Conference PaperPDF Available

Gonorrhoea – An historical potpourri. Robbie Morton Memorial Lecture,

Authors:
R.S. Morton
Memorial Lecture 2007
Gonorrhoea – an historical pot-pourri
Dr David Barlow
St Thomas’ Hospital, London
Blackpool
May 3
‘Gonorrhoea’ RS Morton 1977 Saunders, London
Changes in Gonorrhoea
Epidemiology
Incubation/Infectious period
Symptoms in men and ?women
Reducing incidence of complications
Reducing sensitivity to antibiotics
Importance as co-factor in HIV transmission
Methods and techniques of diagnosis
Sensitivity and specificity of diagnostic tests
Gonorrhoea figures UK: 1918 - 2005
0
10000
20000
30000
40000
50000
60000
70000
18
21
24
27
30
33
36
39
42
45
48
51
54
57
60
63
66
69
72
75
78
81
84
87
90
93
96
99
2002
2005
Methods of diagnosis
Old-fashioned vs epidemiological
Diagnosis before treatment
Treatment before diagnosis
Diagnosis of gonorrhoea
In women
For Chlamydia trachomatis there is no gold standard
For Neisseria gonorrhoeae culture is a gold standard
Methods of diagnosis
Old-fashioned:
Gonorrhoea in women
How sensitive was microscopy and laboratory culture?
How important was infection at different sites?
Was there logic in performing tests of cure?
Are we doing as well today?
Sensitivity of culture for the gonococcus (1)
14th IUSTI – Asia Pacific Conference, Kuala Lumpur, 2006
The sensitivity of culture is at best 70% when compared with
NAATs.”*
*Dr S Y Ho, Principal Scientist, Abbott Laboratories, USA
Sensitivity of culture for the gonococcus (2)
Review: Journal of Molecular Diagnostics, 2006*
When compared with N. gonorrhoeae NAATs, gonococcal culture ranges
in sensitivity from 85 to 95% for acute infections and may fall as low
as 50% for females with chronic infection.
*Whiley et al: Nucleic Acid Amplification Testing for Neisseria gonorrhoeae JMD 8: 3-15
Sensitivity of culture for the gonococcus (3)
UK National screening and testing guidelines for STIs,
2006*
Three NAATs are commercially available. The sensitivity of these tests is high
(>90%) in comparison with culture (50-60%) for all specimens… except
female urines…(iv6)
In women, the sensitivity of a single endocervical culture is 85-95% in detecting
infection with N. gonorrhoeae. (iv7)
*Bignell, Ison and Jungmann Sex Transm Infect 2006 82:supp 4; 6
Sensitivity of culture for the gonococcus (4)
In women, the sensitivity of a single endocervical culture is
85-95% in detecting infection with N. gonorrhoeae. (iv7)
BUT, what is the sensitivity of a single endocervical culture
in detecting infection with N. gonorrhoeae in the cervix?
Perhaps 98% + if techniques are optimal
Sensitivity of culture for the gonococcus (4)
What do we mean by sensitivity?
Do we mean:
How likely is culture to detect a case of gonorrhoea? or,
How likely is culture to detect gonorrhoea at a given,
infected, site?
i.e. Does culture need more than one site or test?
Diagnosis of vaginal discharge
RD Catterall BJVD (1970) 46, 122-4
300 women
T. vaginalis 125 41.6%
C. albicans 102 33.7%
N. gonorrhoeae 95 31.7%
Plus (n): non-specific cervicitis* (32); cervical erosion (8); foreign
body ((8); cervical polyp (6); cervical carcinoma (5); senile [atrophic]
vaginitis (4); undetermined** (30).
* Some of these chlamydial infection?
** Most of these bacterial vaginosis? “…despite repeated tests over 3
months, no cause was found…”
Diagnosis of vaginal discharge
RD Catterall BJVD (1970) 46, 122-4
300 women
“Every patient in the series had at least 4 pelvic
examinations and the majority had six or more genital
tests performed. They were all observed for at least
three months.”
RD Catterall BJVD (1970) 46, 122-4
300 women
a
Thin et al (1971)
BJVD (1971) 47, 27-9
157 women
“...those in whom the findings remained negative were
asked to attend a total of four times for further
investigation.”
Chipperfield (1976)
209 cases
“Gonococci were detected in 91% by the first test;
in 7.1% by the second test, and in 1.9% (four
cases) at the third examination.”
Evans (1976)
210 cases
Barlow 1976
250 cases
Barlow 1978
604 cases
Thin 1979
145 women
Diagnosis of gonorrhoea in women
By visit (%)
Visits: 1st 2nd 3rd
Catteral (1970) 66 20 10
Thin et al (1971) 90 7 3
Chipperfield (1976) 91 7 2
Evans (1976) 88 8 3
Barlow (1976) 97 2.4 0.6
Barlow (1978) 98 1.5 0.5
Thin (1979) 95.2 3.4 1.4
[Mitchell (1988) 97 3 0]
Gonorrhoea microscopy - how sensitive?
Catterall (1970) 67 of 95 cases (69%)*
Thin (1971) 84 of 130 cases (65%)*
Chipperfield (1976) 131 of 209 cases (60%)
Barlow (1976) 108 of 165 cases (65%)
Barlow (1978) 324 of 603 cases (54%)
Thin (1979) 80 of 145 cases (55%)**
* Non-selective culture medium
** Cervical results only
Diagnosis of gonorrhoea
The better the laboratory is at growing the
gonococcus, the lower will be the percentage of
cases diagnosed by microscopy.
“ a poor culture service flatters the microscopist”
If microscopy consistently detects more than 60-65% of
cases of gonorrhoea in women, the laboratory comes
under suspicion. Is the gonococcus being grown?
What is the Sensitivity of endocervical microscopy?
46.2% Anon CDC (1975) unpublished
44.0% Caldwell et al Am J Obs Gyn (1969) 109:463
54.0% Cave et al JAMA (1969) 210:319
55.2% Thin & Shaw BJVD (1979) 55:10-13
*47.6% Barlow and Phillips Lancet (1978); i:761-4
*32.9% Watson and Barlow (2001) unpublished
*p < 0.001 (Chi2 = 19.6; df2)
Thin et al
BJVD (1971) 47, 27-9
Phillips - VCNT 1972
BJVD (1972) 48; 287-291
A three-part study in which results of cultural
sensitivity progressively improved as the
laboratory became more familiar with the
techniques involved.
Phillips - VCNT 1972
Phillips - VCNT 1972
Gonorrhoea contacts - how many are not infected?
Catterall (1970) no record
Thin (1971) 13 of 157 (8%)
Chipperfield (1976) 29 of 127 (23%)
Evans (1976) 50 of 211 (24%)
Barlow (1976) 85 of 250 (35%)
Barlow (1978) no record
Thin (1979) no record
Epidemiological treatment
Barlow Lancet 1978 - 604 women
In the year of study, 16 culture-positive gonorrhoea cases
defaulted from follow-up. Only four of these were
gonorrhoea contacts
Epidemiological treatment would have identified these four,
missed the other twelve, and wrongly diagnosed and
treated 128 women
Gonococcal infection at different sites
Catterall (1970) no record
Thin (1971) no record
Chipperfield (1976) no record
SITE: C U R
Evans (1976) - 8%* -
Barlow (1976) no record
Barlow (1978) 18%* 6%* 4.8%*
Thin (1979) 18.6%* 6.2%* 8.4%*
*only site positive
Gonorrhoea in women
604 women
Diagnosis and exclusion
What sites: U,C,R and T
Which tests: micro x 3; culture x 4 = 7
Tests 1 2 3 4 5 6 7
No +ve 128 183 171 83 33 6 0
Barlow and Phillips Lancet (1978)i
Diagnosis of gonorrhoea in 604
Women by site
Site No’ Tested Micro’ Culture Total
Urethra 603 74 (12.3%) 460 (76.3%) 462 (76.6%)
Cervix 599 286 (47.6%) 513 (85.6%) 537 (89.7%)
Rectum 373 45 (12.1%) 137 (36.7%) 145 ( 38.9%)
Throat 391 - 22 (5.6%) 22 (5.6%)
Vagina 4 1 3 4
Barlow and Phillips Lancet (1978)i
Cervical culture as a
Single screening test
Gives
505 positives (84.3%)
Gonorrhoea in 604 Women
single site only positive
Site No’ Tested Micro’ Micro+cult Culture Total
Urethra 603 1 2 33 36 (6%)
Cervix 599 18 34 56 108 (18%)
Rectum 373 3 5 10 18 (4.8%)
Throat 391 - - 6 6 (1.5%)
Barlow and Phillips Lancet (1978)i
Can gonorrhoea infect at only one site?
It has certainly been found at only one site
cervix 18%; urethra 6%; rectum 4 - 8%
It may be present but not found c.f. ‘anomalies’ (Barlow 1978)
12 cases with, for example, positive urethral microscopy but
negative urethral culture, yet coincidental positive culture from cervix
Is this of more than academic importance?
Good evidence of excess treatment failure from oropharynx and
rectum
‘Gonorrhoea’ RS Morton 1977 Saunders, London
Barlow Lancet 1978
Screening
Wilson and Junger criteria
The condition should be an important problem
The natural history should be understood
There must be a latent or early symptomatic stage
There should be accepted and effective treatment
Facilities for diagnosis and treatment should be available
There should be a suitable test or examination
These should be acceptable to public and professionals
Agreed policy on whom to treat. including equivocal results
Screening should be continuous
The cost of early diagnosis and treatment should be balanced in
economic terms in relation to total expenditure on medical care
Wilson & Junger. Public Health Papers 1968; 34
Diagnosis of gonorrhoea
In women
Women are routinely screened for Chlamydia trachomatis:
Prevalence studies abound
Women are not routinely screened for Neisseria gonorrhoeae:
Prevalence therefore not known
Prevalence of gonorrhoea (1)
There is no shortage of gonorrhoea incidence data
Gonorrhoea prevalence data are scarce
Very, very roughly, prevalence could be incidence
(cases/100,000/year, say) multiplied by infectious period as a
proportion
Infectious period for men (mean) = ? 2 weeks* (or 2/52 year)
i.e. each case is positive for only two weeks and negative for 50
Infectious period for women (mean) = ?? 2 months max
*Sherrard & Barlow Genitourin Med 1999:422-6
Prevalence of gonorrhoea (2)
So, taking prevalence as incidence multiplied by infectious period…
If incidence for men is 52 cases/100,000/year and infectious period is
2 weeks, prevalence at any time
would be 52 x 2/52 = 2
i.e. Prevalence in men (2/100,000) is less than 5% of incidence
(52/100,000)
If infectious period for women is 2 months, each case
will only be positive for 1/6th of the year…
Source: Körner (KC60) reports of new diagnoses of
uncomplicated gonorrhoea infection
Q2 Q2 Q2 Q2 Q2 Q2
2005 2006 2005 2006 2005 2006
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9"! 7/  &  %
   &  , &
Total
PCT
Clinic
Male
Sector
South East
London
South West
London
North Central
London
North East London
North West London
Female
Total
% MSM
Gonorrhoea in Men
South London 2nd Q 2005
MSM
Bromley 1/17
Greenwich 6/23
Lambeth 70/124
Southwark 19/101
Total: 96/271 (35%)
Gonorrhoea in Lambeth, Southwark and
Lewisham*
Age Ethnic group Rate/100,000/year
male female
15-19 White 80.3 171.4
non-white 942.0 1221.8
20-24 White 121.2 90.7
non-white 1258.1 731.1
25-29 White 220.0 37.5
non-white 1632.1 435.5
30-59 White 30.5 4.7
non-white 191.3 24.5
*Low, Daker-White, Barlow & Pozniak BMJ 1997; 3141715-18
Amplified DNA assay in
South London 2003
Sensitivity 97.6%
Specificity 99.6%
Negative predictive value 99.9%
Positive predictive value 93.0%*
*”when patient clinical information taken into account,
Otherwise 88.4%”
Amplified DNA assay in
South London 2003
False positive rate 3/43 on 798 specimens
= 3.759 on 1,000 specimens
= 37.59 on 10,000 specimens
= 375.9 on 100,000 specimens
Gonorrhoea in Lambeth, Southwark and
Lewisham*; add 375.9/100,000
Age Ethnic group Rate/100,000/year
male female
15-19 White 80.3 171.4
non-white 942.0 1221.8
20-24 White 121.2 90.7
non-white 1258.1 731.1
25-29 White 220.0 37.5
non-white 1632.1 435.5
30-59 White 30.5 4.7
non-white 191.3 24.5
*Low, Daker-White, Barlow & Pozniak BMJ 1997; 3141715-18
Gonorrhoea in Lambeth, Southwark and
Lewisham*; add 375.9/100,000
Age Ethnic group Rate/100,000/year
male female
15-19 White 456.2 547.3
non-white 1317.9 1597.7
20-24 White 497.1 466.6
non-white 1634 1107
25-29 White 595.9 413.4
non-white 2008 811.4
30-59 White 406.4 380.6
non-white 567.2 400.4
*Low, Daker-White, Barlow & Pozniak BMJ 1997; 3141715-18
Gonorrhoea in Lambeth, Southwark and
Lewisham*; add 375.9/100,000
Age Ethnic group percentage true positives male female
15-19 White 17.6% 31.3%
non-white 71.5% 76.5%
20-24 White 24.4% 19.4%
non-white 77.0% 66.0%
25-29 White 36.9% 9.1%
non-white 81.3% 53.7%
30-59 White 7.5% 1.2%
non-white 33.7% 6.1%
*Low, Daker-White, Barlow & Pozniak BMJ 1997; 3141715-18
Gonorrhoea in Lambeth, Southwark and
Lewisham*; add 375.9/100,000
Age Ethnic group percentage false positives male female
15-19 White 82.4% 68.7%
non-white 28.5% 23.5%
20-24 White 75.6% 80.6%
non-white 33.0% 34.0%
25-29 White 63.1% 90.9%
non-white 18.7% 46.3%
30-59 White 92.5% 98.8%
non-white 66.3% 93.9%
*Low, Daker-White, Barlow & Pozniak BMJ 1997; 3141715-18
Amplified DNA assay in
*South London 2003
False positive rate in this study 7.0%
Van Dyke et al J Clin Microbiol 2001 0.0%
Chan et al Arch Pathol Lab Med 2000 11.4%
Akduman et al J Clin Microbiol 2002 10.5%
*”…positive results should be confirmed by retesting, preferably by
using a 2nd test targeted at a different gene, and both culture data and
clinical information should be taken into consideration.”
Amplified DNA assay in
*South London 2003
‘False positive rate’ in this study 7.0%
BUT
The important denominator is not 43
The important denominator is 798
Amplified DNA assay in
South London 2003
False positive rate 3/43 on 798 specimens
= 3.759 on 1,000 specimens
= 37.59 on 10,000 specimens
= 375.9 on 100,000 specimens
Methods of diagnosis
Old-fashioned:
Gonorrhoea in women
How sensitive was microscopy and laboratory culture?
How important was infection at different sites?
Was there logic in performing tests of cure?
Are we doing as well today?
Leviticus Chapter 15
Infectious period
Verse 13:
And when he that hath an issue is cleansed of
his issue; then he shall number to himself
seven days for his cleansing, and wash his
clothes, and bathe his esh in running water,
and shall be clean
Leviticus Chapter 15
Oropharyngeal transmission
Verse 8:
And if he that hath the issue spit upon him
that is clean, then he shall wash his clothes
and bathe himself in water, and be unclean
until the even
Leviticus Chapter 15
Transmission from lavatory seats
Verse 6:
And he that sitteth on anything whereon he
sat that hath the issue shall wash his
clothes, and bathe himself in water, and be
unclean until the even
Gonorrhoea Mars Sex
(G M S)
Glucose Maltose Sucrose
N.gonorrhoeae + - -
N.meningitidis + + -
N.pharyngitidis sicca + + +
N.catarrhalis - - -
Oxidase Reaction
colourless 1% solution of tetramethyl-p-phenylenediamine dihydrochloride
A purple colour develops within 10 seconds:
GC workload from April 2004
at St Thomas’ Hospital
Monoclonal antibody for GC diagnosis
GUM workload from April 2004
at St Thomas’ Hospital
GUM workload from April 2004
at St Thomas’ Hospital
Gonorrhoea in women
Diagnosis and exclusion
604 women with gonorrhoea
What sites?
Which tests?
Barlow and Phillips Lancet (1978)i
Value of urethral microscopy
Total urethral slide positive 74
Total urethra only site positive 36
Total urethral slides only positive at 1st test 16
Urethral slide only positive 1
Value of Urethral microscopy
In year of study,
6,647 urethral samples
Were stained and examined
Gonorrhoea in women at St Thomas’
Ethnic Groups 2001 & 1976
0%
10%
20%
30%
40%
50%
60%
70%
white Black
Ethnic
Group
Asian Other
2001
1976
Data differences in population with
gonorrhoea 1976 & 2001
Year 1976 2001
Number 570 338
CRE1 62% 24%
CRE2/3/4 37% 69%
Other 1% 6%
GC contact 50% 30%
TDQ No Yes
Gonorrhoea at St Thomas’ Hospital 2001
Partner ethnicity of white females
0
10
20
30
40
50
60
White No details Black Other
Number
Percentage
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