Frequently Asked Questions and Questions that Should Be Asked Frequently

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Frequently Asked Questions and Questions that
Should Be Asked Frequently

• Regarding Laboratory Testing for Chlamydia,
  Gonorrhea and HSV
• Bobbie McDonald, WI State Lab

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• One who asks a question is a fool for five
  minutes one who does not ask a question remains
  a fool forever.
• Chinese Proverb

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• Any man who knows all the answers most likely
  misunderstood the questions
• Unknown

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Just the FAQ s???

• Questions, questions
• From clinicians
• From their patients
• From our colleagues
• From the bench-level to the Lab Director
• Questions We need to ask
• Of our submitters (of their patients)
• Of our colleagues
• Of manufacturers and technical people
• Of Public Health

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Who, What, How?

• Questions asked OF and BY Laboratorians
• Who should be tested?
• What tests should be done?
• What tests are appropriate for the population?
• What specimens can be tested?
• How should results be interpreted?
• How accurate are results
• How should results be used?

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• You can tell whether a man is clever by his
  answers. You can tell whether a man is wise by
  his questions.
• Naguib Mahfouz
• 1988 Nobel Laureate in Literature

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• Who should be tested?

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Common Beliefs Re STD Testing

• My patients are not at risk for STDs.
• I was tested for everything.
• Testing patients with symptoms is enough.
• I can tell on examination whether someone is
  infected.
• Lab results dont lie.

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Who should be tested for Chlamydia?

• Most commonly reported STD
• 929,462 cases reported to CDC in 2004
• 5.9 increase in cases over 2003
• Most prevalent in 15-19, then 20-24 year olds
• Frequently asymptomatic, especially in women
• Untreated infections can lead to PID, infertility
  and ectopic pregnancy, ? HIV transmission
• Highly accurate screening tests are widely
  available

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Who should be tested for Chlamydia?

• CDC recommendations
• Sexually active/under age 25/ 2x year
• 3-4 months after a positive test (NOT t.o.c.)
• Other testing recommendations/ screening criteria
  when funding is a consideration
• Blanket under 25 may yield low positivity in
  some settings (low PPV)
• Evidence-based screening criteria may include
  demographic, behavioral and clinical factors,
  based on local data

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Who should be tested for Gonorrhea?

• Duh! Whoever is being tested for Chlamydia!
• Marketing of CT-GC combination tests
• Stand-alone tests often unavailable!
• Risk factors, symptoms indistinguishable
• But! GC prevalence is much lower
• 330,132 cases reported to CDC in 2004 (2)
• Geographic distribution of infection rates
• Predictive value, cost effectiveness concerns
• No general screening recommendations

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Who? Ct GCWhat about Males?

• Screening recommendations for females
• Majority of testing, cases are in females
• Obviously males play an important role in
  transmission of STDs!
• Why not more male testing?
• Lack of prevalence/screening data in males
• Cost-effectiveness not proven (public health)
• Lack of access point for screening men
• Does not mean we should not test men when we have
  the opportunity!

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• "It is better to know some of the questions than
  all of the answers."
• James Thurber (1894-1961)
• American humorist, writer

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• What Tests should be done?

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What Ct/GC Tests should we use?

• Nucleic Acid Amplification tests (NAAT) are
  common, but many Ct methods are available
• EIA tests, including Rapid point-of-care tests
• DFA (direct fluorescent antibody)
• Nucleic Acid Probe (non-amplified)
• Signal Amplification (Digene)
• Culture
• NAAT for GC may be the most common, but Culture
  and NAP are still used
• Serology tests not very useful for diagnosis

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What factors affect test selection?

• Performance/Accuracy/Reliability of results
• Appropriateness to the population to be tested
• Available specimen types (swabs, urine, etc.)
• Predictive value of a positive result/
  availability of confirmatory (supplemental/repeat)
  testing
• Complexity/ logistical issues
• Specimen handling requirements
• Lab space, expertise, throughput/ volume
• Turnaround time
• Cost!

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Which Ct-GC test has the best

• accuracy?
• NAATs are highly sensitive, specific
• Culture is 100 specific, can lack sensitivity
• specimen and handling options?
• EIA/NAP cervical or urethral only
• NAAT also urine, one cleared for vaginal swabs
• Culture still only option for oral, rectal
• Transport time/temp. vary among NAATs, up to 30
  days at room temp.!

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Which test has the best

• turnaround time?
• Most non-culture tests can be performed in a
  matter of hours, but TAT depends on the lab
• Rapid tests done while the patient waits
• Relatively insensitive, less specific expensive
• CDC should NOT be used other than as a
  point-of-care test!
• cost?
• CT culture gt NAAT gt non-amp gt GC culture
• Cost highly dependant on volume of testing

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How to test non-routine specimens?

• Need for testing oral and rectal specimens?
• Non-culture tests, including NAAT, NAP and EIA
  are not labeled for oral or rectal swabs
• In-house verification studies can be done, if
  enough specimens/positives can be obtained
• Chlamydia Culture is available at some labs
• Specificity is high, Sensitivity can be lower
• Gonorrhea culture is available at some labs and
  health departments
• Oral CT infection less common than oral GC

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Testing Other Alternative Specimens

• Women who have undergone hysterectomy/ lack a
  cervix (or no pelvic exam)
• Urine NAAT is the specimen of choice
• NOT recommended for sexual abuse investigations
  however
• Vaginal swabs may be acceptable for some tests
  (Gen Probe Aptima)
• Culture may also be appropriate
• Self-collected swab specimens are showing promise
  with some NAATs in some settings!

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What about LGV?

• Lymphogranuloma venereum (LGV)
• Systemic infection caused by certain CT strains
• Very few cases seen in U.S., often with history
  of travel to endemic parts of the world
• Cases detected in 2004 and 2005 in U.S. and
  Europe raised concern about re-emergence
• Most cases were rectal infections in MSM
• CDC case surveillance, information available at
  http//www.cdc.gov/std/lgv/default.htm
• Testing available for symptomatic patients (no
  screening at this time)

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• He must be very ignorant for he answers every
  question he is asked.
• Voltaire

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• What About Other STDs?

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Who to testOther STDs?

• If HSV is the most common STD, why so little
  testing?
• Screening tests do not exist, or are not
  routinely done for many STDs
• Not as simple as screening for everything
• Nature of some infections make lab diagnosis a
  challenge in absence of symptoms (HPV/HSV)
• Lack of reporting requirements limit data for
  some common infections (HPV, HSV)
• What to do with results if no cure?

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Who to test for Herpes?

• Distinction between testing and screening
• Recent studies debunk some common beliefs about
  HSV infection
• Most people infected with HSV do not have or
  recognize their symptoms
• Shedding and transmission do frequently occur
  when no symptoms are present/recognized
• HSV type 1 is increasing as a cause of
  first-episode genital infection

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Why test for Herpes?

• Clinical diagnosis is insensitive nonspecific
• In a large national sero-prevalence study
• 22 (adolescents/adults) were positive -HSV2
• Only 12 of these knew they had herpes
• Distinction between types 1 2 is important
• Prognosis for recurrence greater with type 2
• Awareness of infection ? reduced transmission
• Suppressive therapy may protect partners
• Role of HSV in HIV acquisition

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What HSV Test to Use?

• Visual exam alone
• High rates of clinician error due to atypical
  presentations, asymptomatic infections.
• Viral Culture
• Standard test in many settings. Sensitivity
  varies, dependant on timing of specimen
  collection. High specificity. Expensive.
• Antigen tests, Tzanck smear
• Poor sensitivity and specificity
• should not be relied on for diagnosis of HSV
  infection. CDC STD Treatment guidelines

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What HSV Test to Use?

• Nucleic Acid Amplification (PCR)
• Highly sensitive and specific, not commercially
  available to laboratories. Expensive.
• Serology
• Older tests do not accurately distinguish type
  (despite claims) and should not be used.
• Western Blot Gold Standard serologic test
  highly accurate, not commercially available to
  labs.
• New Type-Specific tests based on glycoprotein
  G1/ G2 are more sensitive and specific than older
  tests.

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What HSV Test Virologic Tests?

• Virologic diagnosis generally for patients
  presenting with lesions
• Culture may be diminishing in availability
• Requires viable virus, so collection, timing and
  handling are critical to sensitivity
• Nucleic acid amplification tests developed
  in-house by some labs, not yet widely available
• Preferred over culture for CNS diagnosis
• Promise higher sensitivity in genital specimens

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What HSV Test Serologic Tests?

• What about the vast majority of asymptomatic or
  unrecognized HSV infections?
• Must assure that any type specific serology
  testing done is glycoprotein-G based
• Currently available FDA-approved gG tests
• HerpeSelect ELISA for HSV-1 or HSV-2
• HerpeSelect Immunoblot for HSV-1 HSV-2
• Biokit (formerly PoCkit)

HerpeSelect is a registered trademark of Focus
Technologies, Inc.
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Who to TestHSV Serology?

• The gG type-specific tests are relatively new,
  but consensus is emerging regarding the
  usefulness of testing
• Patients with suspicious symptoms and negative
  virologic tests (culture)
• Asymptomatic patients with HSV partners (past
  or present)
• Patients diagnosed by exam only, want
  confirmation and/or typing

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Who to TestHSV Serology?

• The utility of other proposed screening uses of
  type-specific HSV tests is less certain
• Prenatal screen
• Patients requesting general STD testing
• Other screening criteria, such as diagnosis of
  another STD
• Meaningfulness of some HSV serology results
  difficult to determine
• Many positive for HSV-1, but no way to
  distinguish oral from genital infection

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• To find the exact answer, one must first ask the
  exact question.
• S. Tobin Webster
• Sometimes the questions are complicated and the
  answers are simple.
• Theodor Geisel (Dr. Seuss)

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• What do test results really mean?

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What does it mean when

• A patient tests positive for CT or GC and is in a
  long-term relationship?
• A patient tests positive and then tests negative
  without treatment?
• A patient tests positive and her long-term
  partner tests negative?
• A patient tests positive but there is just no
  way she could possibly have Chlamydia?
• A clinician calls to ask, What is the
  false-positive rate?

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What is the real question?

• When someone asks about the false-positive rate
  of a test, we must distinguish between
• The pre-test chance of a false-positive, and
• The likelihood that a given positive result is a
  false positive
• The second is the more likely scenario, but what
  is the difference?
• The real question is What is the Positive
  Predictive Value?

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What is the Positive Predictive Value?

• SPECIFICITY is the likelihood that a test will be
  negative is infection is absent
• SENSITIVITY is the likelihood a test will be
  positive when infection is present.
• Both are inherent performance characteristics of
  tests
• Established in studies, part of FDA clearance
• PREVALENCE is defined as the percentage of
  infected individuals in a population.
• Can also be thought of as risk or the
  likelihood that an individual with certain
  characteristics is infected
• Specificity is close to the False Positive Rate
  but not the whole story

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What is the Positive Predictive Value?

• Sensitivity and Specificity relate to the test
• Prevalence (risk) relates to the patient
• Positive Predictive Value (PPV) is dependant on
  BOTH the Specificity of the test and the
  Prevalence of infection, and relates to a
  positive test result
• PPV is defined as the likelihood that a positive
  test result represents an actual infection.
• Differs from specificity in that an actual
  positive test has occurred
• Negative Predictive Value is based on prevalence
  and Sensitivity, and is the probability that a
  negative test result is a true negative.

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Comparing Discordant Results

• The real question is, what is the PPV of the
  positive and the NPV of the negative result
• Can the two be compared?
• Need to know sensitivity, specificity of the
  tests, and prevalence i.e. RISK of the patient
• Regarding tests done at unknown labs
• All tests are not created equal, and not all labs
  are performing NAAT-level testing
• It is difficult to make accurate assumptions
  about tests performed in unknown laboratories
• Why the test was done is an important
  consideration

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PPV Results Discordant with Expectations

• Patient expectations I couldnt possibly have
  Chlamydia!
• Clinician expectations This patient should not
  be positive.
• Do we believe the patient, clinician or result?
• A test result is only one part of a diagnosis
• Why was the patient tested in the first place?
• An opportunity to double-check lab systems

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Factors Affecting Test Accuracy

• Performance characteristics of the test type
• Sensitivity, specificity (relating to test)
• PPV, NPV (prevalence/riskrelating to patient)
• Adherence to specimen collection/ handling
  requirements
• Materials, procedure, technique, time, temp. etc.
• Nature of the patient and the infection
• Duration of infection, amount of agent present,
  presence of interfering substances

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Questions Regarding Interpretation of Lab Results

• A Lab Result is NOT a diagnosis!
• However, as laboratorians, we must provide our
  clinicians with
• The most appropriate tests for the population
  served, and
• The information necessary to interpret results
• Lab results are not as black and white as
• We would like them to be
• Clinicians ( patients) might expect them to be!

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• Every clarification breeds new questions.
• Arthur Bloch
• (American writer and humorist)

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• When someone says, That's a good question, you
  can be sure it's a lot better than the answer
  you're going to get.
• Unknown Source

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• What are YOUR Questions???
• Bobbie McDonald
• bobbie_at_mail.slh.wisc.edu