Syphilis

Syphilis is a complex, systemic disease caused by the spirochaete Treponema pallidum (T. pallidum), a gram-negative bacterium. Syphilis is preventable and curable with effective and inexpensive antibiotics. The only known natural hosts are humans, and the pathogen is not able to survive outside its host due to limited metabolic capacities to synthetise its own bio-nutrients. Syphilis spirochetes, like other treponemas, cannot be cultivated in vitro. The primary mode of syphilis transmission is by sexual contact (acquired syphilis). Vertical transmission from infected mother to child is possible (congenital syphilis), either in utero (transfer across the placenta) or through contact with an active genital lesion during delivery (Singh, 1999). Untreated syphilis can adversely affect pregnancy outcomes, resulting in spontaneous abortion, stillbirth, premature delivery, or perinatal death. Prematurity and low birth weight have been observed in 10 to 40% of infants born to untreated mothers (Salojee, 2004). The rate of infection through sexual intercourse with an infected partner has been estimated at about 50% (Ficarra & Carlos, 2009).

In Europe and other high-income countries, the transmission via blood or blood products is rare because of the low incidence rates of the disease and improved blood screening and blood donor testing for syphilis (Tramont, 2005).

Only 50% of those infected with T. pallidum will develop symptoms (RKI, 2003). Primary syphilis lasts from two weeks to six months (Baughn & Musher, 2005). Secondary syphilis may last  two to eight weeks (Zetola, 2007). Early latent disease is diagnosed less than one year after infection (WHO, 2003; MMWR, 2010). Late latent syphilis infection is diagnosed after more than one year (WHO, 2003; MMWR, 2010).

Health outcomes and  states associated with syphilis infection in adults

The incubation period for primary syphilis is on average three weeks (10–90 days) and depends on bacterial load, the immune status of the infected person and the existence of other co-morbid conditions (e.g. HIV/AIDS) (Weir & Fisman, 2002; Krause, 2006). Acquired syphilis is divided into primary, secondary, latent and tertiary syphilis. The disease can also be divided into early and late syphilis. Early syphilis implies the primary, secondary and early latent stages. Late syphilis refers to late latent syphilis and tertiary syphilis (Hook, 1992).

Primary syphilis is characterised by an ulcer and/or chancre at the site of infection or inoculation. This primary lesion appears about three weeks after exposure as an indurated, painless ulcer and may not be clinically evident (i.e. it may be in the rectum or the cervix). Invasion of the bloodstream precedes the initial lesion. In 50% of cases, the chancre is accompanied by regional lymphadenopathy (a firm, non-tender satellite lymph node) (Genc, 2000). After three to six weeks the chancre begins to involute, but may persist in the secondary stage in 15–30% of those infected  (Zetola, 2007; Krause, 2006; Parish, 2000).

After 2–12 weeks on average (sometimes 12 months) the untreated infection may progress to secondary syphilis caused by the haematogenic spread and lymphatic dissemination of T. pallidum in the body. The time at which the secondary lesions manifest depends on the bacterial load of the treponeme and the immune response of the host (Baughn, 2005). This stage is characterised by skin rash, condylomata lata (5–22% of patients), mucocutaneous lesions, alopecia (5–7% of patients), and generalised lymphadenopathy (Ficarra & Carlos, 2009). A patient with secondary syphilis may have one, several or all of the signs of the secondary stage. Since each of the signs may also be associated with other diseases, none are specific to syphilis. Neurological involvement in secondary syphilis (known as syphilitic meningitis) can occur, especially in HIV co-infected patients (Marra, 2004). The manifestations of secondary syphilis last two to eight weeks and then may resolve, even without treatment (Zetola, 2007).

After resolution of the secondary manifestations, around one-third of untreated patients will enter into a latent phase. The latent or asymptomatic stage of syphilis is defined as the period from disappearance of the secondary manifestations until therapeutic cure or development of late sequelae. An infection without any clinical symptoms lasting less than one year is referred to as early latent syphilis, whereas an infection of more than one year’s duration without clinical evidence of treponemal infection is referred to as late latent syphilis (WHO, 2003). The definitions of duration may vary across countries. The early latent period corresponds to the highest risk of transmission.

Tertiary syphilis may appear after a long period of untreated syphilis (5–20 years after initial infection) and its manifestations can include gummas (late benign syphilis), cardiovascular symptoms and neurosyphilis (Hutto, 2001). In developed countries gummas and cardiovascular symptoms  are rarely seen and most of the late sequelae are associated with neuro-syphilis. The timescale for development of neuro-syphilis may vary  from a period of one  or two years to more than 30 years after primary syphilis, and may involve 5–10% of untreated patients (Gjestland, 1955). It is characterised by the involvement of the central nervous system which leads to a number of different syndromes, included in the health outcome ’neuro-syphilis’ in our model. In two thirds of patients the infection will not progress to late complications (Mindel, 2000).

Health outcomes and states associated with congenital syphilis infection

Postnatal manifestations of congenital syphilis are divided into early and late stages. Clinical manifestations occurring within the first two years after birth (<2 years) are categorised as early congenital syphilis. Clinical manifestations which occur later than two years after birth are late congenital syphilis (Parish, 2000). For the underlying model, and due to scarce data, only congenital syphilis was included, with no distinction between early or late.

Outcome tree parameters

Due to the high complexity of syphilis outcomes and for reasons of feasibility, the outcome tree for the adult population was split into symptomatic and asymptomatic infections at the first level of disaggregation. The natural course of syphilis was subdivided into the three main disease states: primary, secondary and neuro-syphilis. The focus was on neuro-syphilis because other forms of late syphilis sequelae are very rare in developed countries.

The percentage of asymptomatic cases was estimated at 50% (RKI 2003, Singh, 1999; Ficarra, 2009; Genc, 2000; Parish, 2000). Gerbase and colleagues presented treatment rates of 85% for both primary and secondary symptomatic syphilis cases in regions with established market economies (Gerbase, 2000). As a result of high cure rates (up to 100%), it was estimated that about 85% of all primary syphilis cases are treated and subsequently cured. The remaining 15% of untreated symptomatic cases have a 30–50% possibility of developing secondary syphilis, resulting in a probability of 4.5–7.5% that they will develop secondary syphilis, after having had primary syphilis (Singh, 1999; Weir & Fisman, 2002; Krause, 2006; Gerbase, 2000; Golden, 2003). In asymptomatic primary syphilis the primary chancre is not visible and will generally go unnoticed, meaning that it is less likely to be treated, hence the greater risk of progression to secondary syphilis (30–50%).

Furthermore, 85% of symptomatic secondary syphilis cases are treated and again, as a result of the high cure rates (around 100%), the remaining 15% of untreated cases have a probability of 5–12% of developing neuro-syphilis. Thus, the proportion of people developing neuro-syphilis from preceding secondary syphilis was set at 0.75–1.88% (Tramont, 2005; Zetola, 2007; Gerbase, 2000; Goldmeier & Guallar, 2003).

The probability of dying due to syphilis before reaching the late (tertiary) phase of the disease is very low and there is little evidence of a case fatality ratio associated with syphilis in general, or neurosyphilis in particular, within Europe. We assumed that neurosyphilis in Europe is successfully treated; although with a possibility of developing permanent disabilities for which it was impossible to define the impact due to lack of data. Antibiotic treatment is highly effective and is therefore not associated with a case fatality ratio.

For infants the main outcome is congenital infection with a probability of 20% (2–64%) for an infected child (Singh, 1999; Salojee, 2004; Genc, 2000; Gerbase, 2000). In total, 1% of all children with congenital infection die (Gerbase, 2000).

Model input summary

Table 1. Transition probabilities and distributions used in the outcome tree

Health outcome
(Health state)

Transition probability

Source/assumption

Acquired

 

 

Primary syphilis from infection

50%

RKI, 2003

Secondary syphilis from asymptomatic infection

30–50%

Singh, 1999; Weir & Fisman, 2002; Gerbase, 2000; Golden 2003

Secondary syphilis from symptomatic infection

4.5–7.5%

Singh, 1999; Weir & Fisman, 2002; Gerbase, 2000; Golden 2003

Neuro-syphilis

0.75–1.88%

Tramont, 2005; Zetola, 2007; Krause, 2006; Weir&Fisman, 2002; Gerbase, 2000; Golden, 2003; Goldmeier, 2003

Fatal cases due to neurosyphilis

0%

Assuming all cases are identified and treated, and no treatment failure

Congenital

 

 

Symptomatic infection

20% (2–64%)

Singh, 1999; Saloojee, 2004; Genc & Ledger, 2000

Fatal cases due to congenital infection

1%

Genc & Ledger, 2000

Table 2. Disability weights and duration

Health outcome
(Health state)

Disability Weight (DW) (Haagsma, 2015)

Duration

DW

Label

In years

Source

Acquired

 

 

 

 

Primary syphilis

0.007 (0.005-0.01)

Infectious disease, acute episode, mild

0.121-0.5

Baughn & Musher, 2005

Latency period (from primary to secondary)

0

 

0.23 (0.038-1)

Baughn, 2005

Secondary syphilis

0.125 (0.104-0.152)

Infectious disease, acute episode, severe

0.038-0.153

Zetola, 2007

Latency period (from secondary to neurosyphilis)

0

 

4.77-19.77

Hutto, 2001

Neurosyphilis

0.407 (0.36-0.46)

Motor plus cognitive impairments, severe

0.027-0.038

Workowski, 2010
Assuming 10–14 days of treatment

Congenital

 

 

 

 

Symptomatic infection

0.125 (0.104-0.152)

Infectious disease, acute episode, severe

3

Kwong, 2010

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