Gonorrhoea

Gonorrhoea is the second most commonly reported sexually transmitted disease (STD) in the United States of America (Skolnik & Neil, 2008). Neisseria gonorrhoeae is almost exclusively transmitted by sexual contact and perinatally (from mother to child during labour) (Handsfield & Sparling, 2005). The bacteria affect the mucous membranes of the urethra and the cervix. Less frequently, mucous membranes of the rectum, oropharynx and conjunctivae are also involved during infection. N. gonorrhoeae primarily infects columnar and cuboidal epithelium. Gonorrhoeal infections in women may lead to pelvic inflammatory disease (PID) and may be a cause of female infertility. Further complications resulting from infection with N. gonorrhoeae are epididymitis, ophthalmitis, ectopic pregnancy and disseminated gonococcal infection (DGI). Untreated infections mostly resolve spontaneously over time (several weeks or months) but can lead to serious sequelae associated with adverse effects on health. Even though the duration of disease is hard to estimate, mean duration is assumed to be several days for men and less than two weeks for women. The incubation period is short and re-infection is common (Handsfield & Sparling, 2005).

The true number of gonorrhoea cases is largely affected by under-estimation due to high percentages of asymptomatic cases and diagnosed cases not being reported to the surveillance system. It was estimated that the true number of new infections is twice as high as the reported number (CDC, 2002). Brunham and Embree reported that gonorrhoea is posing serious threats in Africa, Latin America, Asia and eastern Europe (Brunham & Embree, 1992). In 2008, WHO estimated that there were around 46.8 million cases of STDs in the European Region, with 3.4 million cases being due to N. gonorrhoeae (WHO, 2012).

About 40–80% of women are asymptomatically infected (De Maio & Zenilman, 1998; Nelson, 2007). For men symptomatic rates of up to 95-99% were observed for genital infection (De Maio & Zenilman, 1998; Nelson, 2007; Stamm, 2005).

Health outcomes and health states associated with gonococcal infection

Infection with N. gonorrhoeae results in different clinical pictures in women, men and infants. In our study, we only considered disease models which reflect genital infection; pharyngeal and rectal infections are not considered to be the cause of significant short or long-term sequelae and therefore do not contribute to the burden of gonorrhoea.

Infections in men

An uncomplicated infection presents as an acute urethritis, infection in the pharynx or rectum are likely to be asymptomatic. In 2013, 36% of reported gonorrhoea cases were detected at these sites. In most cases (95–99%) the disease has a symptomatic course with typical signs of dysuria and urethral discharge (De Maio & Zenilman, 1998; Nelson, 2007; Stamm, 2005). In a few cases the infection remains asymptomatic and is neither recognised nor diagnosed (Sherrard, 1996). These infections pose a serious problem as they provide a pool of further transmissible infections. In most cases gonococcal urethritis resolves spontaneously over several weeks but may also trigger sequelae (Handsfield & Sparling, 2005).

The most common sequela of gonococcal infections in men is the acute epididymitis (Stamm, 2005; Trojian, 2009). The symptoms associated with epididymitis are oligospermia during the acute phase, swollen epididymis (and/or testicles), and dysuria. The association between epididymitis and future infertility is an ongoing debate in research with no clear evidence (Stamm, 2005). Uncommon complications are penile oedema, penile lymphangitis, periurethral abscess, acute prostatitis, seminal vasculitis and Tyson’s or Cowper’s gland infections (Handsfield & Sparling, 2005). Due to their rare occurrence they are not considered in the outcome tree.

Infections in women

Uncomplicated infections in women mostly affect the endocervix and N. gonorrhoeae are also recovered from the urethra, rectum or occasionally from the periurethral (Skene’s) glands and the ducts of Bartholin’s glands. Many women with gonococcal infections only develop minor symptoms or are entirely asymptomatic and thus do not seek medical advice and are consequently not reported to the surveillance system.

A major complication resulting in remarkable disease burden is pelvic inflammatory disease (PID) (Handsfield & Sparling, 2005; De Maio & Zenilman, 1998). Studies report 10–40% of infected women developing PID (Handsfield, 1974; McCormack, 1977; Westrom, 1980; Westrom, 1992). In a cost effectiveness analysis, Bernstein and colleagues estimated a base case scenario of 30% (range 10–40%) of infected women developing PID (Bernstein, 2006). Women with PID have an increased risk of developing infertility in the future (Handsfield & Sparling, 2005; De Maio & Zenilman, 1998; Westrom, 1980; Westrom, 1992; Ross, 2002). The study of Weström (1992) and colleagues reported a 10% probability of infected women developing tubal infertility. The risk of infertility is linked to number and severity of PID episodes. Ross reported 15–20% and 50–80% of infected women developing tubal infertility after one and three or more PID episodes, respectively. PID itself is also a cause of further (long-term) sequelae such as chronic pelvic pain, ectopic pregnancy and perihepatitis. Pelvic pain occurs in 20% of cases and ectopic pregnancy in 9.1% of PID cases (Handsfield & Sparling, 2005; Westrom, 1980). Infections with N. gonorrhoeae during pregnancy can result in spontaneous abortion, premature labour, early rupture of fetal membranes and perinatal infant mortality (Handsfield & Sparling, 2005). The cost effectiveness study by Bernstein and colleagues estimated transition probabilities from PID to chronic pelvic pain, ectopic pregnancy and tubal factor infertility of 18% (range 15–30), 7.8% (range 7.8–9.1%), and 15% (range 9–18%), respectively (Bernstein, 2006).

Sequelae reported for both sexes

As a result of bacteraemic dissemination, disseminated gonococcal infection (DGI) can occur in 0.5–3% of people infected with N. gonorrhoeae. This may cause infective arthritis and also be the cause of endocarditis and meningitis in very rare cases (Holmes, 2007).

Gonococcal infections in infants

Infants born to infected mothers can suffer from gonococcal conjunctivitis (ophthalmia neonatorum). Gonococcal conjunctivitis affects 30–35% of children born to infected mothers and is a major problem in many developing countries causing blindness (De Maio & Zenilman, 1998; Nelson, 2007). Ophthalmia neonatorum can lead to corneal scars, resulting in low-vision or complete blindness. Effective treatment is available which has led to very low numbers of sequelae resulting from ophthalmia neonatorum in the developed world (Darling, 2010; Schaller & Klauss, 2001). Consequently, we did not consider corneal-scar-related ‘low-vision’ or ‘blindness’ in our model.

Infected infants may have a low birth weight; some studies relate low birth weight to gonococcal infections (15% from Gerbase, 2000), however the attribution of this condition to the infection is extremely difficult in a developed country setting. Therefore, we decided to discard this relationship.

Case fatality proportion

Fatal cases resulting from gonococcal infections are extremely rare and mainly result from endocarditis, meningitis and DGI. Estimating the mortality of PID is complicated due to the lack of standardised case definitions, inconsistent reporting practices and unclear aetiology (percentage of fatal cases attributable to gonococcal PID) (De Meaio & Zenilman, 1998).

Outcome tree parameters

Male outcome-tree

The proportion of infections in men who develop symptoms is set at 95–99% (De Maio & Zenilman, 1998; Trojian, 2009, Nelson, 2007). The probability of developing DGI (which is part of the initial symptomatic phase of the disease) is set at 0.5–3% (Holmes, 2007), whereas the probability of developing epididymitis is set to 3% (1–5%) (Bernstein, 2006). Debate is currently ongoing as to whether asymptomatic cases also develop epididymitis, however, due to lack of a proven association, this was not taken into account.

Female outcome-tree

Information on the proportion of symptomatic (20–60%) and asymptomatic (40–80%) gonococcal infections were taken from reviews, clinical text books and a study conducted by Weström (Handsfield & Sparling, 2005; De Maio & Zenilman, 1998; Nelson, 2007; Westrom, 1992). Information on PID as a major sequela were obtained from reviews, clinical text books and a cost effectiveness analysis which provided an estimate that 30% (10–40%) of women were symptomatically infected (Bernstein, 2006). The probabilities of developing an ectopic pregnancy (7.8-9.1%), chronic pelvic pain (18%, range 15–30%) or tubal infertility (15%, range 9–18%) were taken from Bernstein`s cost-effectiveness study (Bernstein, 2006). Case fatality proportions from ectopic pregnancies were estimated at 0.038% (Goldner, 1993). The probability of developing a tubo-ovarian abscess is set at 0.8% (Ness, 2002). However, diagnosis and treatment have significantly improved it was therefore decided not to include a case fatality event for tubo-ovarian abscess.

Congenital outcome-tree

The burden studies on STDs by Gerbase and colleagues and Nelson et al. report 30–35% of cases developing ophthalmia neonatorum (Nelson, 2007; Gerbase, 2000).

Assuming that in EU/EEA Member States all notified cases will have had symptoms, in our model all cases of symptomatic infant gonococcal infections manifest as ophthalmia neonatorum and will represent the only health state included in the model.

Model input summary

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

Health outcome
(health state)

Distribution of health states in health outcome

Transition probability

Source/assumption

Men

 

 

 

Symptomatic infection

(Urethritis)
- Uncomplicated
- Complicated



97–99.5%
0.5–3%

95–99%

De Maio & Zenilman, 1998; Nelson, 2007; Stamm, 2005
Holmes, 2007

Epididymitis from symptomatic

 

3% (1–5%)

Bernstein, 2006

Women

 

 

 

Symptomatic infection
(Cervicitis)
- Uncomplicated
- Complicated



97–99.5%
0.5–3%

20–60%

Handsfield & Sparling, 2005; De Maio & Zenilman, 1998; Nelson, 2007; Westrom, 1992;
Holmes, 2007

Pelvic Inflammatory Disease (PID) from symptomatic and asymptomatic

 

30% (10–40%)

Bernstein, 2006

Ectopic pregnancy

 

7.8–9.1%
Age dep.
See Table 4

Bernstein, 2006
Female reproductive age 15-49

Tubo-ovarian abscess

 

0.8%

Ness, 2002

Chronic pelvic pain syndrome

 

18% (15–30%)

Bernstein, 2006

Tubal infertility

 

15% (9–18%)
Age dep.
See Table 4

Bernstein, 2006
Female reproductive age 15-49

Fatal cases due to ectopic pregnancy

 

0.038%

Goldner, 1993

Congenital

 

 

 

Symptomatic infection
(Ophthalmia neonatorum)

 

100%

 

Table 2. Disability weights and duration

Health outcome (health state)

Disability Weight (DW) (Haagsma, 2015)

Duration

DW

Label

In years

Source

Men

 

 

 

 

Uncomplicated
Complicated

0.051 (0.039-0.06)
0.125 (0.104-0.152)

Infectious disease, acute episode, moderate
Infectious disease, acute episode, severe

0.02
0.02

Trojian, 2009
Trojian, 2009

Epididymitis

0.176 (0.143-0.208)

Epididymo-orchitis

0.08

Trojian, 2009

Women

 

 

 

 

Uncomplicated
Complicated

0.051 (0.039-0.06)
0.125 (0.104-0.152)

Infectious disease, acute episode, moderate
Infectious disease, acute episode, severe

0.03
0.03

Murray, 1996
Murray, 1996

Pelvic Inflammatory Disease (PID)

0.123 (0.1-0.15)

Abdominopelvic problem, moderate

0.07

De Maio & Zenilman, 1998

Tubo-ovarian abscess

0.31 (0.262-0.355)

Abdominopelvic problem, severe

0.01

Goharkhay, 2007; Teisala, 1990

Chronic pelvic pain

0.123 (0.1-0.15)

Abdominopelvic problem, 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 years
See Table 4

Congenital

 

 

 

 

Symptomatic infection (Ophthalmia neonatorum)

0.015 (0.011-0.019)

Conjunctivitis without corneal scar

0.038

American Academy of Pediatrics, 2012.
Assuming 2 weeks of treatment

Table 3. Duration of tubal infertility

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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