Layout 1 (Page 2)

Laboratory Update for
Healthcare Professionals
Using Type-Specific Serology Tests
to Help Diagnose Herpes Infections
Genital herpes continues to spread and studies suggest links between herpes
1
infection and acquiring HIV. Today, the availability of accurate tests and
effective treatment afford an opportunity to reduce the spread of infection.
Today, at least 45 million adults (about 1 in 5) in the U.S. are infected with herpes
simplex virus type-2 (HSV-2) and are capable of infecting others in the absence of
symptoms. Globally, type-2 incidence varies with the regions of the world.
Additionally, women exhibit a higher incidence of herpes type 2 infection than
men throughout the world.
The global incidence for both sexes is 23%, however, Japan, Australia, New
Zealand and Western Europe are significantly lower. Sub-Saharan
Africa, Eastern Asia, South and South-East Asia, Latin America,
and the Caribbean are significantly higher.2
Studies have shown that HSV-2 infection increased the
risk of HIV-acquisition about two-fold.1 While such
numbers are disturbing to healthcare workers and
patients alike, recent studies have shed new light on
the nature of HSV infections, and new antiviral
therapies offer hope for patients faced with managing
a life-long disease. Laboratory tests – specifically accurate
type-specific serology tests – are available to healthcare
professionals to help diagnose, counsel and treat their patients.
This pamphlet summarizes current information about HSV laboratory testing for
healthcare professionals in clinical practice.
Provided as an educational service of
Focus Diagnostics, Inc.
Current medical knowledge of herpes has changed.
Clinical practice has changed with the availability of type-specific serologies and specific therapies.
Q
A
Why has genital herpes continued to spread?
Q
Herpes simplex virus may cause ‘classic’ lesions or ulcers, but most often symptoms are non-specific or
absent. When present, symptoms can mimic other conditions including yeast infection, dermatitis, ‘jock itch’
and many other possible diagnoses.
Is testing for herpes IgM antibodies useful in
diagnosing HSV infection?
A
The presence of type-specific IgM antibodies in HSV infections is
difficult to interpret and may be confusing because unlike IgG,
IgM is not type-specific. The presence of IgM may indicate a true
primary infection however the test has low sensitivity and negative
predictive value (NPV).10 Additionally, the presence of IgM may
be due to the reactivation of a latent HSV-1 or HSV-2 infection.
For this reason, IgM testing is not recommended as a differential
diagnostic tool, but may offer information about a particular
patient’s antibody response.
A
• Approximately 75 to 90% of people with HSV-2 infections have not been diagnosed.3 Some patients are
truly asymptomatic (~20%), but in up to 60% of cases the disease is simply not recognized. In patients with
symptoms, HSV-2 infection is difficult to diagnose based on visual
exam alone.4
A
• Studies on viral shedding have shown that even in the absence
of symptoms, patients shed HSV-2 virus at about the same
rate (number of days) as symptomatic patients.5 Most
infections are transmitted when no ‘typical’ lesions are
present; without accurate diagnosis, genital herpes can spread
silently but steadily.
Q
A
Q
A
Q
A
Q
A
Q
A
What is the connection between HSV-2 and HIV?
Studies show that HSV-2 infection about doubles the risk of acquiring HIV.1 This is due to the recurrent
outbreaks patient experience with HSV-2 which act as a portal for the HIV infection. Additional studies have
also found that HSV-2 may increase the progression of HIV along with the infectiousness of the virus.6
I send cultures to the lab on all suspected herpes lesions. Isn’t that adequate?
While a positive culture is diagnostic for herpes simplex virus, a negative culture does not rule out HSV
infection. A sample of the virus is difficult to obtain unless the lesion is very fresh and moist, so the culture
result depends on the quality and handling of the specimen. Culture and direct viral detection (DFA) used
together can improve the overall sensitivity, but both tests are dependent on the quality of the specimen.
Culture should not be attempted on crusted or old lesions. Many cultures taken after day 4 or 5 of an
outbreak will be falsely negative. Serological testing with a type-specific assay in addition to culture
provides a more complete assessment of a patient’s herpes status.7
Q
A
I’ve heard type-specific HSV antibody tests are available. How well do they work?
A type-specific test must be based on detecting antibodies to
gG1 (from HSV-1) or gG2 (from HSV-2), the major proteins
known to elicit type specific responses. Newer tests on the
market, including the HerpeSelect® family of products from
Focus Diagnostics, use recombinant gG1 and gG2. Older test
kits detect antibodies to type-common antigens and are not
type-specific despite their labeling claims since studies show
that they cause inaccurate results up to 50% of positive patients.8
Performance Data for HerpeSelect ®
Compared to Western Blot
Immunoblot
Method
ELISA
Method
Pregnant Women
HSV-1
HSV-2
Sensitivity Specificity
Sensitivity Specificity
100
93
100
94
Sexually Active Adults
99
95
97
98
Pregnant Women
96
95
100
96
Sexually Active Adults
91
92
96
97
Can HSV-1 cause genital herpes and is it important?
Oral HSV-1 is very common (seroprevalence of 50 to 90% in most populations), and studies show HSV-1 is
responsible for up to 50% of first episodes of genital herpes in the United States.7 However, recurrences and
subclinical shedding are much less frequent for genital HSV-1 infection than genital HSV-2 infection. So, whether
genital herpes is caused by HSV-1 or HSV-2 influences prognosis and counseling. In the absence of HSV-2
antibodies, genital lesions should be confirmed by culture and/or PCR testing.4
Why should I use a HSV type-specific antibody test?
A HSV type-specific antibody test can help guide the physician
towards the appropriate choice of treatment and patient
counseling. A clinical diagnosis (visual) of genital herpes should
be confirmed with laboratory tests since genital lesions can be
caused by other infections.4 Studies show that about around 75
to 90% of people with HSV-2 antibodies are unaware that they
have genital herpes. People who are negative for HSV-1 and/or
HSV-2, but are sexually active and don’t know their partners HSV
status, are at risk for acquiring infection.11 Women who become
infected with either HSV-1 or HSV-2 during pregnancy run the risk
of passing the virus to their neonates.12 Furthermore, HSV-2
infection has also been linked to a higher risk of sexually acquired
HIV, and it can increase the progression of HIV-infected individuals.
What about PCR testing and viral shedding?
PCR is the choice for HSV infections of the central nervous system,
while culture traditionally has been the choice for HSV genital infections.
Some experts believe that HSV PCR will likely replace culture as the
choice for testing for genital herpes in people with active mucocutaneous lesions. However, both culture and PCR have limitations. A
negative culture or PCR test result does not rule out HSV infection, as
viral shedding is intermittent.13 In one study of HSV-2 positive women,
virus (and corresponding nucleic acid) was shed vaginally an average of
28% of days (ranging from 0 to 77% of days) when lesions were absent.13
In contrast, antibody positivity fluctuates very little over time.9
Q
How can I find out if my laboratory performs gG-based
type-specific HSV testing?
A
Ask your laboratory if they are using a glycoprotein G-based test,
®
such as the HerpeSelect test for HSV-1 and HSV-2 antibodies. If
the laboratory is not using a glycoprotein G-based test, it is not
®
performing true type-specific testing. HerpeSelect HSV-1 and
HSV-2 testing and diagnostic test kits are available from Focus
Diagnostics, 800-838-4548 or 714-220-1900. Ask for
®
HerpeSelect by name.
Excerpts from CDC,
Sexually Transmitted Diseases
Treatment Guidelines 2006:
“Because false-negative HSV
cultures are common, especially
in patients with recurrent
infection or with healing lesions,
type-specific serologic tests are
useful…”
“…older assays that do not
accurately distinguish HSV-1
from HSV-2 antibody, despite
claims to the contrary, remain
on the market.”
“…serologic type-specific
gG-based assays should be
specifically requested when
serology is performed.”
Gynecologic Herpes Simplex
Virus Infections: ACOG
Practice Bulletin: Clinical
Management Guidelines for
Obstetrician-Gynecologists,
Number 57, November 2004.
“Clinical suspicion of genital
herpes should be confirmed
using reliable laboratory
testing.”
“Antibodies to HSV-2 are
detected 2 to 12 weeks after
acquisition of infection and
persist indefinitely.”
“Only tests that are based on the
detection of antibody response
to glycoprotein G-2 for HSV-2
and glycoprotein G-1 for HSV-1
are type specific because much
of the immune response is
type-common for both HSV
types. Many serologic tests on
the market are not type specific,
despite labeling claims to
the contrary.”
References & Resource Material
1) Freeman EE, Weiss HA, Glynn JR, et al. “Herpes simplex virus 2 infection increases HIV acquisition in men and
women: systematic review and meta-analysis of longitudinal studies.” AIDS. 2006; 20: 73-83.
2) Looker, K, Garnett,G., Schmid, G 2008. “An Estimate of the global prevalence and incidence of herpes simplex
virus type 2 infection.” Public Health Reviews, Bulletin of the World Health Organization 2008;86:805-812
3) The Herpes Testing Toolkit. American Social Health Association (ASHA) – 2006.
4) Langenberg A, L Corey, R Ashley, WP Leong, S Straus. 1999. “A Prospective Study of New Infections with
Herpes Simplex Virus Type 1 and Type 2.” New England Journal of Medicine. Nov. 4, 1432-8.
5) Wald A, J Zeh, S Selke, T Warren, A Ryncarz, R Ashley, J Krieger, and L Corey. 2000. “Reactivation of Genital
Herpes Simplex Virus Type 2 Infection in Asymptomatic Seropositive Persons.” New England Journal of
Medicine. Mar. 23, 844-850.
6) McClelland RS, Wang CC, Overbaugh J, et al. “Association between cervical shedding of herpes simplex virus
and HIV-1.” AIDS. 2002; 16: 2425-2430.
7) Sexually Transmitted Diseases Treatment Guidelines — 2006 (CDC). MMWR Recommendations and Reports.
Vol. 55/No. RR-11/August 4, 2006.
8) Morrow, RA and D Friedrich. 2003. “Inaccuracy of Certain Commercial Enzyme Immunoassays in Diagnosing Genital
Infections with Herpes Simplex Virus Types 1 or 2.” American Journal of Clinical Pathology. Vol. 120, No. 6.
9) Cherpes TL, Ashley RL, Meyn LA, Hillier SL. “Longitudinal reliability of focus glycoprotein G-based type-specific
enzyme immunoassays for detection of herpes simplex virus types 1 and 2 in women.” J Clin Microbiol. 2003
Feb;41(2):671-4. http://jcm.asm.org/cgi/content/full/41/2/671?view=long&pmid=12574265
10) Warren T. “Importance of Testing and Diagnosis in Genital Herpes.” Medscape Infectious Diseases. 2004.
11) Allen B, B Branagan, P Kerndt, J Klausner, S Guerry, H Bauer and G Bolan. Summary Guidelines for the Use of
Herpes Simplex Virus (HSV) Type 2 Serologies. California STD Controllers Association/California Department
of Health Services.
12) Gynecologic Herpes Simplex Virus Infections: ACOG Practice Bulletin: Clinical Management Guidelines for
Obstetrician-Gynecologists, Number 57, November 2004.
13) Wald A, Corey L, Cone R, Hobson A, Davis G, Zeh J. “Frequent genital
herpes simplex virus 2 shedding in immunocompetent women.” J Clin
Invest. 1997 Mar 1;99(5):1092-7. www.jci.org/articles/view/119237
Other Useful References
• Ashley R and A Wald. 1999. “Genital Herpes: Review of the
Epidemic and Potential Use of Type-Specific Serology.”
Clinical Microbiology Reviews. Jan. 1-8.
• Garcia-Corbeira P, W Hogrefe, L Aguilar, J Garcia-de-Lomas,
A Gil, J M Bayas, A Villella and R Dal-Re. 1999. “Whole Cell
Lysate Immunoassay vs. Recombinant Glycoprotein G2-Based
Immunoassays for HSV-2 Seroprevalence Studies.” Journal of
Medical Virology. 59:502-506.
• Prince H, C Ernst, W Hogrefe. 2000. “Evaluation of an Enzyme
Immunoassay System for Measuring Herpes Simplex Virus (HSV)
Type 1-Specific and Type 2-Specific Antibodies.” Journal of Clinical
Laboratory Analysis. 14:13-16.
• Fleming, DT et al. Herpes Simplex Virus Type 2 in the United States, 1976
to 1994. NEJM 1197; 337(16): 1105-11.
For more detailed information or to receive a Directory of Services,
contact Client Services at 800-445-4032. Visit our website at www.focusdx.com.
Also, visit our herpes education website at www.herpeselect.com for additional
physician and patient herpes information.
Cypress, California 90630 USA
714-220-1900 • 800-445-0185
Fax 714-995-1592
DXPHC1008
© 2008, Focus Diagnostics, Inc.