Genital Herpes Screening, Diagnosis and Treatment: Knowledge is Power
It has been 25 years since Time Magazine’s memorable cover, the word “Herpes” emblazoned in red across the page with the caption: “Today’s Scarlet Letter”, and a grim-faced heavily clothed couple beneath. Since then the stigma remains, and the incidence of genital herpes has blossomed. The Center for Disease Control estimates there are 50 million infected adults in the United States, making this the most prevalent STD, with 1 million new cases annually. (1,2) Yet only one in ten affected persons knows they have had the infection, with many having symptoms that have been attributed to other diagnoses. While the classic presentation of genital herpes is easier to diagnose, it is less common than the atypical presentation. The infection often recurs, and asymptomatic shedding is common. The disease is relatively easy to transmit to others, and transmission frequently occurs in the absence of symptoms. The diagnosis of herpes can result in significant physical and emotional consequences, as well as potential harm to newborns. Since the Time article, effective pharmacologic therapy has become available, but can only be offered to patients if the diagnosis is made. Treatment with antiviral medications controls and reduces the frequency of outbreaks, and by reducing asymptomatic shedding of the virus, reduces transmission to uninfected partners. Treatment in the third trimester of pregnant women with a history of herpes decreases the incidence of cesarean sections, and may reduce newborn transmission. The recent United States Preventive Services Task Force statement on HSV screening of asymptomatic patients has created some confusion about herpes testing.
TIME Cover © 1982 Time Inc. TIME and the Red Border Design are trademarks of Time Inc., registered in the U.S. and other countries. Used with permission.
Herpes simplex 1 (HSV 1), or “oral herpes”, causes cold sores or fever blisters, and initial oral infections frequently occur in childhood, with the majority of adults exhibiting antibodies to the virus. The virus often recurs around the lips or facial area, frequently associated with stress or illness. Persons without prior infection may contract HSV 1 in the genitals by recipient oral sex from a partner shedding the virus from their mouth. 30-50% of newly diagnosed primary genital HSV infections are Type 1 (3-7) but infrequently recurs or sheds from the genitals after the first infection, so it carries less of a long-term implication. Contracting primary (first episode) HSV 1 infection late in pregnancy can cause severe neonatal herpes infection.
Herpes simplex 2 (HSV 2) causes genital herpes infections, with the vast majority (over 95%) of recurrent herpes, viral shedding, and transmission due to HSV 2. It can cause significant symptoms, can recur in “non-genital” sites below the waist, and can result in severe neonatal infections. Though there is the possibility of getting a primary HSV 2 infection in the mouth with oral sex, it rarely will recur in that site. Contracting primary HSV 2 infection late in pregnancy can cause severe neonatal herpes infection.
Data from the 2005-2010 National Health and Nutrition Examination Survey indicate that the prevalence of HSV-2 infection ranged from 1.2% in adolescents aged 14 to 19 years to 25.6% in adults aged 40 to 49 years, with prevalence in women twice that of men.(8)
HSV becomes dormant in the body after the initial infection, only to later reactivate or cause asymptomatic shedding and then transmission to others.
A primary episode occurs when someone first gets infected with the virus, and has no circulating antibodies against the pathogen. Any symptomatic episode after the development of antibodies is considered a recurrence. The classic appearance of primary genital herpes infection is quite characteristic, with painful ulcerations and sores in the genital region, sometimes causing dysuria, itching and discharge, and local lymphadenopathy associated with malaise, fever, headache, and fatigue. This may last 2-3 weeks if not treated.
However, most primary infections are asymptomatic or minor, or cause internal genital lesions that do not get recognized. Person who had a prior oral HSV 1 may get minimal symptoms because of the ameliorating effects of their HSV 1 antibodies. Even though these antibodies do not protect against getting HSV 2, they modify the response.
After the initial infection, the virus retreats down the sensory nerves and sets up residence in the ganglia lower spine ganglia. Later, the virus may travel back up to the surface and cause symptoms in genital or extragenital sites such as the lower abdominal wall, rectum or anus, buttocks, or thighs. Genital recurrences are almost always due to HSV 2.
The diagnosis of a primary infection requires simultaneous serologic testing for HSV antibodies. Sometimes a severe episode with systemic symptoms may actually be a recurrence, where the actual first episode was asymptomatic, or a minor lesion with no additional symptoms may be a primary lesion.
The 2015 CDC STD Guidelines state: “Most persons infected with HSV-2 have not had the condition diagnosed. Many such persons have mild or unrecognized infections but shed virus intermittently in the anogenital area. As a result, most genital herpes infections are transmitted by persons unaware that they have the infection or who are asymptomatic when transmission occurs.” (1)
Occasionally HSV causes lesions or infections on the finger (a “Whitlow” – usually HSV 1, and usually from simultaneous infection at the time of a primary episode). More rarely, infections can occur on the cornea or in the nervous system. Infants can be infected in utero, or at delivery if significantly exposed to the virus, and neonatal infections can cause meningitis, blindness, and death.
Most primary infections go unrecognized. Recurrences may be eroneously diagnosed as recurrent yeast or UTI or irritation from shaving, or sexual friction, or an allergy to latex or soap. Recurrences may look like an abrasion or a fissure, either of which should be considered herpes until proven otherwise. There may only be itching or vaginal discharge with no obvious lesions, or only introital or labial redness. Anal symptoms are often attributed to hemorrhoids or pinworms, and skin lesions on the thighs or abdomen or buttocks are often diagnosed as furuncles, ingrown hairs, spider bites, poison ivy or heat rash (14) Genital herpes needs to be in the differential diagnosis of any recurrent genital (or regional cutaneous) symptoms.
Images 1-6 below, illustrate various episodes of HSV.
First Episode Primary HSV
The patient presented with complaints of severe pain and burning upon urination. She had a fever of 103º F, headache, and malaise.
Examination revealed multiple tender ulcers bilaterally. One cannot visually distinguish between HSV-1 and HSV-2. The culture yielded a positive result for HSV-1. This is a typical first episode primary herpes outbreak with associated constitutional symptoms.
First Epidode Nonprimary HSV
The patient is a 20-year old female presenting with tender ulcers of 2 days duration.
The patient gave no past history of genital herpes outbreaks. The culture was positive for HSV 2 and the serology was also positive for HSV-2 antibodies. The patient thus had a previous likely asymptomatic acquisition of HSV-2, and this is her first recognized herpes outbreak.
The patient had been shaving her genital area for a year. She first noticed an area of irritation 7 months ago. This was the third time she had these sores in the same spot, which she had through was the result of her shaving.
The patient saw her physician who cultured the sores. The culture was positive for HSV-2. This is a typical episode of recurrent HSV.
The patient had been complaining of intermittent episodes of anal pain and itching for the past 7 months. She had been treating herself for hemorrhoids.
An examination revealed unilateral tender perianal ulcers, which were culture positive for HSV-2. Though not acquired anally, the recurrences are occurring in the distribution of the involved nerve distribution.
Atypical Presentation – Excoriation
The patient presented to her gynecologist stating that she had cut herself while scratching with her fingernails 1 day before.
While this may look like a traumatic excoriation, a culture was positive for HSV-2. Six months before, the patient had a bilateral primary genital herpes outbreak. This is her first recurrence of genital herpes. It is important to remember that all genital excoriations should be evaluated for HSV.
Atypical Presentation – Erythema
The patient complained of vulvar pain and redness of 2 days duration. Examination revealed bilateral erythema of the vulva. Her physician initially made the diagnosis of vulvar candidiasis.
On occasion, genital herpes may present with only erythema. There may be no vesicles, pustules, or ulcers. In this case, there was no yeast present, but a culture taken from the highlighted fissure was positive for HSV-2.
Atypical Recurrent HSV
The patient had been to her doctor 3 times over the past 8 months with a pruritic and mildly painful rash on her right buttock. She had been told that it was an irritation from riding a bicycle. She initially thought it was a spider bite.
This outbreak reveals grouped ulcers on an erythematous base. The culture was positive for HSV-2. Because of the atypical location of the outbreak, a diagnosis of genital herpes had not been considered.
The CDC states “the clinical diagnosis of genital herpes is both insensitive and nonspecific. Both virologic and type-specific serologic tests for HSV should be available in clinical settings that provide care for patients with STDs or those at risk for STDs.” (1)
Herpes virus culture was long-considered the gold standard for testing of a visible lesion. However, there is a high false-negative rate if inadequate numbers of viral particles are being shed. Polymerase chain reaction (PCR) testing for the presence of HSV DNA is now the test of choice, as it is significantly more sensitive, and routinely differentiates between HSV 1 and HSV 2 (which needs to be requested when doing a culture). Although a positive culture or PCR is definitive, a negative test does not rule out herpes. Cytology is not helpful. (1,15-17)
Following infection, herpes IGG antibodies develop, first appearing about 3 weeks after exposure and by 3-4 months. Older “non-specific” tests did not distinguish between Type 1 and 2, and create confusion and misinformation. Now that “type-specific” HSV 1 and HSV 2 IGG tests are available, they are the only ones that should be ordered.
The CDC notes that false negatives are more likely in the early stages of infection, and that the HerpeSelect HSV-2 Elisa could have a false positive result at low index values (1.1-3.5), recommending that low values be confirmed with a Biokit or Western Blot testing. Western Blot testing, considered to the the gold standard of serologic testing, is available through the University of Washington Clinical Virology Laboratory, but may be difficult or impossible to obtain depending on the state the sample is coming from. (1, 19-21) Since virtually all HSV 2 is acquired sexually, a positive HSV 2 antibody (particularly at index values over 3.5) implies prior genital infection (1); however, a positive antibody for HSV 1 does not distiguish between oral and genital infection, but can be helpful in deciding if a confirmed genital HSV 1 infection is primary or recurrent. Screening for HSV 1 antibodies is not helpful as an STD screen, since most positive results reflect a prior oral infection.
Herpes IgM testing, sometimes done for other viral infections to look for acute antibody production, does not distinguish between HSV 1 and 2, has low sensitivity and specificity, and can be positive due to prior non-herpes viral infections. It is a meaningless test, and should never be done.(1,22)
A negative serology with a positive culture or PCR is confirmatory for a primary episode. A positive serologic test confirms prior herpes, but cannot provide an answer as to when the actual first exposure occurred. When a positive serology is obtained, with education most patients learn to identify their herpetic recurrences.
Who are candidates for serologic testing?
Patients in whom the clinical diagnosis is being entertained, and cultures are being done, to evaluate for primary vs. recurrent.
Patients with recurrent genital symptoms, such as cyclic UTIs (where urine cultures are negative) or recurrent vaginitis patients, where an “atypical presentation” is suspected.
Patients diagnosed with other sexually transmitted diseases.
Patients with HIV.
Patients who request screening for STDs (frequently, testing for HSV is neglected in these patients, especially with the latest USPSTF statement, which will be further addressed below). The 2015 CDC STD Guideline states “HSV serologic testing should be considered for persons presenting for an STD evaluation.”
Patients whose partners have been diagnosed with herpes.
Patients who have been clinically diagnosed in the past with herpes without a confirming culture.
Screening for HSV 1 and HSV 2 in the general population is not recommended. (1)
Most patients diagnosed with herpes react with shock and disbelief, though some respond with less surprise because they had wondered if they had it due to prior known exposures or symptoms. Often, they want to know “when, how, why”, and much of the management of the herpes diagnosis involves helping them learn about the infection, answering those questions that can be answered, and explaining those that can’t. Often there are misconceptions about the diagnosis, such as that it causes cancer (it does not) or that it means they can never have children or deliver vaginally (untrue). Patients also often fear that they will never be able to have a normal sex life, or have another intimate relationship (also untrue). There may be anger at having become infected, and there are appropriate fears about transmission to future partners. Counseling and education are vitally important, with provision of information about partner notification, risk of asymptomatic viral shedding and transmission, and dispelling misconceptions. Patients also need to be informed that there are effective and safe medications available that help to treat and control the infection, and reduce the risk of transmission to an uninfected partner, with education on appropriate use of condoms. Excellent web sites and hot lines are available for patient education, as well as written materials.
USPSTF Statement on Screening
In 2016, the United States Preventive Services Task Force published a statement on HSV testing. (25) It noted that “genital herpes is a prevalent sexually transmitted infection in the United States, occurring in almost 1 in 6 persons aged 14 to 49 years” and “reviewed the evidence on the accuracy, benefits, and harms of serologic screening for HSV-2 infection in asymptomatic persons, as well as the effectiveness and harms of preventive medications and behavioral counseling interventions to reduce future symptomatic episodes and transmission to others.” The USPSTF concluded “that the harms outweigh the benefits for population-based screening for genital HSV infection in asymptomatic adolescents and adults, including those who are pregnant,” largely based on concerns about the risk of a false positive screen with the currently available tests (specificity) (26) and “the potential anxiety and disruption of personal relationships related to diagnosis”. They recommended “further development of screening and diagnostic tests with higher specificity that detect both asymptomatic genital HSV 1 and HSV 2 infections.” As an alternative, the USPSTF recommended “intensive behavioral counseling interventions to reduce the likelihood of acquiring an STI for all sexually active adolescents and for adults at increased risk.” It then acknowleged that “persons with genital herpes can spread the infection to sexual partners even when they are asymptomatic. Studies suggest that up to 85% of persons who are found to be infected with HSV-2 and who report no prior symptoms of genital herpes have a symptomatic outbreak within 6 months of being tested. … persons who receive education about genital herpes may be more likely to recognize and report its symptoms. …. some persons who are considered ‘asymptomatic’ may have actually experienced symptoms but not identified them as genital herpes.”
The mainstay of therapy is antiviral medication that interact with viral thymidine kinase and stops viral replication, including acyclovir, valacylovir, and famciclovir. Each has specific dosing for treatment of a primary episode, recurrent episodes, and suppression of recurrences. (1). Recommendations for patient treatment and counseling can be accessed via the CDC website at https://www.cdc.gov/std/tg2015/herpes.htm.
Some health care practitioners are hesitant to provide testing for herpes, feeling patients are better off not knowing they have it because of the emotional issues and stigma involved. However, what our patient does not know can hurt her, and knowledge is power. With the diagnosis, appropriate treatment can be provided for typical as well as atypical presentations, misdiagnoses and unnecessary treatments are avoided, and potential transmission to others or to newborns may be averted. Genital HSV 1 infections can be differentiated from genital HSV 2 infections, and appropriate counseling given. Patients have the right to receive an accurate diagnosis and appropriate therapy, even when it may involve emotional distress or awkwardness on the part of the patient or the provider. It should not be the role of the provider to decide that we should avoid anxiety in our patients by withholding access to information about their HSV status, in particular when doing requested STD screens. Patients should be advised of the risk of false positive serologic testing, and low-positive serologic results need to be interpreted carefully and/or confirmed with additional testing. However, HSV 2 is the most prevalent STD. If HSV 2 serologic screening is not included when a patient requests STD testing, this should be done with the knowledge and consent of the patient, so they do not erroneously inform partners that they have been screened for “everything."
Case Studies From the Author’s Practice
Stacy is a 19-year-old coed who developed painful ulcerations on her vulva, and was told by the student health service that she had genital herpes, confirmed by culture. She is quite distressed by this diagnosis, since she has not yet had intercourse. She has been recipient of oral sex, though her partner has no history of oral lesions. The lab had frozen the specimen, and on request did typing, which showed HSV 1. Her boyfriend was positive for HSV 1 on serologic testing, negative for HSV 2, and she tested negative for both on blood testing, confirming the diagnosis of primary genital HSV 1. She responded to antiviral therapy, and has had no recurrences. She also is quite relieved by the diagnosis of “oral” HSV in the genitals, because it “isn’t really genital herpes”, and is unlikely to recur or be transmitted.
Angela is 30 years old, 35 weeks into her first pregnancy, and presents with painful vulvar ulcerations and systemic symptoms suggestive of a new herpetic infection. The culture is positive for HSV 2. She has had no history of prior gynecologic problems other than episodic recurrent yeast and urinary tract infections during earlier years. Her husband has no history of herpes, but has had rare “pimples” on his penis in the past, and occasional “jock itch”. Her obstetrician initially counsels her about the significant risk associated with primary herpes late in pregnancy. She is placed on a 10 day antiviral course. Her antibody screen is positive for HSV 2, indicating an atypical severe recurrent outbreak, and makes likely the conclusion that her earlier milder recurrent genital symptoms were herpetic. Her husbands’ serology is positive as well, so it is unclear whether either of them gave it to the other or if both brought the infection into the relationship independently. She is treated for the outbreak and placed on prophylactic acyclovir for the balance of the pregnancy. Because she has antibodies present, her risk of neonatal transmission is felt to be low in the absence of lesions, and she has an uncomplicated vaginal delivery at term with no HSV recurrences and no neonatal consequences. Her severe first clinical HSV manifestation is felt to be the consequence of her alteration of immunity by the pregnancy.
23 year old Mary comes for a routine pap smear, and on examination is noted to have an abrasion between the labia minora and majora on the left. She states this is from shaving, which she began recently due to a new relationship. A viral culture is positive for HSV 2, and her antibody screen is negative, which means this is a primary infection, with an atypical presentation likely modified because HSV 1 antibodies are present.
Karlin, 35 years old, has a recurring sore area on her right buttocks. It periodically recurs, and looks like a cluster of spider bites. However, thorough house cleaning and a visit by the exterminator has failed to resolve the problem. A culture taken during an episode was negative, but PCR was positive for HSV 2, as was Karlin’s type specific antibody screen.
Janice is a 22 year old newlywed who presents with fever, chills, malaise, and severe ulcerations covering her vulva and vagina and cervix. Her cervix is swollen to twice its normal size, and fragments on touching. She is unable to void due to edema of the labia and periurethral tissues. Pathology on a cervical fragment shows marked inflammation. There is profuse exudate from the vagina. History reveals recent oral sex, and her husband had an oral cold sore come out the next day. She is admitted, a foley catheter is placed to allow for voiding, and she is treated with IV Acyclovir pending cultures. Her HSV culture is positive for HSV 1, as is the culture for staph aureus, and in the next 24-48 hours she develops liver function abnormalities and cutaneous sloughing consistent with toxic shock syndrome. Additional antibiotics are administered, and she responds to treatment. She has a complete recovery, had 2 subsequent uncomplicated vaginal births, and never has another apparent recurrence.
1) Sexually Transmitted Diseases Treatment Guidelines, 2015
Morbidity and Mortality Weekly June 5, 2015 Report Vol. 64 / No. 3:27-32.
U.S. Department of Health and Human Services Centers for Disease Control and Prevention.
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Literature review current through: Aug 2017. This topic last updated: Jan 10, 2017.
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