Chlamydia

Chlamydia trachomatis is a bacterium that causes a sexually transmitted infection (STI). WHO estimates a global annual incidence of about 90 million cases. Chlamydia trachomatis affects both women and men and can cause severe harm to the reproductive system of women. Additionally, children born to infected mothers are at high risk of developing severe complications (e.g. ophthalmia neonatorum, pneumonia). C. trachomatis has various serovars with different transmission modes and consequences. Serovars A, B, Ba and C, often transmitted by close eye-to-eye contact, cause ocular trachoma and are responsible for about 7–9 million cases of blindness (Stamm, 2005). Serovars D–K, responsible for genital infections, are associated with various adverse health outcomes in both men and women (Carey & Beagley, 2010). Serovars L1, L2 and L3 cause Lymphogranuloma venerum, a systemic STI mainly observed in the high-risk group of men having sex with men (MSM) (Martin-Iguacel, 2010). For the current outcome trees only serovars D–K responsible for genital infection are taken into consideration.

C. trachomatis mostly affects the young and sexually-active population with a female-male sex ratio of 1:0.7 (in tested individuals) (ECDC, 2014a). The genito-urinary infections present different disease patterns in the female and male hosts.

The asymptomatic infection poses serious threats to the health of the population as asymptomatic carriers represent a pool for new infections, and asymptomatic infections are associated with the risk of developing severe sequelae.

Rates of asymptomatic cases reported in literature vary widely. More than 50% of the infections due to C. trachomatis in males do not produce any symptoms or present a mild symptomatic illness (van de Laar & Morre, 2007). In a study of male army recruits, 85.6% of men testing positive for Chlamydia reported no symptoms (Cecil, 2001). Comparable rates were also reported by McKay and colleagues, with 88% of infected men being asymptomatic (McKay, 2003). Long-term sequelae due to chronic asymptomatic infections in men are still under discussion, but the pool of asymptomatic C. trachomatis carriers poses a serious threat to women’s health due to continuous transmission and re-infection. Gaydos and Quinn refer to a percentage of asymptomatic male cases above 50%, in line with the above-mentioned estimates (Gaydos & Quinn, 2012).

Genital infections in women may present with short-term acute symptoms of cervicitis and urethritis (Stamm, 2005). Women also face a high number of asymptomatic infections. In total, 70–90% of all female and 50–88% of all male chlamydial infections do not present any symptoms (Stamm, 2005; Gaydos, 1998; Kalwij, 2010). Quinn and colleagues noted that around 79% of women with a Chlamydia infection attending a STI clinic were asymptomatic (Quinn, 1996). Clinical textbooks report a range of 70–90% of female cases being asymptomatic (Stamm, 2005; Gaydos & Quinn, 2012).

For the model we decided to use a range of 70–90% for the asymptomatic proportion (Stamm, 2005; Gaydos & Quinn, 2012) for female and 50–88% for male cases (Stamm, 2005; Gaydos, 1998; Kalwij, 2010).

Health outcomes associated with chlamydial infection

Genital infection in men

Urethritis: with an incubation period of 7–14 days, urethritis causes symptoms of dysuria and urethral discharge (Stamm, 2005). We selected a range of 12–50% of infected men to represent symptomatic cases developing non-gonococcal urethritis (NGU) (Carey & Beagley, 2010; McKay, 2003).

Epididymitis: epididymitis is an acute inflammation of the epididymis (Carey & Beagley, 2010). The symptoms are oligospermia during the acute phase, swollen epididymis (and/or testicles), and dysuria. Fever and chills may occur in some cases. The association between epididymitis and future (in)fertility is an ongoing debate in research with no clear indication (Stamm, 2005).

Proctitis and proctocolitis: this clinical picture is most common in the MSM community. The classic symptoms are rectal pruritus, -pain and -bleeding. Fever often accompanies the initial proctitis and proctocolitis (Stamm, 2005; Carey & Beagley, 2010). This health outcome was not considered in the model due to lack of information.

Reactive arthritis: a further clinical picture is sexually-acquired reactive arthritis occurring as an acute aseptic arthritis or presenting as Reiter’s syndrome. Reiter’s syndrome includes symptoms of arthritis, conjunctivitis, urethritis and skin lesions (Stamm, 2005; Keat, 1983).

Genital infection in men can also include chronic pelvic pain. However, due to lack of information we decided not to include it in the model (Haggerty, 2010).

Genital infection in women

Urethritis/cervicitis

The acute form of C. trachomatis infection in women is urethritis and/or cervicitis. The majority of cases of both urethritis and cervicitis are asymptomatic, but can lead to severe sequelae (Low, 2007).

Pelvic inflammatory disease (PID)

Both symptomatic and asymptomatic infections can lead to serious consequences. Pelvic inflammatory disease is a commonly reported health outcome of a chlamydial infection. The literature shows very heterogeneous patterns regarding the transition probabilities from acute infection to PID. Carey and Beagley state that 12–50% of women infected with C. trachomatis develop PID (Carey & Beagley, 2010). In other literature the risk of PID after lower genital tract infection with Chlamydia varied from 0 to 30% (Risser & Risser, 2007) and from 0 to 72% (Boeke, 2005). Cates and Wasserheit reported that 40% of women with an untreated C. trachomatis infection develop PID (Cates & Wasserheit, 1991). Van Valkengoed and colleagues reported that complications of Chlamydia trachomatis infections are overestimated in the literature. They found five Cost Effectiveness Analyses (CEA) using decision trees to estimate the effect of screening programmes (Van Valkengoed, 2004). In these studies the estimates of the probability of developing PID after infection varied from 25 to 80%.  ECDC has undertaken a systematic literature review and found a risk of developing PID from chlamydial infections of 9% (4–19%) (ECDC, 2014b).

Acute PID with pelvic pain, lasting for about 15 days, and silent PID with no or mild symptoms can cause severe long-term sequelae (Carey & Beagley, 2010; Westrom, 1980).

The estimated risk of tubal infertility as a sequelae of PID varies between 10–20% (Carey & Beagley, 2010; Lan, 1995; Land, 2010). Land and colleagues estimated the risk of tubal infertility after asymptomatic Chlamydia infection to be around 0.07% (Land, 2010). The risk of tubal infertility was found to be dependent on the course of infection (mild vs. severe) and the frequencies of re-infection (e.g. after three episodes of PID the risk is five-fold compared to a single episode.) ECDC’s systematic review found that 16% of women with PID will develop infertility (ECDC, 2014b), which applies to women of reproductive age.

In total, 7–9% of pregnant women develop ectopic pregnancy after PID (Lan, 1995). Around 15% of women with previous PID develop chronic pelvic pain (Rogstad, 2008). Tubo-ovarian abscesses (tubal pathology) incur a risk of 7–16% for women who have previously had PID (Kottmann, 1995). The risk of cervical neoplasia is still under debate due to the fact that most cervical neoplasia are due to human papilloma virus (HPV) (Stamm, 2005).

Based on registration data from Amsterdam it was estimated that 0.07% and 0.02% of women exposed to chlamydia infection develop ectopic pregnancy and tubal factor infertility, respectively (Van Valkengoed, 2004).

Perinatal infections

Perinatal chlamydia may complicate as conjunctivitis (ophthalmia neonatorum) and neonatal pneumonia. We considered the ONBoID study for the input parameters which estimated that 15% of cases would develop ophthalmia neonatorum and 16% neonatal pneumonia (Kwong 2012). Assuming that in EU/EEA Member States all notified cases will have had symptoms, we used the same proportion: 48.39% are affected by ophthalmia and 51.61% will present pneumonia.

Outcome-tree parameters

Male outcome tree

For the male outcome tree a minimum of 50% and maximum of 88% was estimated as the percentage of asymptomatic cases (Carey & Beagley, 2010; McKay, 2003). The probability of developing epididymitis from symptomatic infections (10%) was taken from the World Health Organization STD Burden of Disease Study by Gerbase and colleagues (Gerbase, 2000). For asymptomatic infections a probability of 1–4% was taken from the cost effectiveness analysis of Welte and colleagues (Welte, 2001). Data on sexually acquired reactive arthritis (1% of symptomatic urethritis) and the resulting Reiters’ syndrome (33% of reactive arthritis) were taken from a clinical text book (Stamm, 2005).

Female outcome tree

For the percentage of asymptomatic cases a range of 70–90% was included in the model (Stamm, 2005; Gaydos & Quinn, 2012; Gaydos, 1998; Kalwij, 2010; Stamm, 1999).

For the development of PID, estimates are included from the systematic review conducted by ECDC for the minimum (4%) (Van Valkengoed, 2004), maximum (19%) and most likely values (9%) (ECDC, 2014b).

Although ectopic pregnancy and tubal infertility normally are a consequence of PID, experts considered that evidence relating these outcomes directly to the chlamydia infection was stronger than that relating it to PID (mainly because of the heterogeneous definition of PID). The probability of developing ectopic pregnancy and tubal infertility after chlamydia infection is set to 0.07% and 0.02% respectively (Van Valkengoed, 2004). The probability of dying due to ectopic pregnancy was set to 0.038%, based on the study from Goldner (Goldner, 1993).

The risk of moving from PID to chronic pelvic pain was set at 18–75% and from PID to tubo-ovarian abscess at 0.8% (ECDC, 2014b; Ness, 2002, Soper 2010).

We decided to set the case fatality proportion for abscesses that have not ruptured to zero. Current mortality proportions for patients with ruptured abscesses are not reported in the literature; data from the 1960s suggested a mortality proportion ranging from 1.7 to 3.7 percent (Pedowitz, 2004; Paik, 2006). Due to the fact that these figures come from old studies and that diagnostics and treatment have significantly improved, we decided not to include the risk of dying from tubo-ovarian abscess.

Model input summary

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

 Health outcome
 (Health state)

Distribution of health states within health outcome

Transition probability

Source/assumption

 Men

Symptomatic infection

 


12–50%


Carey & Beagley, 2010; McKay, 2003

Epididymitis following symptomatic infection

 

10%

Gerbase, 2000

Reactive arthritis

(Mild)

(Severe)

 

67%

33%

1%

Stamm, 2005

Stamm, 2005

Stamm, 2005

Epididymitis following asymptomatic infection

 

1–4%

Gerbase, 2000; Welte, 2001

 Women

Symptomatic infection

 


10–30%


Stamm, 1999; Stamm, 2005; Gaydos & Quinn, 2012; Gaydos, 1998; Kalwij, 2010

Pelvic inflammatory disease (PID)

 

9% (4–19%)

ECDC, 2014b

Tubo-ovarian abscess from PID

 

0.8%

Ness, 2002

Chronic pelvic pain after PID

 

18–75%

ECDC, 2014b; Soper 2010

Ectopic pregnancy

 

0.07%

Age dep. See Table 4

van Valkengoed, 2004

Female reproductive age 15-49

Tubal Infertility

 

0.02%

Age dep. See Table 4

Land, 2010; ECDC, 2014b

Female reproductive age 15-49

Fatal cases following ectopic pregnancy

 

0.038%

Goldner, 1993

Perinatal

 

 

 

Symptomatic infection

(Neonatal pneumonia) (Ophthalmia neonatorum)

 

48.39%

51.61%

 

 

Kwong, 2012

Assuming that all reported cases have symptoms, we used the same proportion

Table 2. Disability weights and duration

Health outcome
(Health state)

Disability Weight (DW) (Haagsma, 2015)

Duration

DW

ECDC European Disability Weight Project (2014)

In years

Source

Men

 

 

 

 

Symptomatic infection

 

0.007 (0.005–0.01)

Infectious disease, acute episode, mild

0.02

Trojian, 2009

 

Epididymitis

0.176 (0.143–0.208)

Epididymo-orchitis

0.04

Murray, 1996

Reactive arthritis

(Mild)



(Severe)

 

0.344 (0.3-0.391)



0.518 (0.457–0.576)

 

Musculoskeletal problems, generalised, moderate
Musculoskeletal problems, generalised, severe

 

0.13–0.28


0.41

 

Özgül, 2006; Hannu, 2002

 

Miehle, 2003

Women

 

 

 

 

Symptomatic infection

0.007 (0.005–0.01)

Infectious disease, acute episode, mild

0.03

Murray, 1996

Pelvic inflammatory disease (PID)

0.018–0.310

Abdominopelvic problem, mild to severe

0.04

Westrom, 1980

Tubo-ovarian abscess

0.31 (0.262–0.355)

Abdominopelvic problem, severe

0.01

Goharkhay, 2007; Teisala, 1990

Chronic pelvic pain

0.018–0.123

Abdominopelvic problem, mild to moderate

2.8

Sharma, 2011

Ectopic pregnancy

0.31 (0.262–0.355)

Abdominopelvic problem, severe

0.08

Murray, 1996

Tubal infertility

0.007 (0.005–0.01)

Infertility, secondary

See Table 3

Female reproductive age 15-49 (See Table 4)

Perinatal

 

 

 

 

Neonatal pneumonia

0.125 (0.104–0.152)

Infectious disease, acute episode, severe

0.038

Zar, 2005

Assuming two weeks of treatment

Ophthalmia neonatorum

0.015 (0.011–0.019)

Conjunctivitis without corneal scar

0.038

American Academy of Pediatrics, 2012.

Assuming two weeks of treatment

Table 3. Duration of tubal infertility (female outcome tree)

Age

Duration in years

15–19

32

20–24

27

25–29

22

30–34

17

35–39

12

40–44

7

45–49

2

Table 4. Age-group risk (only reproductive age)

Age

%

0–14

0

15–49

100

≥50

0

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