HIV-2 has been found to be less pathogenic than HIV-1. [ 36 ]  The mechanism of HIV-2 is not clearly defined, nor the difference from HIV-1, however the transmission rate is much lower in HIV-2 than HIV-1. Both viruses can lead to AIDS in infected individuals and both can mutate to develop drug resistance. [ 34 ]  Disease monitoring in patients with HIV-2 includes clinical evaluation and CD4 cell counts, while treatment includes  anti-retroviral therapy  (ART),  nucleoside reverse transcriptase inhibitors  (NRTIs),  protease inhibitors  (PI), and  non-nucleoside reverse transcriptase inhibitors  (NNRTIs) with the addition of  CCR5 co-receptor antagonists  and  fusion inhibitors . [ 37 ]


Choice of initial and/or second-line therapy for HIV-2 has not yet been defined. HIV-2 appears to be resistant to NNRTIs intrinsically, but may be sensitive to NRTIs, though the mechanism is poorly understood. Protease inhibitors have shown variable effect, while integrase inhibitors are also being evaluated.  Combination regimens of the above listed therapies are being looked into as well, also showing variable effect depending on the types of therapies combined. While the mechanisms are not clearly understood for HIV-1 and HIV-2, it is known that they use different pathways and patterns, making the algorithms used to evaluate HIV-1 resistance-associated mutations irrelevant to HIV-2. [ 34 ]


Each virus can be contracted individually, or they can be contracted together in what is referred to as co-infection. HIV-2 seems to have lower mortality rates, less severe symptoms and slower progression to AIDS than HIV-1 alone or the co-infection. In co-infection, however, this is largely dependent on which virus was contracted first. HIV-1 tends to out compete HIV-2 for disease progression. Co-infection seems to be a growing problem globally as time progresses, with most cases being identified in West African countries, as well as some cases in the USA. [ 37 ]  A study found that individuals who contract HIV-2 before HIV-1 tend to have a slower rate of disease progression, suggesting that the immune response to HIV-2 may limit the proliferation of HIV-1. [ 38 ]


If a pregnant mother is exposed, screening is performed as normal. If HIV-2 is present, a number of perinatal ART drugs may be given as a prophylactic to lower the risk of mother-to-child transmission.  After the child is born, a standard six-week regimen of these prophylactics should be initiated. Breast milk may also contain viral particles of HIV-2; therefore, breastfeeding is strictly advised against. [ 35 ]


The rapid evolution of HIV can be attributed to its high mutation rate. During the early stages of mutation, evolution appears to be neutral due to the absence of an evolutionary response. However, when examining the virus in several different individuals, convergent mutations can be found appearing in these viral populations independently. [ 39 ]


HIV evolution within a host influences factors including the virus' set-point  viral load . If the virus has a low set-point viral load, the host will live longer, and there is a greater probability that the virus will be transmitted to another individual. If the virus has a high set-point viral load, the host will live for a shorter amount of time and there is a lower probability that the virus will be transmitted to another individual. [ 40 ]  HIV has evolved to maximize the number of infections to other hosts, and this tendency for selection to favor intermediate strains shows that HIV undergoes stabilizing selection. [ citation needed ]


The virus has also evolved to become more infectious between hosts. There are three different mechanisms that allow HIV to evolve at a population level. [ 40 ]  One includes the continuous battle to evolve and overcome the immune system which slows down the evolution of HIV and shifts the virus’ focus towards a population level. Another includes the slow evolution of viral load due to viral load mutations being neutral within the host. The last mechanism focuses on the virus' preference to transmit founding viral strains stored during the early stages of infection. This preference of the virus to transmit its stored genome copies explains why HIV evolves more quickly within the host than between hosts. [ 40 ]


HIV is evolving toward a milder form, but it is still "an awfully long way" from no longer being deadly, [ 41 ] [ 42 ]  with severe variants still appearing. [ 43 ] [ 44 ]


Isolates of HIV-1 and HIV-2 with resistance to antiretroviral drugs arise through  natural selection  and genetic mutations, which have been tracked and analyzed. The Stanford HIV Drug Resistance Database and the International AIDS Society publish lists of the most important of these; first year listing 80 common mutations, and the latest year 93 common mutations, and made available through the  Stanford HIV RT and Protease Sequence Database . [ citation needed ]


Syphilis  ( / ˈ s ɪ f ə l ɪ s / ) is a  sexually transmitted infection  caused by the  bacterium   Treponema pallidum   subspecies   pallidum . [ 1 ]  The signs and symptoms depend on the stage it presents: primary, secondary, latent or tertiary. [ 1 ] [ 2 ]  The primary stage classically presents with a single  chancre  (a firm, painless, non-itchy  skin ulceration  usually between 1 cm and 2 cm in diameter), though there may be multiple sores. [ 2 ]  In secondary syphilis, a diffuse  rash  occurs, which frequently involves the palms of the hands and soles of the feet. [ 2 ]  There may also be sores in the mouth or vagina. [ 2 ]  Latent syphilis has no symptoms and can last years. [ 2 ]  In tertiary syphilis, there are  gummas  (soft, non-cancerous growths), neurological problems, or heart symptoms. [ 3 ]  Syphilis has been known as " the great imitator ", because it may cause symptoms similar to many other diseases. [ 2 ] [ 3 ]


Syphilis is most commonly spread through  sexual activity . [ 2 ]  It may also be  transmitted from mother to baby  during pregnancy or at birth, resulting in  congenital syphilis . [ 2 ] [ 7 ]  Other diseases caused by  Treponema  bacteria include  yaws  ( T. pallidum  subspecies  pertenue ),  pinta  ( T. carateum ), and  nonvenereal endemic syphilis  ( T. pallidum  subspecies  endemicum ). [ 3 ]  These three diseases are not typically sexually transmitted. [ 8 ]  Diagnosis is usually made by using  blood tests ; the bacteria can also be detected using  dark field microscopy . [ 2 ]  The  Centers for Disease Control and Prevention  (U.S.) recommends for all pregnant women to be tested. [ 2 ]


The risk of sexual transmission of syphilis can be reduced by using a  latex  or  polyurethane   condom . [ 2 ]  Syphilis can be effectively treated with  antibiotics . [ 4 ]  The preferred antibiotic for most cases is  benzathine benzylpenicillin   injected into a muscle . [ 4 ]  In those who have a severe  penicillin allergy ,  doxycycline  or  tetracycline  may be used. [ 4 ]  In those with  neurosyphilis ,  intravenous   benzylpenicillin  or  ceftriaxone  is recommended. [ 4 ]  During treatment, people may develop fever, headache, and  muscle pains , a reaction known as  Jarisch–Herxheimer . [ 4 ]


In 2015, about 45.4 million people had syphilis infections, [ 5 ]  of which six million were new cases. [ 9 ]  During 2015, it caused about 107,000 deaths, down from 202,000 in 1990. [ 6 ] [ 10 ]  After decreasing dramatically with the availability of penicillin in the 1940s, rates of infection have increased since the turn of the millennium in many countries, often in combination with  human immunodeficiency virus  (HIV). [ 3 ] [ 11 ]  This is believed to be partly due to unsafe drug use, increased  prostitution , and decreased use of  condoms . [ 12 ] [ 13 ] [ 14 ]


Syphilis can  present  in one of four different stages: primary, secondary, latent, and tertiary, and may also occur  congenitally . [ 15 ]  There may be  no symptoms . [ 16 ]  It was referred to as "the great imitator" by  Sir William Osler  due to its varied presentations. [ 3 ] [ 17 ] [ 18 ]


Primary syphilis is typically acquired by direct sexual contact with the infectious lesions of another person. [ 19 ]  Approximately 2–6 weeks after contact (with a range of 10–90 days) a skin lesion, called a  chancre , appears at the site and this contains infectious bacteria. [ 20 ] [ 21 ]  This is classically (40% of the time) a single, firm, painless, non-itchy  skin ulceration  with a clean base and sharp borders approximately 0.3–3.0 cm in size. [ 3 ]  The lesion may take on almost any form. [ 22 ]  In the classic form, it evolves from a  macule  to a  papule  and finally to an  erosion  or  ulcer . [ 22 ]  Occasionally, multiple lesions may be present (~40%), [ 3 ]  with multiple lesions being more common when coinfected with HIV. [ 22 ]  Lesions may be painful or tender (30%), and they may occur in places other than the genitals (2–7%). [ 22 ]  The most common location in women is the  cervix  (44%), the  penis  in heterosexual men (99%), and  anally  and  rectally  in  men who have sex with men  (34%). [ 22 ]   Lymph node enlargement  frequently (80%) occurs around the area of infection, [ 3 ]  occurring seven to 10 days after chancre formation. [ 22 ]  The  lesion  may persist for three to six weeks if left untreated. [ 3 ]


Secondary syphilis occurs approximately four to ten weeks after the primary infection. [ 3 ]  While secondary disease is known for the many different ways it can manifest, symptoms most commonly involve the  skin ,  mucous membranes , and  lymph nodes . [ 23 ]  There may be a symmetrical, reddish-pink, non-itchy  rash  on the trunk and extremities, including the palms and soles. [ 3 ] [ 24 ]  The rash may become  maculopapular  or  pustular . [ 3 ]  It may form flat, broad, whitish, wart-like lesions on mucous membranes, known as  condyloma latum . [ 3 ]  All of these lesions harbor bacteria and are infectious. [ 3 ]  Other symptoms may include  fever ,  sore throat ,  malaise ,  weight loss ,  hair loss , and  headache . [ 3 ]  Rare manifestations include  liver inflammation ,  kidney  disease,  joint inflammation ,  periostitis ,  inflammation of the optic nerve ,  uveitis , and  interstitial keratitis . [ 3 ] [ 25 ]  The acute symptoms usually resolve after three to six weeks; [ 25 ]  about 25% of people may present with a recurrence of secondary symptoms. [ 23 ] [ 26 ]  Many people who present with secondary syphilis (40–85% of women, 20–65% of men) do not report previously having had the classical chancre of primary syphilis. [ 23 ]


Latent syphilis is defined as having  serologic  proof of infection without symptoms of disease. [ 19 ]  It develops after secondary syphilis and is divided into early latent and late latent stages. [ 27 ]  Early latent syphilis is defined by the  World Health Organization  as less than 2 years after original infection. [ 27 ]  Early latent syphilis is infectious as up to 25% of people can develop a recurrent secondary infection (during which bacteria are actively replicating and are infectious). [ 27 ]  Two years after the original infection the person will enter late latent syphilis and is not as infectious as the early phase. [ 25 ] [ 28 ]  The latent phase of syphilis can last many years after which, without treatment, approximately 15-40% of people can develop tertiary syphilis. [ 29 ]


Tertiary syphilis may occur approximately 3 to 15 years after the initial infection and may be divided into three different forms: gummatous syphilis (15%), late  neurosyphilis  (6.5%), and cardiovascular syphilis (10%). [ 3 ] [ 25 ]  Without treatment, a third of infected people develop tertiary disease. [ 25 ]  People with tertiary syphilis are not infectious. [ 3 ]


Gummatous syphilis or late  benign  syphilis usually occurs 1 to 46 years after the initial infection, with an average of 15 years. [ 3 ]  This stage is characterized by the formation of chronic  gummas , which are soft, tumor-like balls of inflammation which may vary considerably in size. [ 3 ]  They typically affect the skin, bone, and liver, but can occur anywhere. [ 3 ]


Cardiovascular syphilis usually occurs 10–30 years after the initial infection. [ 3 ]  The most common complication is  syphilitic aortitis , which may result in  aortic aneurysm  formation. [ 3 ]


Neurosyphilis  refers to an infection involving the  central nervous system . Involvement of the central nervous system in syphilis (either asymptomatic or symptomatic) can occur at any stage of the infection. [ 21 ]  It may occur early, being either asymptomatic or in the form of  syphilitic meningitis ; or late as meningovascular syphilis, manifesting as  general paresis  or  tabes dorsalis . [ 3 ]


Meningovascular syphilis involves inflammation of the small and medium arteries of the central nervous system. It can present between 1–10 years after the initial infection. Meningovascular syphilis is characterized by stroke, cranial nerve palsies and  spinal cord inflammation . [ 30 ]  Late symptomatic neurosyphilis can develop decades after the original infection and includes 2 types; general paresis and tabes dorsalis. General paresis presents with dementia, personality changes, delusions, seizures, psychosis and depression. [ 30 ]  Tabes dorsalis is characterized by gait instability, sharp pains in the trunk and limbs, impaired positional sensation of the limbs as well as having a positive  Romberg's sign . [ 30 ]  Both tabes dorsalis and general paresis may present with  Argyll Robertson pupil  which are pupils that constrict when the person focuses on near objects ( accommodation reflex ) but do not constrict when exposed to bright light ( pupillary reflex ).


Congenital syphilis is that which is transmitted during pregnancy or during birth. [ 7 ]  Two-thirds of syphilitic infants are born without symptoms. [ 7 ]  Common symptoms that develop over the first couple of years of life include  enlargement of the liver and spleen  (70%), rash (70%), fever (40%), neurosyphilis (20%), and  lung inflammation  (20%). [ 7 ]  If untreated,  late congenital syphilis  may occur in 40%, including  saddle nose  deformation,  Higouménakis' sign ,  saber shin , or  Clutton's joints  among others. [ 7 ]  Infection during pregnancy is also associated with  miscarriage . [ 31 ]  The main dental defects seen in congenital syphilis are the peg-shaped, notched incisors known as  Hutchinson's teeth  and so-called  mulberry molars  (also known as Moon or Fournier molars), defective permanent molars with rounded, deformed crowns resembling a  mulberry . [ 32 ]


Treponema pallidum  subspecies  pallidum  is a spiral-shaped,  Gram-negative , highly mobile bacterium. [ 11 ] [ 22 ]  Two other human diseases are caused by related  Treponema pallidum  subspecies,  yaws  (subspecies  pertenue )  and  bejel  (subspecies  endemicum ), and one further caused by the very closely related   Treponema carateum ,  pinta . [ 3 ] [ 33 ]  Unlike subspecies  pallidum , they do not cause neurological disease. [ 7 ]  Humans are the only known  natural reservoir  for subspecies  pallidum . [ 34 ]  It is unable to survive more than a few days without a  host . [ 22 ]  This is due to its small genome (1.14 Mbp ) failing to encode the metabolic pathways necessary to make most of its macronutrients. [ 22 ]  It has a slow  doubling time  of greater than 30 hours. [ 22 ]  The bacterium is known for its ability to evade the immune system and its invasiveness. [ 35 ]


Syphilis is transmitted primarily by sexual contact or during  pregnancy  from a mother to her baby; the bacterium is able to pass through intact mucous membranes or compromised skin. [ 3 ] [ 34 ]  It is thus transmissible by  kissing  near a lesion, as well as  manual ,  oral ,  vaginal , and  anal sex . [ 3 ] [ 36 ] [ 37 ]  Approximately 30% to 60% of those exposed to primary or secondary syphilis will get the disease. [ 25 ]  Its  infectivity  is exemplified by the fact that an individual  inoculated  with only 57 organisms has a 50% chance of being infected. [ 22 ]  Most new cases in the United States (60%) occur in men who have sex with men; and in this population 20% of syphilis cases were due to oral sex alone. [ 3 ] [ 36 ]  Syphilis can be transmitted by  blood products , but the risk is low due to screening of  donated blood  in many countries. [ 3 ]  The risk of transmission from  sharing needles  appears to be limited. [ 3 ]


It is not generally possible to contract syphilis through toilet seats, daily activities, hot tubs, or sharing eating utensils or clothing. [ 38 ]  This is mainly because the bacteria die very quickly outside of the body, making transmission by  objects  extremely difficult. [ 39 ]


Syphilis is difficult to diagnose clinically during early infection. [ 22 ]  Confirmation is either via  blood tests  or direct visual inspection using  dark field microscopy . [ 3 ] [ 41 ]  Blood tests are more commonly used, as they are easier to perform. [ 3 ]  Diagnostic tests are unable to distinguish between the stages of the disease. [ 42 ]


Blood tests are divided into  nontreponemal  and treponemal tests. [ 22 ]


Nontreponemal tests are used initially and include  venereal disease research laboratory  (VDRL) and  rapid plasma reagin  (RPR) tests.  False positives  on the nontreponemal tests can occur with some viral infections, such as  varicella  (chickenpox) and  measles . False positives can also occur with  lymphoma ,  tuberculosis ,  malaria ,  endocarditis ,  connective tissue disease , and  pregnancy . [ 19 ]


Because of the possibility of false positives with nontreponemal tests, confirmation is required with a treponemal test, such as  Treponema pallidum  particle agglutination assay  (TPHA) or  fluorescent treponemal antibody absorption test  (FTA-Abs). [ 3 ]  Treponemal antibody tests usually become positive two to five weeks after the initial infection [ 22 ]  and remain positive for many years. [ 43 ]  Neurosyphilis is diagnosed by finding high numbers of  leukocytes  (predominately  lymphocytes ) and high protein levels in the  cerebrospinal fluid  in the setting of a known syphilis infection. [ 3 ] [ 19 ]


Dark field microscopy  of  serous fluid  from a chancre may be used to make an immediate diagnosis. [ 22 ]  Hospitals do not always have equipment or experienced staff members, and testing must be done within 10 minutes of acquiring the sample. [ 22 ]  Two other tests can be carried out on a sample from the chancre:  direct fluorescent antibody  (DFA) and  polymerase chain reaction  (PCR) tests. [ 22 ]  DFA uses  antibodies  tagged with  fluorescein , which attach to specific syphilis proteins, while PCR uses techniques to detect the presence of specific syphilis  genes . [ 22 ]  These tests are not as time-sensitive, as they do not require living bacteria to make the diagnosis. [ 22 ]


As of 2018 [update] , there is no  vaccine  effective for prevention. [ 34 ]  Several vaccines based on treponemal proteins reduce lesion development in an  animal model  but research continues. [ 44 ] [ 45 ]


Condom  use reduces the likelihood of transmission during sex, but does not eliminate the risk. [ 46 ]  The  Centers for Disease Control and Prevention  (CDC) states, "Correct and consistent use of latex condoms can reduce the risk of syphilis only when the infected area or site of potential exposure is protected. [ 47 ]  However, a syphilis sore outside of the area covered by a latex condom can still allow transmission, so caution should be exercised even when using a condom." [ 48 ]


Abstinence  from intimate physical contact with an infected person is effective at reducing the transmission of syphilis. The CDC states, "The surest way to avoid transmission of sexually transmitted diseases, including syphilis, is to abstain from sexual contact or to be in a long-term mutually  monogamous  relationship with a partner who has been tested and is known to be uninfected." [ 48 ]


Congenital syphilis in the newborn can be prevented by screening mothers during early pregnancy and treating those who are infected. [ 50 ]  The  United States Preventive Services Task Force  (USPSTF) strongly recommends universal screening of all pregnant women, [ 51 ]  while the  World Health Organization  (WHO) recommends all women be tested at their first antenatal visit and again in the  third trimester . [ 52 ] [ 53 ]  If they are positive, it is recommended their partners also be treated. [ 52 ]  Congenital syphilis is still common in the developing world, as many women do not receive  antenatal care  at all, and the antenatal care others receive does not include screening. [ 50 ] [ 54 ]  It still occasionally occurs in the developed world, as those most likely to acquire syphilis are least likely to receive care during pregnancy. [ 50 ]  Several measures to increase access to testing appear effective at reducing rates of congenital syphilis in low- to middle-income countries. [ 52 ]   Point-of-care testing  to detect syphilis appeared to be reliable, although more research is needed to assess its effectiveness and into improving outcomes in mothers and babies. [ 55 ]


The CDC recommends that sexually active men who have sex with men be tested at least yearly. [ 56 ]  The USPSTF also recommends screening among those at high risk. [ 57 ]


Syphilis is a  notifiable disease  in many countries, including Canada, [ 58 ]  the  European Union , [ 59 ]  and the United States. [ 60 ]  This means health care providers are required to notify  public health  authorities, which will then ideally provide  partner notification  to the person's partners. [ 61 ]  Physicians may also encourage patients to send their partners to seek care. [ 62 ]  Several strategies have been found to improve follow-up for STI testing, including email and text messaging of reminders for appointments. [ 63 ]


As a form of  chemotherapy , elemental mercury had been used to treat skin diseases in Europe as early as 1363. [ 64 ]  As syphilis spread, preparations of mercury were among the first medicines used to combat it. Mercury is in fact highly anti-microbial: by the 16th century it was sometimes found to be sufficient to halt development of the disease when applied to ulcers as an  inunction  or when inhaled as a  suffumigation . It was also treated by ingestion of mercury compounds. [ 65 ]  Once the disease had gained a strong foothold, however, the amounts and forms of mercury necessary to control its development exceeded the human body's ability to tolerate it, and the treatment became worse and more lethal than the disease. Nevertheless, medically directed  mercury poisoning  became widespread through the 17th, 18th, and 19th centuries in Europe, North America, and India. [ 66 ]  Mercury salts such as  mercury (II) chloride  were still in prominent medical use as late as 1916, and considered effective and worthwhile treatments. [ 67 ]


The first-line treatment for uncomplicated syphilis (primary or secondary stages) remains a single dose of  intramuscular   benzathine benzylpenicillin . [ 68 ]  The bacterium is highly vulnerable to penicillin when treated early, and a treated individual is typically rendered non-infective in about 24 hours. [ 69 ]   Doxycycline  and  tetracycline  are alternative choices for those allergic to penicillin; due to the risk of  birth defects , these are not recommended for pregnant women. [ 68 ]   Resistance  to  macrolides ,  rifampicin , and  clindamycin  is often present. [ 34 ]   Ceftriaxone , a third-generation  cephalosporin   antibiotic , may be as effective as penicillin-based treatment. [ 3 ]  It is recommended that a treated person avoid sex until the sores are healed. [ 38 ]  In comparison to azithromycin for treatment in early infection, there is lack of strong evidence for superiority of azithromycin to benzathine penicillin G. [ 70 ]


For neurosyphilis, due to the poor penetration of benzathine penicillin into the  central nervous system , those affected are given large doses of  intravenous   penicillin G  for a minimum of 10 days. [ 3 ] [ 34 ]  If a person is allergic to penicillin, ceftriaxone may be used or penicillin  desensitization  attempted. [ 3 ]  Other late presentations may be treated with once-weekly intramuscular benzathine penicillin for three weeks. [ 3 ]  Treatment at this stage solely limits further progression of the disease and has a limited effect on damage which has already occurred. [ 3 ]  Serologic cure can be measured when the non-treponemal titers decline by a factor of 4 or more in 6–12 months in early syphilis or 12–24 months in late syphilis. [ 21 ]


One of the potential side effects of treatment is the  Jarisch–Herxheimer reaction . [ 3 ]  It frequently starts within one hour and lasts for 24 hours, with symptoms of fever, muscle pains, headache, and a  fast heart rate . [ 3 ]  It is  results from the release of pro-inflammatory cytokines by the immune system in response to  lipoproteins  released from rupturing syphilis bacteria. [ 72 ]


Penicillin is an effective treatment for syphilis in pregnancy [ 73 ]  but there is no agreement on which dose or route of delivery is most effective. [ 74 ]


In 2012, about 0.5% of adults were infected with syphilis, with 6 million new cases. [ 9 ]  In 1999, it is believed to have infected 12 million additional people, with greater than 90% of cases in the  developing world . [ 34 ]  It affects between 700,000 and 1.6 million pregnancies a year, resulting in  miscarriages ,  stillbirths , and congenital syphilis. [ 7 ]  During 2015, it caused about 107,000 deaths, down from 202,000 in 1990. [ 6 ] [ 10 ]  In  sub-Saharan Africa , syphilis contributes to approximately 20% of  perinatal deaths . [ 7 ]  Rates are proportionally higher among  intravenous drug users , those who are infected with  HIV , and men who have sex with men. [ 12 ] [ 13 ] [ 14 ]  In the United States about 55,400 people are newly infected each year as of 2014 [update] . [ 76 ]   African Americans  accounted for almost half of all cases in 2010. [ 77 ]  As of 2014, syphilis infections continue to increase in the United States. [ 78 ] [ 79 ]  In the United States as of 2020, rates of syphilis have increased by more than threefold; in 2018 approximately 86% of all cases of syphilis in the United States were in men. [ 21 ]  In 2021, preliminary CDC data illustrated that 2,677 cases of congenital syphilis were found in the population of 332 million in the United States. [ 80 ]


Syphilis was very common in Europe during the 18th and 19th centuries. [ 11 ]   Flaubert  found it universal among 19th-century Egyptian prostitutes. [ 81 ]  In the developed world during the early 20th century, infections declined rapidly with the widespread use of  antibiotics , until the 1980s and 1990s. [ 11 ]  Since 2000, rates of syphilis have been increasing in the US, Canada, the UK, Australia and Europe, primarily among men who have sex with men. [ 34 ]  Rates of syphilis among US women have remained stable during this time, while rates among UK women have increased, but at a rate less than that of men. [ 82 ]  Increased rates among heterosexuals have occurred in China and Russia since the 1990s. [ 34 ]  This has been attributed to unsafe sexual practices, such as sexual promiscuity, prostitution, and decreasing use of barrier protection. [ 34 ] [ 82 ] [ 83 ]


Left untreated, it has a mortality rate of 8% to 58%, with a greater death rate among males. [ 3 ]  The symptoms of syphilis have become less severe over the 19th and 20th centuries, in part due to widespread availability of effective treatment, and partly due to  virulence  of the bacteria. [ 23 ]  With early treatment, few complications result. [ 22 ]  Syphilis increases the risk of HIV transmission by two to five times, and coinfection is common (30–60% in some urban centers). [ 3 ] [ 34 ]  In 2015,  Cuba  became the first country to eliminate mother-to-child transmission of syphilis. [ 84 ]


Paleopathologists  have known for decades that syphilis was present in the Americas before European contact. [ 86 ] [ 87 ]  The situation in Europe and  Afro-Eurasia  has been murkier and caused considerable debate. [ 88 ]  According to the Columbian theory, syphilis was brought to Spain by the men who sailed with  Christopher Columbus  in 1492 and spread from there, with a serious epidemic in  Naples  beginning as early as 1495. Contemporaries believed the disease sprang from American roots, and in the 16th century physicians wrote extensively about the new disease inflicted on them by the returning explorers. [ 89 ]


Most evidence supports the Columbian origin hypothesis. [ 90 ]  However, beginning in the 1960s, examples of probable  treponematosis —the parent disease of syphilis,  bejel , and  yaws —in skeletal remains shifted the opinion of some towards a "pre-Columbian" origin. [ 91 ] [ 92 ]  A 2024 study published in  Nature  supported an emergence postdating human occupation in the Americas. [ 93 ]


When living conditions changed with urbanization, elite social groups began to practice basic hygiene and started to separate themselves from other social tiers. Consequently, treponematosis was driven out of the age group in which it had become endemic. It then began to appear in adults as syphilis. Because they had never been exposed as children, they were not able to fend off serious illness. Spreading the disease via sexual contact also led to victims being infected with a massive bacterial load from open sores on the genitalia. Adults in higher socioeconomic groups then became very sick with painful and debilitating symptoms lasting for decades. Often, they died of the disease, as did their children who were infected with congenital syphilis. The difference between rural and urban populations was first noted by Ellis Herndon Hudson, a clinician who published extensively about the prevalence of treponematosis, including syphilis, in times past. [ 94 ]  The importance of bacterial load was first noted by the physician Ernest Grin in 1952 in his study of syphilis in Bosnia. [ 95 ]


The most compelling evidence for the validity of the pre-Columbian hypothesis is the presence of syphilitic-like damage to bones and teeth in medieval skeletal remains. While the absolute number of cases is not large, new ones are continually discovered, most recently in 2015. [ 96 ]  At least fifteen cases of acquired treponematosis based on evidence from bones, and six examples of congenital treponematosis based on evidence from teeth, are now widely accepted. In several of the twenty-one cases the evidence may also indicate syphilis. [ 97 ]


In 2020, a group of leading paleopathologists concluded that enough evidence had been collected to prove that treponemal disease, almost certainly including syphilis, had existed in Europe prior to the voyages of Columbus. [ 98 ]  There is an outstanding issue, however. Damaged teeth and bones may seem to hold proof of pre-Columbian syphilis, but there is a possibility that they point to an endemic form of treponemal disease instead. As syphilis, bejel, and yaws vary considerably in mortality rates and the level of human disease they elicit, it is important to know which one is under discussion in any given case, but it remains difficult for paleopathologists to distinguish among them. (The fourth of the treponemal diseases is  pinta , a skin disease and therefore unrecoverable through paleopathology.) Ancient  DNA  (aDNA) holds the answer, because just as only aDNA suffices to distinguish between syphilis and other diseases that produce similar symptoms in the body, it alone can differentiate  spirochetes  that are 99.8 percent identical with absolute accuracy. [ 99 ]  Progress on uncovering the historical extent of syndromes through aDNA remains slow, however, because the bacterium responsible for treponematosis is rare in skeletal remains and fragile, making it notoriously difficult to recover and analyse. Precise dating to the medieval period is not yet possible but work by Kettu Majander et al. uncovering the presence of several different kinds of treponematosis at the beginning of the early modern period argues against its recent introduction from elsewhere. Therefore, they argue, treponematosis—possibly including syphilis—almost certainly existed in medieval Europe. [ 100 ]


Despite significant progress in tracing the presence of syphilis in past historic periods, definitive findings from paleopathology and aDNA studies are still lacking for the medieval period. Evidence from art is therefore helpful in settling the issue. Research by Marylynn Salmon has demonstrated that deformities in medieval subjects can be identified by comparing them to those of modern victims of syphilis in medical drawings and photographs. [ 101 ]  One of the most typical deformities, for example, is a collapsed nasal bridge called  saddle nose . Salmon discovered that it appeared often in  medieval illuminations , especially among the men tormenting Christ in scenes of the crucifixion. The association of saddle nose with evil is an indication that the artists were thinking of syphilis, which is typically transmitted through sexual intercourse with promiscuous partners, a mortal sin in medieval times.


It remains mysterious why the authors of medieval medical treatises so uniformly refrained from describing syphilis or commenting on its existence in the population. Many may have confused it with other diseases such as leprosy ( Hansen's disease ) or  elephantiasis . The great variety of symptoms of treponematosis, the different ages at which the various diseases appear, and its widely divergent outcomes depending on climate and culture, would have added greatly to the confusion of medical practitioners, as indeed they did right down to the middle of the 20th century. In addition, evidence indicates that some writers on disease feared the political implications of discussing a condition more fatal to elites than to commoners. Historian Jon Arrizabalaga has investigated this question for  Castile  with startling results revealing an effort to hide its association with elites. [ 102 ]


The first written records of an outbreak of syphilis in Europe occurred in 1495 in  Naples, Italy , during a French invasion ( Italian War of 1494–98 ). [ 11 ] [ 42 ]  Since it was claimed to have been spread by French troops, it was initially called the "French disease" by the people of Naples. [ 103 ]  The disease reached  London  in 1497 and was recorded at St Bartholomew's Hospital as infecting 10 out of the 20 patients. [ 104 ]  In 1530, the pastoral name "syphilis" (the name of a character) was first used by the Italian physician and poet  Girolamo Fracastoro  as the title of his  Latin  poem in  dactylic hexameter   Syphilis sive morbus gallicus  ( Syphilis or The French Disease ) describing the ravages of the disease in Italy. [ 105 ] [ 106 ]  In Great Britain it was also called the "Great Pox". [ 107 ] [ 108 ]


In the 16th through 19th centuries, syphilis was one of the largest public health burdens in  prevalence , symptoms, and disability, [ 109 ] : 208–209  [ 110 ]  although records of its true prevalence were generally not kept because of the fearsome and sordid status of  sexually transmitted infections  in those centuries. [ 109 ] : 208–209   According to a 2020 study, more than 20% of individuals in the age range 15–34 years in late 18th-century London were treated for syphilis. [ 111 ]  At the time the  causative agent  was unknown but it was well known that it was spread sexually and also often from mother to child. Its association with sex, especially  sexual promiscuity  and  prostitution , made it an object of fear and revulsion and a taboo. The magnitude of its morbidity and mortality in those centuries reflected that, unlike today, there was no adequate understanding of its  pathogenesis  and no truly effective treatments. Its damage was caused not so much by great sickness or death early in the course of the disease but rather by its gruesome effects decades after infection as it progressed to  neurosyphilis  with  tabes dorsalis .  Mercury  compounds and isolation were commonly used, with treatments often worse than the disease. [ 107 ]


The causative organism,  Treponema pallidum , was first identified by  Fritz Schaudinn  and  Erich Hoffmann , in 1905. [ 112 ]  The first effective treatment for syphilis was  arsphenamine , discovered by  Sahachiro Hata  in 1909, during a survey of hundreds of newly synthesized organic  arsenical  compounds led by  Paul Ehrlich . It was manufactured and marketed from 1910 under the trade name  Salvarsan  by  Hoechst AG . [ 113 ]  This  organoarsenic compound  was the first modern  chemotherapeutic agent .


During the 20th century, as both  microbiology  and  pharmacology  advanced greatly, syphilis, like many other infectious diseases, became more of a manageable burden than a scary and disfiguring mystery, at least in  developed countries  among those people who could afford to pay for timely diagnosis and treatment. Penicillin was discovered in 1928, and effectiveness of treatment with  penicillin  was confirmed in trials in 1943, [ 107 ]  at which time it became the main treatment. [ 114 ]


Many famous historical figures, including  Franz Schubert ,  Arthur Schopenhauer ,  Édouard Manet , [ 11 ]   Charles Baudelaire , [ 115 ]  and  Guy de Maupassant  are believed to have had the disease. [ 116 ]   Friedrich Nietzsche  was long believed to have gone mad as a result of  tertiary syphilis , but that diagnosis has recently come into question. [ 117 ]


The earliest known depiction of an individual with syphilis is  Albrecht Dürer 's  Syphilitic Man  (1496), a woodcut believed to represent a  Landsknecht , a Northern European  mercenary . [ 118 ]  The myth of the  femme fatale  or "poison women" of the 19th century is believed to be partly derived from the devastation of syphilis, with classic examples in literature including  John Keats ' " La Belle Dame sans Merci ". [ 119 ] [ 120 ]


The Flemish artist  Stradanus  designed a print called  Preparation and Use of Guayaco for Treating Syphilis , a scene of a wealthy man receiving treatment for syphilis with the tropical wood  guaiacum  sometime around 1590. [ 121 ]


The "Tuskegee Study of Untreated Syphilis in the Negro Male" was an infamous, unethical and racist  clinical study  conducted between 1932 and 1972 by the  U.S. Public Health Service . [ 122 ] [ 123 ]  Whereas the purpose of this study was to observe the  natural history  of untreated syphilis; the African-American men in the study were told they were receiving free treatment for "bad blood" from the United States government. [ 124 ]


The Public Health Service started working on this study in 1932 in collaboration with  Tuskegee University , a  historically black college  in Alabama. Researchers enrolled 600 poor, African American  sharecroppers  from  Macon County ,  Alabama  in the study. Of these men, 399 had contracted syphilis before the study began, and 201 did not have the disease. [ 123 ]  Medical care, hot meals and free burial insurance were given to those who participated. The men were told that the study would last six months, but in the end, it continued for 40 years. [ 123 ]  After funding for treatment was lost, the study was continued without informing the men that they were only being studied and would not be treated. Facing insufficient participation, the Macon County Health Department nevertheless wrote to subjects to offer them a "last chance" to get a special "treatment", which was not a treatment at all, but a spinal tap administered exclusively for diagnostic purposes. [ 122 ]  None of the men infected were ever told that they had the disease, and none were treated with  penicillin  even after the antibiotic had been proven to successfully treat syphilis. According to the  Centers for Disease Control , the men were told they were being treated for "bad blood"—a colloquialism describing various conditions such as fatigue,  anemia  and syphilis—which was a leading cause of death among southern African American men. [ 123 ]


The 40-year study became a textbook example of poor  medical ethics  because researchers had knowingly withheld treatment with  penicillin  and because the subjects had been misled concerning the purposes of the study. The revelation in 1972 of these study failures by a  whistleblower ,  Peter Buxtun , led to major changes in U.S. law and regulation on the protection of participants in clinical studies. Now studies require  informed consent , [ 125 ]  communication of  diagnosis , and accurate reporting of test results. [ 126 ]


Similar experiments were carried out in  Guatemala  from 1946 to 1948. It was done during the administration of American President  Harry S. Truman  and Guatemalan President  Juan José Arévalo  with the cooperation of some Guatemalan health ministries and officials. [ 127 ]  Doctors infected soldiers, prostitutes, prisoners and  mental patients  with syphilis and other  sexually transmitted infections , without the  informed consent  of the subjects and treated most subjects with  antibiotics . The experiment resulted in at least 83 deaths. [ 128 ] [ 129 ]  In October 2010, the U.S. formally apologized to Guatemala for the ethical violations that took place. Secretary of State  Hillary Clinton  and Health and Human Services Secretary  Kathleen Sebelius  stated "Although these events occurred more than 64 years ago, we are outraged that such reprehensible research could have occurred under the guise of public health. We deeply regret that it happened, and we apologize to all the individuals who were affected by such abhorrent research practices." [ 130 ]  The experiments were led by physician  John Charles Cutler  who also participated in the late stages of the Tuskegee syphilis experiment. [ 131 ]


Syphilis was first called  grande verole  or the "great pox" by the French. Other historical names have included "button scurvy", sibbens, frenga and dichuchwa, among others. [ 132 ] [ 133 ]  Since it was a disgraceful disease, the disease was known in several countries by the name of their neighbouring, often hostile country. [ 114 ]  The English, the Germans, and the Italians called it "the French disease", while the French referred to it as the "Neapolitan disease". The Dutch called it the "Spanish/Castilian disease". [ 114 ]  To the Turks it was known as the "Christian disease", whilst in India, the Hindus and Muslims named the disease after each other. [ 114 ]


Syphilis  is a bacterial infection transmitted by sexual contact [ 2 ]  and is believed to have infected  12 million  people in 1999 with greater than 90% of cases in the  developing world . [ 3 ]  It affects between 700,000 and 1.6 million pregnancies a year, resulting in  spontaneous abortions ,  stillbirths , and  congenital syphilis . [ 4 ]  In  Sub-Saharan Africa  syphilis contributes to approximately 20% of  perinatal deaths . [ 4 ]


In the developed world, syphilis infections were in decline until the 1980s and 1990s due to widespread use of antibiotics. Since the year 2000, rates of syphilis have been increasing in the US, UK, Australia, and Europe primarily among  men who have sex with men  (MSM). [ 3 ]  This is attributed to unsafe sexual practices. [ 3 ]  A  sexually transmitted infection  (STI) Surveillance study done by the  Centers for Disease Control and Prevention  in 2016 showed that men who have sex with men only account for over half (52%) of the 27,814 cases during that year. Nationally, the highest rates of primary and secondary syphilis in 2016 were observed among men aged 20–34 years, among men in the West, and among Black men. [ 5 ]


Increased rates among heterosexuals have occurred in China and Russia since the 1990s. [ 3 ]  Syphilis increases the risk of  HIV  transmission by two to five times and co-infection is common (30–60% in a number of urban centers). [ 3 ] [ 6 ]


Untreated, it has a mortality rate of 8% to 58%, with a greater death rate in males. [ 6 ]  The higher incidence of mortality among males compared to females is not well understood, but is thought to be related to immunological differences across gender. [ 7 ]  The symptoms of syphilis have become less severe over the 19th and 20th century in part due to widespread availability of effective treatment and partly due to  decreasing virulence  of the spirochete. [ 8 ]  With early treatment few complications result. [ 9 ]


In China, rates of syphilis have increased from the 1990s to the 2010s. [ 10 ]  This occurred after a successful campaign to reduce rates was carried out in the 1950s. [ 10 ]  Rates of diagnosis are higher in urban coastal areas. [ 10 ]  This may be due to sexual practices or better diagnosis in these areas. [ 10 ]


Rates of syphilis in 2000–2005 among low-risk groups such as women without children and unmarried people were about 0.3–0.6% while rates among high-risk groups such as drug users and MSM were about 7–15%. [ 11 ]  Rates are greatest among men who have sex with men and  sex workers . [ 10 ]


The increase has been attributed to a number of factors including: migration from rural communities to urban environments, increased numbers of unmarried men, limited screening for disease, partners not always getting notification, and the fact that high-risk groups frequently do not seek health care. [ 10 ]


Co-infection of HIV and syphilis is probably a major reason behind resurgence in syphilis prevalence among men who have sex with men in China. It is hypothesized that the association observed between syphilis and HIV among MSM is probably due to similar risks associated with both infections. Analysis of data from a survey among MSM in seven Chinese cities reveal that the factors significantly associated with co-infection are older age, education up to senior high school, unprotected anal intercourse, recent STI symptoms, and incorrect knowledge about routes of transmission. [ 12 ]


One reason for increasing syphilis infection rates in China is suboptimal testing uptake among key populations.  SESH , a research partnership dedicated to developing creative, equitable, and effective solutions to sexual health dilemmas, has looked extensively into ways to improve syphilis detection among MSM. Research suggests that testing can be optimized by offering rapid STI testing at MSM-focused centers, improving confidentiality, and ensuring test accuracy. [ 13 ]


In 2021, twenty-eight  EU / EEA  countries reported 25,270 confirmed syphilis cases, giving an overall notification rate of 7.0 per 100,000 population, [ 14 ]  up from 6.0 in 2015. [ 15 ]


The majority (77%) of cases with information on transmission category were reported in men who have sex with men (MSM), [ 14 ]  consistent with the global trend. This is up from 62% in 2015. [ 15 ]


By age, 62% of cases belonged collectively to two groups: 25–34 years and 45 years or above. Young people aged 15–24 accounted for 12% of reported cases. [ 14 ]


Within the region, the country with the highest rate of reported cases was Malta at 32.2 per 100,000 population, while the lowest number was reported from Croatia, at 0.9 per 100,000 people. [ 14 ]


The number of HIV co-infections remains a prevalent issue with a worsening trend, especially in the "men who have sex with men" transmission category. [ 14 ]


Rates of congenital syphilis have decreased between the 1980 and 2000s due to better access to  prenatal care . [ 16 ]
A five-year study among 250 patients in each year among attendees in an STI clinic in West Bengal found significantly decreased(p<0.05) Syphilis prevalence from 10.8% (in 2004) to 3.6% (in 2008). [ 17 ]  A study conducted in 2015 found a falling trend of syphilis in STI clinic attendees, but a rising trend in intro-venus drug users, pregnant women, HIV-seropositive individuals, and patients from other wards and OPD's. This study was conducted at a tertiary care center so the results may not reflect the true prevalence of syphilis in the country. [ 18 ]


In the United States rates of syphilis have increased among men between 2000 and 2007. [ 19 ]  Rates are six times greater in men than women and seven times greater in African Americans than Caucasians. [ 19 ]  More than 60% of cases are in men who have sex with men. [ 19 ]  It occurs most commonly in those between 15 and 40 years of age. [ 20 ]


In the United States, rates of syphilis as of 2007 were six times greater in men than women while they were nearly equal in 1997. [ 21 ]  Rates are also greater in African Americans and Hispanics than in Caucasians. [ 21 ]


According to a report from the Centers for Disease Control and Prevention, between 2000 and 2016, the rising rates of primary and secondary syphilis were attributed to men, mostly who have sex with men, no matter how they identify. However, since 2013, according to the same report, rates among men and women have increased. These increases were in every region within the United States and across racial identities as well. The groups with the highest rates in 2016 were men aged 20–34, men from the western region of the United States, and black men. In 2016, there were 27,814 reported cases of syphilis, primary and secondary, in the United States, a 17.6% increase from the previous year and a 74% increase from the reported cases in 2012. [ 22 ]


Primary and secondary syphilis have a high correlation to an HIV-coinfection, particularly in men who have sex with men (MSM). In 2016, in cases with a known HIV-status, 47% of men who had sex with men were HIV-positive along with their syphilis infections. The rates among men who have sex with women (MSW) and women were much lower at 10.7% (MSW) and 41.% (women). [ 22 ]


Cases of  congenital syphilis  have been increasingly rising in the 2010s. The  Centers for Disease Control and Prevention  (CDC) reported 918 cases for 2017, what is more than twice the figures of four years earlier. [ 23 ]
CDC data shows that in 2020, 134,000 cases of syphilis were reported in the United States, rising to 176,000 in 2021, a large jump from the rate of syphilis recorded in the early 2000s, where only about 30,000 cases per year were registered. [ 24 ]
Reports in 2023 show a rise of more than 900 percent in  Mississippi  over five years. [ 25 ] [ 26 ] [ 27 ] [ 28 ]


China  had a great deal of syphilis during the first part of the 20th century and basically eliminated it from 1960 to 1980. [ 29 ]  During the 1950s China was believed to have one of the worst cases of syphilis in human history. Different surveillance programs determined that 84% of Chinese prostitutes had the infection and as many as 5% of citizens had the disease in large cities. [ 29 ]


The communist government under  Mao Zedong , in response to the syphilis epidemic, issued free treatment for all those infected and increased screening for the disease. [ 29 ]  In the 1960s it was found that syphilis was almost completely eradicated in China [ citation needed ] Recent studies show evidence that the disease has seen a resurgence. In a study entitled "Syphilis in China: Results of a National Surveillance Program", researchers found that during 1993 the number of cases of reported syphilis was 0-2 per 100,000. During a national surveillance program in 2005 there were found to be 5-7 cases per 100,000 throughout the country. [ 29 ]  In that same study it showed that the city with the most prevalence of syphilis was  Shanghai , with an estimated 55 patients with syphilis per 100,000 citizens. The second highest was  Zhejiang , which had approximately 35 people with syphilis per 100,000; the third was  Fujian , which had 28 patients per 100,000. [ 29 ]


All of these cities are on the southeastern edge of the country, facing the ocean. The greatest increase in syphilis is in female  sex workers , drug users, and gay men. [ 29 ]  According to an article published in  The Lancet  titled "Syphilis Resurgent in China", the main cause of syphilis being more prevalent in China is due to the recent economic growth of China and increased globalization, which has caused an increase of the sex trade, internal and external migration, and a bigger economic inequality among its citizens. [ 30 ]


Something else that is credited is that China's earlier efforts to control the disease helped increase the susceptibility of citizens to the disease. [ vague ] [ citation needed ]  China's increase in syphilis is not self-contained;  Russia , the United Kingdom, Ireland, and the United States have all seen a great increase in patients with syphilis recently. [ citation needed ]


Russia is one of the main areas around the world that has been affected by the syphilis epidemic. An article titled "Epidemics of syphilis in the Russian Federation: trends, origins, and priorities for control", published in  The Lancet , discussed syphilis trends in Russia. Like China, Russia basically eliminated the disease during the 1960s, though there was a slight increase during 1978 and 1979 with an estimated 28 cases per 100,000. The rate dropped slightly only to rise between 1988, where there were four patients per 100,000 citizens, to 263 patients per 100,000 in 1996, which is 62 times more than it had been. [ 31 ]


The most commonly affected individuals are found to be young men and women. It is also reported that the estimated number of patients in Russia with syphilis who do not report their disease rose from around 0% in 1989 to 30% in 1993. [ 31 ]


Many of the reasons for this increase in syphilis within Russia stem from  political restructuring  and a declining economy, causing many people's standard of living to decline. The  gross national income  of the country dropped about 12% between 1990 and 1994. [ 31 ]  The government funding of health services and social institutions went down and in turn caused fewer people to receive treatment for syphilis. This broad decline in the economy within Russia also led to an increase in the crossing of the country's borders, causing a mixing of surrounding area and more migration within and outside of Russia. [ 31 ]  In  Moscow  especially, a lot of travel has been done between other large cities. This increase in travel is similar to China's recent [ when? ]  increase in travel. Both have increased the number of sexual encounters with prostitutes and varied ideas of sexual ideology. [ citation needed ]


Russia right now is focused on making an increase in prevention and treatment programs throughout the country, making sure that the lower class of people have access to medical services and many health promotions are being made. [ 31 ]


The  United Kingdom  and other parts of Western Europe have also seen a major increase in syphilis in recent times. A study called "Are trends in HIV, gonorrhea, and syphilis worsening in western Europe?" in a journal of medicine called BMJ outlines the data collected from 1995 to 2000 on sexually transmitted infections throughout western Europe. As with Russia and China there was a big decline in syphilis before 1980 but a big resurgence during the 1990s. [ 32 ]


Another major way of spreading the disease is the sharing of needles between drug users. [ 32 ]


England and Wales saw a slight drop and then increase of syphilis cases between 1995 and 2000 and a drastic increase in syphilis contraction through homosexual men in 2000. [ 32 ]  The increase in Western Europe can be attributed to the practice of unprotected sex and young people are having more sex than they have had in the past. Due to a lack of modern surveillance programs and various governments in Europe there is not definitive data to show how prevalent the spread of syphilis is throughout every country in Western Europe. [ 32 ]


The United States mirrored the global trend with a sharp increase in syphilis during the 1990s up till the present. The United States saw a big decrease in the number of cases in the 1950s, with only around 6500 cases were reported per year, which was statistically about what other countries were seeing at the time. This continued with a varying increase around the 1960s and 1970s with around 19,000 and 26,000 cases per year up until the beginning of the 1990s. [ 33 ]
The  Centers for Disease Control and Prevention  (CDC) published their findings in 2013 with 19,738,800 almost 15% of those were from syphilis. It has been found that men and women are equally as likely to have syphilis in the United States. It is thought that the number of new cases of syphilis along with the current amount is around 117,000 people have syphilis in the United States. [ 34 ]


To combat the increase in syphilis and other various sexually transmitted infections, the United States focuses on prevention programs where the focus is on practicing safe sex and being aware of whether ones partner has syphilis. Pregnant women, which have a high risk of infecting their children, are required to take syphilis screening and given treatment if they are found to be carrying the disease. [ 34 ]


All of these countries have in common a theme of travel in between countries which increases how prevalent and far reaching the disease can reach. Not only is travel linked to the reemergence of syphilis but also the  Internet  has been a major factor in syphilis being transferred from person to person.
A study done in 2000 titled "Tracing a Syphilis Outbreak Through Cyberspace" published in  The Journal of the American Medical Association  shows that Internet chat rooms increase the frequency of sexual contact between people, especially those of gay men. [ 35 ]


In a specific outbreak in  San Francisco  gay men with syphilis were found to be a lot more probable to have met their significant other through the Internet. The ratio was found to be that 67% of the men met their partner through an Internet chat room and only 19% of those with reported syphilis were not linked to the Internet. [ 35 ]


The Internet is a global force that facilitates sexual encounters among people which spreads the disease to many people who otherwise would not be in contact with syphilis. [ citation needed ]


This global re-emergence of syphilis is a major problem for every country affected. According to a study titled "Global Prevalence and Incidence Estimates of Selectable Curable STD's" in a journal named Sex Transm Inf the number of syphilis cases reported within the 9 main UN territories in 1995 was roughly around 12 million cases. [ 36 ]  The main population that was reported to have the disease was the people who were lower in the economy and younger people are reported to have more of the disease than older people. [ citation needed ]


Out of the nine UN regions that were surveyed the region that syphilis was the most prevalent was south and south eastern Asia. The second highest was found to be in the sub Saharan parts of Africa and the third highest was  Latin America  and the Caribbean areas. [ 36 ]  This study in 1995 was one of the first big attempts by the  World Health Organization  to find a good estimate of the total population of people with syphilis and other STIs. [ citation needed ]


Studies by the World Health Organization pinpoint how prevalent syphilis is globally. An article called "Congenital syphilis re-emerging" in a medical journal titled JDDG outlines the World Health Organizations findings as recently as 2008. It is estimated that globally 12 million people acquire the disease every year and of these 12 million patients 2 million are pregnant women. [ 37 ]
This high number of pregnant women with the disease estimates that it will cause about 50% of the pregnancies to result in  stillbirth  or prenatal death. The World Health Organization estimates that syphilis in within the mother can cause syphilis in the baby between 713,600 cases and 1,575,000 cases. [ 37 ]


Because of the increased numbers of patients globally there have been many initiatives to prevent the spread of the disease and there has been a global effort to eradicate the disease. An article titled "A Road Map for the Global Elimination of Congenital Syphilis" within a medical journal called  Obstetrics and Gynecology International  outlines the global efforts to combat congenital syphilis mostly dealing with the World Health Organization. Many of the efforts are focused on screening women who are pregnant for the disease and treating them. [ 38 ]
Of the two million pregnancies each year that test positive for syphilis they make up 1.5% of every pregnancy throughout the world. [ 38 ]  In 2007, the World Health Organization estimated that in the countries that are affected most by congenital syphilis, it would cost roughly 3 to 4 million dollars to start a program that could potentially eliminate most of the threat of congenital syphilis by focusing a lot more on screening and treatment. [ 38 ]


Countries in  Sub-Saharan Africa  find it difficult to implement these kinds of treatment due to a lack of health services for their citizens which in turn makes this area a big breeding ground for congenital syphilis and the spread of syphilis through sexual contact.
The World Health Organization outlines a four-pillar plan that could help countries eliminate or at least decrease the numbers of cases of congenital syphilis. The four pillars are "ensure advocacy and sustained political commitment for a successful health initiative, increase access to, and quality of, maternal and newborn health services, screen and treat pregnant women and partners, and establish surveillance, monitoring, and evaluation systems." [ 38 ]
The  United Nations  has also added goals related to the lowering of syphilis which they call the  Millennium Development Goals . These goals include reducing infant death from syphilis and increasing the health of mothers with syphilis. [ 37 ]  The United Nations have taken steps to include on site screening and testing for syphilis among other sexually transmitted infections along with an increase in partner notification. [ citation needed ]


The  Treponema pallidum  particle agglutination assay  (also called  TPPA  test) is an indirect agglutination assay used for detection and titration of antibodies against the causative agent of  syphilis ,  Treponema pallidum  subspecies  pallidum . It also detects other  treponematoses . [ citation needed ]


In the test, gelatin particles are sensitized with  T. pallidum  antigen.  Patient serum is mixed with the reagent containing the sensitized gelatin particles.  The particles aggregate to form clumps when the patient serum is positive for syphilis.  In other words, the patient's serum contains antibodies to  T. pallidum . A negative test shows no clumping of gelatin particles.  This is a type of specific treponemal test for syphilis.  [ citation needed ]


A similar specific treponemal test for syphilis is the  Treponema pallidum  hemagglutination assay  or  TPHA .  TPHA is an indirect hemagglutination assay used for the detection and titration of antibodies against the causative agent of  syphilis ,  Treponema pallidum  subspecies  pallidum . [ citation needed ]


In the test, red blood cells ( erythrocytes ) are sensitized with antigens from  T. pallidum pallidum . The cells then aggregate on the surface of a test dish if exposed to the serum of a patient with syphilis. It is used as a confirmatory test for syphilis infection.  A negative test result shows a tight button or spot of red blood cells on the surface of the test dish.  Often a plastic test plate containing many small "wells" is used as the test dish so that many patients may be tested at the same time but their results can be kept separate from each other. Please note the image (Fig 1) of the wells on the test plate and the positive and negative test results look different. [ 1 ]


For  primary syphilis , TPPA has a  sensitivity  of 85% to 100%, and a  specificity  of 98% to 100%. [ 2 ]  In secondary and late-latent syphilis, TPPA has a sensitivity of 98% to 100%. [ 2 ]


Antibodies against other treponemal organisms, such as the  T. pallidum  subspecies  endemicum ,   pertenue , or  carateum , can cause false positive results. Not all these disease are venereal; it has been recommended that a careful explanation of this fact be included with test results. [ 3 ]  A variety of methods exist to adsorb these antibodies from the test sample before hemagglutination. [ citation needed ]


Syphilitic aortitis   is  inflammation  of the  aorta  associated with the  tertiary stage of syphilis infection . SA begins as inflammation of the  outermost layer  of the blood vessel, including the blood vessels that supply the aorta itself with blood, the  vasa vasorum . [ 3 ]  As SA worsens, the vasa vasorum undergo  hyperplastic  thickening of their walls thereby restricting blood flow and causing  ischemia  of the outer two-thirds of the aortic wall. Starved for oxygen and nutrients, elastic fibers become patchy and smooth muscle cells die. If the disease progresses, syphilitic  aortitis  leads to an  aortic aneurysm . Overall, tertiary syphilis is a rare cause of aortic aneurysms. [ 3 ]  Syphilitic aortitis has become rare in the developed world with the advent of  penicillin  treatments after  World War II . [ citation needed ]


The infection often has no symptoms until the patient develops an  aneurysm  because of the aortic dilatation. The disease is often discovered after a routine checkup of the heart and aorta. Although easily overlooked, other symptoms of tertiary syphilis might appear such as  gummas  and symptoms of  neurosyphilis  (headache, stiff neck, gait abnormality, dementia etc.). Additionally, in rare cases,  chest pain  and  shortness of breath  might appear as a result of the damage of the aorta and heart valve. [ citation needed ]


Inflammatory involvement of tertiary syphilis begins at the adventitia of the  aortic arch  which progressively causes  obliterative endarteritis  of the vasa vasorum. [ 3 ]  This leads to narrowing of the lumen of the vasa vasorum, causing ischemic injury of the medial aortic arch and then finally loss of elastic support and dilation of the vessel. [ 3 ]   Dissection of the aortic arch  is rare due to medial scarring. As a result of this advanced disease process, normal methods of  angiography / angioplasty  may be impossible for those with suspected  coronary artery disease . [ citation needed ]


Intravenous penicillin has been the primary treatment for syphilitic aortitis since the 1940s. The underlying bacterium of syphilis,  T. pallidum,  continues to be sensitive to penicillin as the lack of horizontal gene transfer mechanisms makes it difficult for the bacterium to mutate and resist treatment. [ 4 ]   In patients with aortic aneurysm, treatment would also involve surgical repair alongside intravenous penicillin, in order to reduce the likelihood of relapse. [ 5 ]


Trichomonas vaginalis  is an  anaerobic ,  flagellated   protozoan  parasite and the causative agent of a  sexually transmitted disease  called  trichomoniasis . It is the most common  pathogenic  protozoan that infects humans in industrialized countries. [ 2 ]  Infection rates in men and women are similar but women are usually symptomatic, while infections in men are usually asymptomatic. Transmission usually occurs via direct, skin-to-skin contact with an infected individual, most often through vaginal intercourse. It is estimated that 160 million cases of infection are acquired annually worldwide. [ 3 ]  The estimates for  North America  alone are between 5 and 8 million new infections each year, with an estimated rate of  asymptomatic  cases as high as 50%. [ 4 ]  Usually treatment consists of  metronidazole  and  tinidazole . [ 5 ]


Alfred Francois Donné  (1801–1878) was the first to describe a procedure to diagnose trichomoniasis through "the microscopic observation of motile protozoa in vaginal or cervical secretions" in 1836. He published this in the article entitled, "Animalcules observés dans les matières purulentes et le produit des sécrétions des organes génitaux de l'homme et de la femme" in the journal,  Comptes rendus de l'Académie des sciences . [ 6 ]  With it, he created the binomial name of the parasite as  Trichomonas vaginalis . [ 7 ]  80 years after the initial discovery of the parasitic protozoan, Hohne declared  Trichomoniasis  as a clinical entity in 1916. [ 8 ]


Most women (85%) and men (77%) with infected with  T. vaginalis  do not have symptoms. Half of these women can develop symptoms within 6 months and can have vaginal  erythema ,  dyspareunia ,  dysuria , and vaginal discharge, which is often diffuse, malodorous, and yellow-green, along with itching in the genital region.  “ Strawberry cervix ,” occurs in about 5% of women. In men, it can cause  urethritis ,  epididymitis  and  prostatitis . [ 9 ]


Some of the complications of  Trichomonas vaginalis  in women include:  preterm delivery , low birth weight, and increased mortality as well as predisposing to  human immunodeficiency virus  infection,  AIDS , and  cervical cancer . [ 10 ]   Trichomonas vaginalis  can be seen in diverse locations within the body, such as," in the  urinary tract ,  fallopian tubes , and pelvis and can cause  pneumonia ,  bronchitis , and oral lesions." [ 11 ]


Classically, with a  cervical smear , infected women may have a transparent "halo" around their superficial cell nucleus but more typically the organism itself is seen with a, "slight cyanophilic tinge, faint eccentric nuclei, and fine acidophilic granules." [ 12 ]  It is unreliably detected by studying a genital discharge or with a cervical smear because of their low  sensitivity .  Trichomonas vaginalis  is also routinely diagnosed via a wet mount, in which motility is observed. Currently, the most common method of diagnosis is via overnight culture, [ 13 ] [ 14 ]  with a sensitivity range of 75–95%. [ 15 ]  Newer methods, such as  rapid antigen testing  and  transcription-mediated amplification , have even greater sensitivity, but are not in widespread use. [ 15 ]


Infection is treated and cured with  metronidazole [ 16 ]  or  tinidazole . The CDC recommends a one time dose of 2 grams of either metronidazole or tinidazole as the first-line treatment; the alternative treatment recommended is 500 milligrams of metronidazole, twice daily, for seven days if there is failure of the single-dose regimen. [ 17 ]  Medication should be prescribed to any  sexual partner (s) as well because they may be  asymptomatic carriers . [ 18 ]


Trichomonas vaginalis  exists in only one morphological stage, a  trophozoite , and cannot encyst (or form cysts.) This protozoan does not typically adhere to one shape, as in different conditions, the parasite has the ability to change. When in culture separate from the host, it usually displays a more "pear" or oval shaped morphology, but when present in a living host, specifically on the epithelial cells of the vaginal wall, the shape is more "amoeboid". [ 19 ]  It is slightly larger than a white blood cell, measuring 9 × 7  μm . In both forms,  Trichomonas vaginalis  has  five flagella – four protruding from the front or anterior of the parasite and the fifth on the back or posterior end. The functionality of the fifth flagellum is not known. [ 20 ]  In addition, a  barb-like  axostyle  projects opposite the four-flagella bundle. All of these flagella are connected to an "undulating" membrane. [ 20 ]  The axostyle may be used for attachment to surfaces and may also cause the tissue damage seen in trichomoniasis. [ 21 ]  The nucleus is usually elongated, and is located near the anterior end of the protozoan within the cytoplasm which contains many  hydrogenosomes  (closed-membrane organelle with the ability to produce both adenosine triphosphate and hydrogen while in anaerobic conditions.) [ 22 ]


While  Trichomonas vaginalis  does not have a  cyst  form, the organism can survive for up to 24 hours in urine, semen, or even water samples. A nonmotile, round, pseudocystic form with internalized flagella has been observed under unfavorable conditions. [ 23 ]  This form is generally regarded as a degenerate stage as opposed to a resistant form, [ 23 ]  although viability of pseudocystic cells has been occasionally reported. [ 24 ]  The ability to revert to trophozoite form, to reproduce and sustain infection has been described, [ 25 ]  along with a microscopic cell  staining  technique to visually discern this elusive form. [ 26 ]


Trichomonas vaginalis  is  an  anaerobe . [ 27 ]  There is an absence of  cytochrome C  and  mitochondria , thus making oxygen uptake and synthesis of adenosine triphosphate via oxidative phosphorylation difficult. [ 27 ]  Although it contains no mitochondria, an analogous structure called a  hydrogenosome , which is the site of fermentative oxidation of pyruvate, carries out many of the same metabolic processes. Carbohydrates, specifically those with alpha1,4- glycosidic linkages, are metabolized and eventually fermented to produce products such as acetate, lactate, malate, glycerol and CO 2  under aerobic conditions. Hydrogen is produced under anaerobic conditions. [ 28 ]  Outside the hydrogenosome, carbohydrate metabolism also occurs freely in the cytoplasm. The  Embden-Meyerhof-Parnas pathway . [ 28 ]  is used to convert glucose into phosphoenolpyruvate which ultimately becomes pyruvate.


Although  Trichomonas vaginalis  exists as a trophozoite in its infective form, its amoeboid form is also an important characteristic that adds to how well it is able to infect its host. The amoeboid form, which is pancake shaped, allows for greater surface area contact with epithelial cells of the vagina, cervix, urethra, and prostate.  [ 29 ]  The pseudocyst form is also a way in which the microbe can infect more efficiently, but this only induced when exposed to cold and other stressors. [ 29 ]  These various forms are accompanied with differing protein phosphorylation profiles which are triggered by environmental pressures. [ 29 ]


One of the hallmark features of  Trichomonas vaginalis  is the adherence factors that allow  cervicovaginal epithelium  colonization in women. The adherence that this organism illustrates is specific to vaginal  epithelial cells  being  pH , time, and temperature dependent. [ 30 ]  A variety of  virulence factors  mediate this process some of which are the microtubules, microfilaments,  bacterial adhesins  (4), and  cysteine   proteinases . The adhesins are four trichomonad enzymes called AP65, AP51, AP33, and AP23 that mediate the interaction of the parasite to the receptor molecules on vaginal epithelial cells. [ 31 ]  The best characterized surface molecule associated with one of the four adhesins is called  Trichomonas vaginalis  lipoglycans. [ 29 ]  This molecule is the most abundant on the surface of  Trichomonas vaginalis , aids in sticking to vaginal epithelial cells, and can also influence how the human immune system responds, affecting inflammatory responses and macrophages in the body. [ 29 ]  Cysteine proteinases may be another virulence factor because not only do these 30 kDa proteins bind to host cell surfaces but also may degrade  extracellular matrix   proteins  like  hemoglobin ,  fibronectin  or  collagen IV . [ 30 ]


The  Trichomonas vaginalis  genome is approximately 160  megabases  in size [ 32 ]  – ten times larger than predicted from earlier gel-based chromosome sizing. [ 33 ]  (The human genome is ~3.5  gigabases  by comparison. [ 34 ] ) As much as two-thirds of the  Trichomonas vaginalis  sequence consists of repetitive and  transposable elements ,  indicative of a recent  drastic, evolutionarily expansion of the genome. The total number of predicted protein-coding genes is ~60,000, with the genome being around 65% repetitive (virus-like, transposon-like,  retrotransposon -like, and unclassified repeats, all with high copy number and low  polymorphism ). [ 35 ]  Approximately 26,000 of the protein-coding genes have been classed as 'evidence-supported' (similar either to known proteins, or to  expressed sequence tags ), while the remainder have no known function.  [ 35 ] These extraordinary genome statistics are likely to change downward as the genome sequence, currently very fragmented due to the difficulty of ordering repetitive DNA, is assembled into chromosomes, and as more transcription data (expressed sequence tags,  microarrays ) accumulate.  [ 35 ]


TrichDB.org  was launched as a free, public genomic data repository and retrieval service devoted to genome-scale trichomonad data. The site currently contains all of the  Trichomonas vaginalis  sequence project data, several expressed sequence tag libraries, and tools for data mining and display.  [ 36 ]  TrichDB is part of the  EupathDB  functional genomics database project funded by the National Institutes of Health and National Institute of Allergy and Infectious Diseases. [ 36 ]


High levels of genetic diversity were detected in  Trichomonas vaginalis  after phenotypic differences were discovered during clinical presentations.  [ 37 ]  Studies into the genetic diversity of  Trichomonas vaginalis  has shown that there are two distinct lineages of the parasite found worldwide; both lineages are represented evenly in field isolates. The two lineages differ in whether or not  Trichomonas vaginalis  virus infection is present.  Trichomonas vaginalis  virus infection is clinically relevant in that, it has an effect on parasite resistance to metronidazole, a first line drug treatment for human trichomoniasis. [ 38 ]


In addition to inflammation that  Trichomonas vaginalis  causes,  the parasite also causes lysis of epithelial cells and red blood cells in the area leading to more inflammation and disruption of the protective barrier usually provided by the epithelium. Having  Trichomonas vaginalis  also may increase the chances of the infected woman transmitting human immunodeficiency virus to her sexual partner(s). [ 39 ] [ 40 ]


The biology of  Trichomonas vaginalis  has implications for understanding the origin of sexual reproduction in eukaryotes.  Trichomonas vaginalis  is not known to undergo  meiosis , a key stage of the eukaryotic sexual cycle.  However, when Malik  et al. [ 41 ]  examined  Trichomonas vaginalis  for the presence of 29 genes known to function in meiosis, they found 27 homologous genes to the ones found in animals, fungi, plants and other protists, including eight of nine genes that are specific to meiosis in  model organisms . [ 41 ]   These findings suggest that  Trichomonas vaginalis  has the capability  for meiotic recombination, and hence  "parasexual " reproduction. [ 41 ]   21 of the 27 meiosis genes were also found in another parasite  Giardia lamblia  (also called  Giardia intestinalis ), indicating that these meiotic genes were present in a common ancestor of  Trichomonas vaginalis  and  G. intestinalis . [ 41 ]   Since these two species are descendants of lineages that are highly divergent among  eukaryotes , these meiotic genes were likely present in a common ancestor of all eukaryotes. [ 41 ]


A  tubo-ovarian abscess  (TOA) is one of the late  complications  of  pelvic inflammatory disease  (PID) and can be life-threatening if the  abscess  ruptures and results in  sepsis . It consists of an encapsulated or confined pocket of  pus  with defined boundaries that forms during an infection of a  fallopian tube  and  ovary . These abscesses are found most commonly in reproductive age women and typically result from upper genital tract infection. [ 1 ] [ 2 ]  It is an inflammatory mass involving the fallopian tube, ovary and, occasionally, other adjacent pelvic organs. A TOA can also develop as a complication of a hysterectomy. [ 3 ] : 103


Symptoms typically include fever, an elevated  white blood cell  count, lower abdominal-pelvic pain, and/or vaginal discharge. Fever and leukocytosis may be absent. TOAs are often polymicrobial with a high percentage of anaerobic bacteria. The cost of treatment in the United States is approximately $2,000 per patient, which equals about $1.5 billion annually. [ 1 ]   Though rare, TOA can occur without a preceding episode of PID or sexual activity. [ 4 ] [ 5 ]


The signs and symptoms of tubo-ovarian abscess (TOA) are the same as with  pelvic inflammatory disease  (PID) with the exception that the abscess can be found with  magnetic resonance imaging  (MRI),  sonography  and  x-ray . [ 1 ]  It also differs from PID in that it can create symptoms of acute-onset pelvic pain. [ 6 ]  Typically this disease is found in sexually active women. [ 4 ] [ 7 ]  Tubo-ovarian abscess can mimic abdominal tumours. [ 8 ]


Complications of TOA are related to the possible removal of one or both ovaries and fallopian tubes.  Without these reproductive structures, fertility can be affected.  Surgical complications can develop and include: [ citation needed ]


The development of TOA is thought to begin with the  pathogens  spreading from the  cervix  to the  endometrium , through the  salpinx , into the  peritoneal cavity  and forming the tubo-ovarian abscess with (in some cases) pelvic peritonitis.  TOA can develop from the  lymphatic system  with infection of the  parametrium  from an  intrauterine device  (IUD). [ 1 ]  Bacteria recovered from  TOAs are  Escherichia coli ,  Bacteroides fragilis , other  Bacteroides  species,  Peptostreptococcus ,  Peptococcus , and  aerobic   streptococci . [ 9 ]  Long term IUD use is associated with TOA. [ 10 ]  Actinomyces is also recovered from TOA. [ 10 ]


Laparoscopy  and other imaging tools can visualize the abscess. Physicians are able to make the  diagnosis  if the abscess ruptures when the woman begins to have lower abdominal pain that then begins to spread.  The symptoms then become the same as the symptoms for  peritonitis .   Sepsis  occurs, if left untreated. [ 3 ] : 103   Ultrasonography is a sensitive enough imaging tool that it can accurately differentiate between pregnancy, hemorrhagic ovarian cysts, endometriosis, ovarian torsion, and tubo-ovarian abscess. Its availability, the relative advancement in the training of its use, its low cost, and because it does not expose the woman (or fetus) to ionizing radiation, ultrasonography an ideal imaging procedure for women of reproductive age. [ 6 ]


Risk factors have been identified which indicate what women will be more likely to develop TOA.  These are: increased age, IUD insertion, chlamydia infection, and increased levels of certain proteins (CRP and CA-125) and will alert clinicians to follow up on unresolved symptoms of PID. [ 12 ]


Treatment for TOA differs from PID in that some clinicians recommend patients with tubo-ovarian abscesses have at least 24 hours of inpatient parenteral treatment with antibiotics, and that they may require surgery. [ 1 ] [ 13 ]  If surgery becomes necessary, pre-operative administration of broad-spectrum antibiotics is started and removal of the abscess, the affected  ovary  and  fallopian tube  is done.   After discharge from the hospital, oral antibiotics are continued for the length of time prescribed by the physician. [ 3 ] : 103


Treatment is different if the TOA is discovered before it ruptures and can be treated with IV antibiotics.  During this treatment, IV antibiotics are usually replaced with oral antibiotics on an outpatient basis.  Patients are usually seen three days after hospital discharge and then again one to two weeks later to confirm that the infection has cleared. [ 3 ] : 103   Ampicillin/sulbactam plus doxycycline is effective against C. trachomatis, N. gonorrhoeae, and anaerobes in women with tubo-ovarian abscess. Parenteral Regimens described by the Centers for Disease Control and prevention are Ampicillin/Sulbactam 3 g IV every 6 hours and Doxycycline 200 mg orally or IV every 24 hours, though other regiments that are used for pelvic inflammatory disease have been effective. [ 14 ]


The epidemiology of TOA is closely related to that of pelvic inflammatory disease  which is estimated to one million people yearly. [ 15 ]


A  vaginal microbicide  is a  microbicide  for  vaginal  use, generally as protection against the contraction of a  sexually transmitted infection  during vaginal  sexual intercourse . Vaginal microbicides are  topical gels  or creams inserted into the vagina.


Researchers have investigated who has interest in using a vaginal microbicide.   Condoms  are highly effective in preventing the transmission of infection, but worldwide, the decision to use condoms is more often a decision made by males than females. [ 1 ]  A vaginal microbicide which could prevent sexual transmission of infection would further empower women to influence the result of their sexual encounters. [ 1 ]  The demographic interested in using the produce included women with the following characteristics: [ 2 ]


The number of women interested in using such a product has been characterized as being significant enough to merit product development and marketing. [ 2 ]


The ideal vaginal microbicide would have the following characteristics: provide protection against infection not require application at the time of intercourse not harm the natural tissue [ 3 ]  As of 2009 [update] , not harming natural tissue was the most troublesome aspect of development. [ 3 ]


Studies for using vaginal microbicides for HIV treatment rapidly increased through 2011 to 2013 due mostly to the observation that antiretroviral drugs designed for HIV treatment sometimes also achieve  preexposure prophylaxis  and significantly reduced HIV risks. [ 4 ]  Several unrelated chemical mechanisms have been proposed for vaginal microbicides treating HIV. [ 1 ]  One obstacle to effective research is that trials may involve social harms for trial participants, although one 2019 study found these social harms to be relatively small. [ 5 ]  There is also often a self-reporting bias in condom and vaginal microbicide use in trials, suggesting the need for vaginal applicator staining to confirm whether the vaginal microbicides were effectively applied. [ 6 ]


The first vaginal microbicide studied was  nonoxynol-9 , which acted as a  surfactant . [ 1 ]


PRO 2000 ,  carrageenan , and cellulose sulphate have been studied as microbicides to block HIV binding. [ 1 ]


Tenofovir  has been studied as a topical  antiretroviral . [ 1 ]  One example of a tenofovir study is  CAPRISA 004  in 2010, finding its use reduced HIV infection risk by 39% overall. [ 4 ]


Venereology  is a branch of  medicine  that is concerned with the study and treatment of  sexually transmitted diseases  (STDs). The name derives from Roman goddess  Venus , associated with love, beauty and fertility. A physician specializing in venereology is called a  venereologist . [ 1 ]  In many areas of the world, the specialty is usually combined with  dermatology . [ 2 ]


The venereal diseases include bacterial, viral, fungal, and parasitic infections. [ 3 ]  Some of the important diseases are  HIV infection ,  syphilis ,  gonorrhea ,  chlamydia ,  candidiasis ,  herpes simplex ,  human papillomavirus  infection, and  genital scabies . Other sexually transmitted infections studied in the field include  chancroid ,  lymphogranuloma venereum ,  granuloma inguinale ,  hepatitis B , and  cytomegalovirus  infection. [ 4 ]


In India, formal training of venereologists started in 1910, prompting microscopy and serology to come into general use throughout the Empire.  Before this, many cases of early syphilis were either diagnosed as chancroid or missed altogether. To come to a diagnosis, doubtful atypical cases were at times left untreated to see whether they developed secondary syphilis. [ 5 ]


In the early part of the twentieth century, the medical science of venereology encompassed only the five classical venereal diseases: gonorrhea, syphilis, chancroid, lymphogranuloma venereum, and granuloma inguinale ( donovanosis ). [ 6 ] [ 7 ]  The  history of virology  shows that, in the first decade of the 20th century, viruses were not well understood.


In the early 1960s there were approximately six STDs described in textbooks and very little research was happening in  sexually transmitted infections . In fact, there were not many medical centers where clinical care was offered for patients with STDs, who were left with few resources. [ 8 ]


Zika fever , also known as  Zika virus disease  or simply  Zika , is an infectious disease caused by the  Zika virus . [ 1 ]  Most cases have no symptoms, but when present they are usually mild and can resemble  dengue fever . [ 1 ] [ 4 ]  Symptoms may include  fever ,  red eyes ,  joint pain , headache, and a  maculopapular rash . [ 1 ] [ 2 ] [ 3 ]  Symptoms generally last less than seven days. [ 2 ]  It has not caused any reported deaths during the initial infection. [ 4 ]   Mother-to-child transmission  during pregnancy can cause  microcephaly  and other brain malformations in some babies. [ 5 ] [ 6 ]  Infections in adults have been linked to  Guillain–Barré syndrome  (GBS). [ 4 ]


Zika fever is mainly spread via the bite of  mosquitoes  of the  Aedes  type. [ 2 ]  It can also be  sexually transmitted  and potentially spread by  blood transfusions . [ 2 ] [ 8 ]  Infections in pregnant women can spread to the baby. [ 5 ] [ 6 ] [ 10 ]  Diagnosis is by testing the blood, urine, or saliva for the presence of the virus's  RNA  when the person is sick, or the blood for  antibodies  after symptoms are present more than a week. [ 1 ] [ 2 ]


Prevention involves decreasing mosquito bites in areas where the disease occurs and proper use of condoms. [ 2 ] [ 8 ]  Efforts to prevent bites include the use of  insect repellent , covering much of the body with clothing,  mosquito nets , and getting rid of standing water where mosquitoes reproduce. [ 1 ]  There is no effective  vaccine . [ 2 ]  Health officials recommended that women in areas affected by the  2015–16 Zika outbreak  consider putting off pregnancy and that pregnant women not travel to these areas. [ 2 ] [ 11 ]  While there is no specific treatment,  paracetamol  (acetaminophen) may help with the symptoms. [ 2 ]  Admission to hospital is rarely necessary. [ 4 ]


The virus that causes the disease was first isolated in Africa in 1947. [ 12 ]  The first documented outbreak among people occurred in 2007 in the  Federated States of Micronesia . [ 2 ]  An  outbreak started in Brazil  in 2015, and spread to the Americas, Pacific, Asia, and Africa. [ 13 ]  This led the  World Health Organization  to declare it a  Public Health Emergency of International Concern  in February 2016. [ 13 ]  The emergency was lifted in November 2016, but 84 countries still reported cases as of March 2017. [ 14 ]  The last proven case of Zika spread in the Continental United States was in 2017. [ 15 ]


Most people who are infected have no or few symptoms. [ 16 ]  Otherwise the most common signs and symptoms of Zika fever are  fever ,  rash ,  conjunctivitis  (red eyes),  muscle  and  joint pain , and headache, which are similar to signs and symptoms of  dengue  and  chikungunya  fever. [ 17 ]  The  time from a mosquito bite to developing symptoms  is not yet known, but is probably a few days to a week. [ 18 ]  The disease lasts for several days to a week and is usually mild enough that people do not have to go to a hospital. [ 1 ] [ 19 ]


Due to being in the same family as dengue, there has been concern that it could cause similar bleeding disorders. However that has only been documented in one case, with blood seen in semen, also known as  hematospermia . [ 20 ]


Zika virus infections have been strongly associated with  Guillain–Barré syndrome  (GBS), which is a rapid onset of muscle weakness caused by the immune system damaging the peripheral nervous system, and which can progress to paralysis. [ 21 ]  While both GBS and Zika infection can simultaneously occur in the same individual, it is difficult to definitively identify Zika virus as the cause of GBS. [ 22 ]  Though Zika virus has been shown to infect human  Schwann cells . [ 23 ]  Several countries affected by Zika outbreaks have reported increases in the rate of new cases of GBS. During the  2013–2014 outbreak in French Polynesia  there were 42 reported cases of GBS over a 3-month period, compared to between 3 and 10 annually prior to the outbreak. [ 24 ]


The disease spreads from  mother to child in the womb  and can cause multiple problems, most notably  microcephaly , in the baby. The full range of birth defects caused by infection during pregnancy is not known, but they appear to be common, with large scale abnormalities seen in up to 42% of live births. [ 25 ] [ 26 ]  The most common observed associations have been abnormalities with brain and eye development such as microcephaly and  chorioretinal  scarring. [ 27 ]  Less commonly there have been systemic abnormalities such as  hydrops fetalis , where there is abnormal accumulation of fluid in the fetus. [ 28 ] [ 29 ]  These abnormalities can lead to intellectual problems,  seizures ,  vision problems ,  hearing problems , problems feeding and slow development. [ 30 ]


Whether the stage of pregnancy at which the mother becomes infected affects the risk to the fetus is not well understood, nor is whether other risk factors affect outcomes. [ 5 ] [ 6 ] [ 10 ]  One group has estimated the risk of a baby developing microcephaly at about 1% when the mother is infected during the first trimester, with the risk of developing microcephaly becoming uncertain beyond the first trimester. [ 31 ]  Affected babies might appear normal but actually have brain abnormalities; infection in newborns could also lead to brain damage. [ 32 ]


Zika virus  is a  mosquito - borne   flavivirus  closely related to the dengue and yellow fever viruses. While mosquitoes are the  vector , the main  reservoir  species remains unknown, though serological evidence has been found in both West African monkeys and rodents. [ 33 ] [ 34 ]


Transmission is via the bite of mosquitoes from the genus  Aedes , primarily  Aedes aegypti  in tropical regions. It has also been isolated from  Ae. africanus ,  Ae. apicoargenteus ,  Ae. luteocephalus , [ 35 ]   Ae. albopictus , [ 36 ] [ 37 ]   Ae. vittatus  and  Ae. furcifer . [ 33 ]  During the 2007 outbreak on Yap Island in the South Pacific,  Aedes hensilli  was the vector, while  Aedes polynesiensis  spread the virus in French Polynesia in 2013. [ 38 ]


Zika virus can also spread by  sexual transmission  from infected men to their partners. [ 39 ] [ 40 ] [ 41 ]  Zika virus has been isolated from  semen  samples, with one person having 100,000 times more virus in semen than blood or urine, two weeks after being infected. [ 42 ]  It is unclear why levels in semen can be higher than other body fluids, and it is also unclear how long infectious virus can remain in semen. There have also been cases of men with no symptoms of Zika virus infection transmitting the disease. [ 43 ]  The CDC has recommended that all men who have travelled to affected areas should wait at least 6 months before trying to attempt  conception , regardless of whether they were ill. [ 44 ]  To date there have been no reported sexual transmissions from women to their sexual partners. [ 41 ]  Oral, anal or vaginal sex can spread the disease. [ 45 ] [ 46 ]


Cases of vertical  perinatal transmission  have been reported. [ 47 ]  The CDC recommends that women with Zika fever should wait at least 8 weeks after they start having symptoms of disease before attempting to conceive. [ 48 ]  There have been no reported cases of transmission from breastfeeding, but infectious virus has been found in breast milk. [ 49 ]


Like other  flaviviruses  it could potentially be transmitted by  blood transfusion  and several affected countries have developed strategies to screen blood donors. [ 19 ] [ 50 ]  The U.S. FDA has recommended universal screening of blood products for Zika. [ 51 ]  The virus is detected in 3% of asymptomatic blood donors in French Polynesia. [ 52 ]


In fruit flies microcephaly appears to be caused by the  flavivirid  virus protein  NS4A , which can disrupt brain growth by hijacking a pathway which regulates growth of new neurons. [ 53 ]


It is difficult to diagnose Zika virus infection based on clinical signs and symptoms alone due to overlaps with other  arboviruses  that are endemic to similar areas. [ 19 ] [ 54 ]  The US  Centers for Disease Control and Prevention  (CDC) advises that "based on the typical clinical features, the differential diagnosis for Zika virus infection is broad. In addition to dengue, other considerations include  leptospirosis ,  malaria ,  rickettsia ,  group A streptococcus ,  rubella ,  measles , and  parvovirus ,  enterovirus ,  adenovirus , and  alphavirus  infections (e.g., chikungunya,  Mayaro ,  Ross River ,  Barmah Forest ,  O'nyong'nyong , and  Sindbis  viruses)." [ 55 ]


In small case series, routine  chemistry  and  complete blood counts  have been normal in most patients. A few have been reported to have mild  leukopenia ,  thrombocytopenia , and elevated liver  transaminases . [ 56 ]


Zika virus can be identified by  reverse transcriptase PCR  (RT-PCR) in acutely ill patients. However, the period of  viremia  can be short [ 4 ]  and the  World Health Organization  (WHO) recommends RT-PCR testing be done on serum collected within 1 to 3 days of symptom onset or on saliva samples collected during the first 3 to 5 days. [ 38 ]  When evaluating paired samples, Zika virus was detected more frequently in saliva than serum. [ 56 ]   Urine samples can be collected and tested up to 14 days after the onset of symptoms, as the virus has been seen to survive longer in the urine than either saliva or serum. [ 57 ]  The longest period of detectable virus has been 11 days and Zika virus does not appear to establish latency. [ 33 ]


Later on,  serology  for the detection of specific  IgM  and  IgG  antibodies to Zika virus can be used. IgM antibodies can be detectable within 3 days of the onset of illness. [ 33 ]  Serological cross-reactions with closely related flaviviruses such as dengue and  West Nile virus  as well as vaccines to flaviviruses are possible. [ 4 ] [ 58 ] [ 59 ]  As of 2019, the  FDA  has authorized two tests to detect Zika virus antibodies. [ 60 ]


The CDC recommends screening some pregnant women even if they do not have symptoms of infection. Pregnant women who have traveled to affected areas should be tested between two and twelve weeks after their return from travel. [ 61 ]  Due to the difficulties with ordering and interpreting tests for Zika virus, the CDC also recommends that healthcare providers contact their local health department for assistance. [ 61 ]  For women living in affected areas, the CDC has recommended testing at the first  prenatal  visit with a doctor as well as in the  mid-second trimester , though this may be adjusted based on local resources and the local burden of Zika virus. [ 61 ]  Additional testing should be done if there are any signs of Zika virus disease. Women with positive test results for Zika virus infection should have their fetus monitored by  ultrasound  every three to four weeks to monitor fetal anatomy and growth. [ 61 ]