphilis can also be contributed by these two stages in a blatantly different manner. Latent syphilis being asymptomatic does not warn the patient of the presence of disease thereby portending to increased risk of sexual transmission. On the contrary, in secondary syphilis, the manifestations are extremely versatile and are often difficult to diagnose. Secondary syphilis lesions harbour the maximum load of infective treponemes, and the chance of transmission is highest in this stage both through the sexual route and otherwise. Maculopapular rash of secondary syphilis used to be the commonest clinical manifestation called roseola syphilitica. But in the last decade, involvement of palms and soles in the form of scaly macules and plaques with Biett's collarette has been observed most commonly. Co-infection with HIV has predisposed the appearance of classic yet rarer features of secondary syphilis to appear more commonly. Condyloma lata, split papules over the angle of mouth, lichenoid lesions, annular and corymbose plaques, and moth-eaten alopecia have also shown an increasing occurrence.²⁴

A retrospective study conducted by Landry et al on the prevalence of tertiary syphilis in Mexico spanning for three decades suggests that asymptomatic neurosyphilis is the commonest form of tertiary syphilis that occurs constituting 91% of cases. Amongst symptomatic tertiary syphilis, ocular syphilis, which was categorised as early neurosyphilis, was the commonest followed by syphilitic meningitis. Three cases of cardiovascular syphilis out of 257 were detected and there were no cases of gummatous syphilis. The majority of the cases with any form of tertiary syphilis were co-infected with HIV.^25,26

Conclusion

The epidemiology of syphilis has seen numerous ups and downs over time, in tandem with improvements in diagnostics and the introduction of penicillin, HIV infection and the evolution of sexual behaviour; however, syphilis continues to present a significant public health problem. Today, syphilis is highly prevalent among MSM and individuals infected with HIV, and the prevalence of infection is on the rise. Many infections remain occult and asymptomatic; hence the need to improve screening programmes among populations at the highest risk. Creative testing strategies such as Internet outreach, opt-out testing, or increasing the frequency of screening rather than increasing the proportion screened offer some promise to increase the rates of early diagnosis. MSM engaging in unprotected anal receptive intercourse, particularly if they have sex with multiple partners, substance use or intravenous drugs, should be routinely screened for syphilis infection. Individuals diagnosed with syphilis infection should be counselled about the limits of sero-adaptive behaviours as they pertain to syphilis transmission. HIV-uninfected MSM with syphilis should be educated about newer HIV prevention modalities, such as oral pre-exposure prophylaxis, as a diagnosis of syphilis is strongly associated with HIV acquisition. However, since pre-exposure prophylaxis will not protect against syphilis, MSM using it should be regularly evaluated for syphilis and other treatable STIs. The significant prevalence of syphilis among MSM can be decreased through culturally tailored prevention counselling, education about pre-exposure prophylaxis and repetitive screening for those who continue to engage in behaviours known to transmit syphilis and HIV.

Disclosure of competing interest

The authors have none to declare.