Transcript Chlamydia Update

Chlamydia and Gonorrhea Lab Update
 Burning Questions
 Laboratory Guidelines
 CT Immunobiology Consultation
The findings and conclusions in this presentation are those of the authors and do not
necessarily represent the views of the Centers for Disease Control and Prevention
Alternate Specimen Verification
 Rectal and oropharyngeal swabs
 FDA clearance being pursued
 Establish an external specimen bank
 Home collected vaginal swabs
 Interest but studies have not commenced (that I’m aware of)
Self-Obtained Vaginal Swabs in a Home
Setting
Considerations
 Performance
 Discreet packaging
 Must meet federal regulations for shipping diagnostic specimens
 Wet vs dry swabs
 Greater temperature ranges than covered in the product insert
 NOT FDA CLEARED
 What are the parameters for an off-label verification study?
 Need sound guidance
Sensitivity of Different Specimens by Three
Different Assays
Assay
FCU
Cx
S-vag
C-vag
TMA
72%
89%
93%
90%
PCR
84%
91%
91%
93%
LCR
98%
96%
98%
100%
Combined
81%
91%
93%
93%
FCU – first catch urine, Cx – endocervix, S-vag – self-collected vaginal swab, C-vag Clinician collected vaginal swab. Schachter J, et al. JCM 41;2003:3784
Preliminary Vaginal Swab Mailing Kit
One Example of a Vaginal Swab Mailing Kit
Follow-up Questionnaire
Swab
Mailing Can
(Gen-Probe® Vaginal Swab Transport Tube, Vaginal Swab,
Inner Medical Specimen Transport Tube, Vaginal Swab
Collection Instructions, Follow-up Questionnaire, and Mailing Can)
Swab Specimen Transport Conditions for
Commercially Available CT/GC NAATs
Test
Swab Condition
Transport
Temperature
Time to Test
BD ProbeTec
Dry (no liquid media)
2 to 27oC
4 to 6 days
GenProbe APTIMA Penetrable top tube
(vaginal swabs FDA containing specimen
cleared)
buffer
2 to 30oC
Up to 60 days
Roche Amplicor
18 to 25oC
Within 1 hour
2 to 8oC
Up to 7 days
Less than -20oC
Up to 30 days
Tubes containing
Chlamydia culture
medium (eg. M4,
2ST, Bartels, etc)
Package Temperature during USPS Transit from St. Louis to New Orleans
Package placed in St. Louis USPS drop box July 22, 2005 and
received at 2:30pm July 26, 2005 in New Orleans. Temperatures
were recorded at 10 minute intervals.
Package Temperature during USPS Transit from Jackson to New Orleans
Package placed in Jackson USPS drop box July 29, 2005 and
received at 2:00pm August 10, 2005 in New Orleans.
Temperatures were recorded at 10 minute intervals.
Residential Mailbox and Outside Air Temperature
50
45
Mailbox
35
Outside Air
30
25
23:21
22:29
21:37
20:45
19:53
19:01
18:09
17:17
16:25
15:33
14:41
13:49
12:57
12:05
11:13
10:21
9:29
8:37
7:45
6:53
20
6:01
Celsius
40
Time
Temperature recorded at 1 minute intervals August 21, 2005.
In Vitro Assessment of Specimen Stability
APTIMA Test Result for Chlamydia
trachomatis (Relative Light Units)
Initial Temperature /
Duration
Final Temperature /
Duration
Inoculum (Inclusion
forming units)
24oC / 24 hours
37oC / 24 hours
10
1104
1102
103
1226
1115
105
1195
1087
In Vitro Assessment of Specimen Stability
APTIMA Test Result for Chlamydia
trachomatis (Relative Light Units)
Initial Temperature /
Duration
Final Temperature /
Duration
Inoculum (Inclusion
forming units)
37oC / 24 hours
56oC / 24 hours
10
1172
1124
103
1133
1114
105
1142
1115
In Vitro Assessment of Specimen Stability
APTIMA Test Result for Chlamydia
trachomatis (Relative Light Units)
Initial Temperature /
Duration
Final Temperature /
Duration
Inoculum (Inclusion
forming units)
56oC / 24 hours
24oC / 24 hours
10
1059
1023
103
1211
1951
105
1147
1113
Alternate Specimen Verification
 Rectal and oropharyngeal swabs
 FDA clearance being pursued
 Establish an external specimen bank
 Home collected vaginal swabs
 Interest but studies have not commenced (that I’m aware of)
 APHL / CDC STD Steering Committee Workgroups to develop
Verification Protocols
 Involve CMS (CLIA)
 Part of revised CDC Laboratory guidelines
LGV Testing
 Specimens submitted to CDC in 2007 for the detection of
LGV
 ompA genotyping (not serology)
Specimen Type
Number
Submitted (%)
Results
Unable to
amplify (%)
CT Negative (%)
CT Positive (%)
LGV (%)
Rectal Swab
52 (85%)
8 (15%)
14 (27%)
25 (48%)
5 (10% of all or
20% of CT+)
Urethral Swab
7 (11%)
3 (43%)
0
4 (57%)
0
Urine
1 (2%)
0
0
1
0
Unknown
1 (2%)
0
0
1
0
LGV Testing
 Importance of differentiating LGV from non-LGV rectal CT
infections
 Course of recommended Tx varies
 No commercial differential test available
 Seems that settings that have been testing for rectal CT infections and
managing those infections as non-LGV have not seen increases in
proctocolitis
• Refer to Dr. Mark Pandori’s presentation at the 2008 STD Prevention meeting
 Sx and Asx infections reported
 CDC does not have a survelliance program LGV
• Submission of specimens for reference testing should be based on local descions
 Serology for rectal LGV testing
 No data
Laboratory Guidelines
Background
 1982
 Laboratory Diagnosis of Chlamydia trachomatis Infections
 Isolation and serology
 1993
 Recommendations for the Prevention and Management of
Chlamydia trachomatis Infections
• Isolation
• Non-culture tests
 Immunoassays, nucleic acid hybridization tests
• Screening
• Sexual assault
• Presumptive Laboratory Diagnosis
Screening Tests to Detect Chlamydia trachomatis
and Neisseria gonorrhoeae Infections - 2002
 Guideline Development



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CDC identified questions
reviewed published literature from 1990 - 2000
prepared tables of evidence
drafted recommendations
 External consultants asked to review the drafted recommendations
• selected on the basis of expertise and/or disciplinary or organizational
affiliations
 CDC considered all suggestions from external consultants and
finalized recommendations
Revising Laboratory Guidelines for the Detection of
Chlamydia trachomatis and Neisseria gonorrhoeae Infections
 Similar format of previous guidelines / consultations
 Convene an expert review panel
 Identify / refine key questions
 Review literature
 External consultants asked to review the drafted recommendations
• selected on the basis of expertise and/or disciplinary or organizational affiliations
 CDC considered all suggestions from external consultants and finalized
recommendations
Issues
 What is the sensitivity and specificity of available tests for CT and GC
 Is it correct to lump NAATs
 Does the sensitivity and specificity of available for CT and GC vary with respect
to the anatomic site from which the specimen was collected and/or the
specimen type
 What class of tests should be recommended for the detection of CT and GC
infection; stratify by anatomic site and/or specimen type
 What test or combination of tests should be recommended confirmation of CT
and GC infection
Issues
 Can routine supplemental testing improve the PPV of certain CT and GC tests
and at what prevalence level should it be recommended
Positive Predictive Value
likelihood that the test accurately predicts the true infection status of the
person tested
Example
Test 1,000 persons
Test Specificity
99.6 %
Prevalence of Infection
10 %
0.4
%
 HIV, syphilis, chlamydia, gonorrhea, etc
True Positive
100
4
Positive Predictive Value
False Positive
100/104
4/8 = 50 =
%96 %
4
Positive Predictive Value
likelihood that the test accurately predicts the true infection status of the
person tested
Example
Test 1,000 persons
Test Specificity
99.6 %
Prevalence of Infection
10 %
 HIV, syphilis, chlamydia, gonorrhea, etc
True Positive
100
Positive Predictive Value
Prevalence of Infection
False Positive
4
100/104 = 96 %
0.4 %
 HIV, syphilis, chlamydia, gonorrhea, etc
True Positive
4
Positive Predictive Value
False Positive
4/8 = 50 %
4
Issues
 Can routine supplemental testing improve the PPV of certain CT and GC tests
and at what prevalence level should it be recommended
 Does pooling urine specimens diminish NAAT performance
 Should recommendations be made on testing in situations involving
medicolegal issues including adult and pediatric CT and GC infections (note:
making a recommendation of any test beyond culture would require a
preliminary discussion recommendations for off-label testing)
Issues
 What test(s) should be recommended for the laboratory diagnosis of LGV and
would these vary based on the presentation (i.e. inguinal versus anorectal
presentation)
 What serologic cut-off values should be used if serology is recommended to aid
LGV diagnosis
 What (if any) recommendations be made concerning in vitro antibiotic
susceptibility testing for GC including but not limited to the actual methodology
for the procedure
Chlamydia Immunology and Control Expert
Advisory Meeting
Atlanta, April 23-25, 2008
 Highlight the key questions related to chlamydia
natural history, pathogenesis, and immunobiology
that have the most important implications for control
of chlamydia and its sequelae
 Assess extent to which existing data address these
key questions, especially with respect to their
potential relevance to prevention programs
 Identify important remaining gaps in knowledge that
would have implications for prevention
Chlamydia trachomatis
Some of what we know
 Pathology is primarily a function of
the host-response
 Little intrinsic toxicity
 Protective immunity has been
demonstrated in animal models or
animals naturally infected with
related chlamydiae
 Mice, guinea pigs, sheep etc
 Th1 type DTH in mice
 Susceptibility to reinfection is
common
 High rates of reinfection
 Early Tx of mice resulted in a
disruption of immunity
 Th2 type DTH in mice
Some of what we don’t know
 Development of pathology poorly
understood
 How long?
 Predisposing factors?
 Reinfection or persistent infection?
 Development of immunity that
protects against subsequent CT
infections has not been conclusively
documented in humans
 Commercial sex workers seem to be
refractory to infection after time
 Human data is lacking (absent) on
the mechanisms associated with
reinfection
 Bacterial?
 Host?
Chlamydia trachomatis
Some of what we know
 Screening and Tx reduce the
natural duration of infection
Some of what we don’t know
 How long does CT persist if left
untreated?
 Brazilian data suggests most half of
the infections are cleared after a
year and all are cleared by 5 years
 Despite screening, reinfection rates
seem to be increasing
 Brunham et al JID 2005
 What are the reasons for increases
in reinfection rates?
 Better Dx tests
 Increased / more targeted screening
 Bacterial changes
 Antibiotic resistance has not been
demonstrated among human CT
isolates
 It has been shown in pig isolates
 Why are some CT infections more
difficult to treat?
 Golden et al NEJM 2005
Some of What we Learned
 Good evidence that repeated episodes of acute diagnosed PID
increase the risk of tubal infertility
 CT related damage is primarily a function of the host response
 Understanding of pathogenesis or timing of occurrence of
damage is more limited than most realized
 additional work needed if new approaches to prevention are to be
developed
 Existing animal model data offer somewhat less insight than
expected but alternative approaches possible
 Data addressing the mechanisms, development, or role of
immunity in humans are quite limited
 But approaches for addressing these gaps provided