Herpes Simplex — Laboratory Diagnosis

Mucocutaneous Herpes simplex virus (HSV) infection usually presents as recurrent clusters of vesicles (initially), ulcers (resolving), or crusts (resolved).  HSV-Type 1 usually involves the mouth (oro-labial), Type-2 the genitals, but either type can occur at either site, and for that matter, anywhere on the body.  Herpes Gladiatorum, total body Herpes, afflicts wrestlers.  In the pre-HIV era (i.e. before gloves & universal precautions were ever used), dentists & nurses would get Herpes Whitlow — paronychial HSV around the fingernail. A baby developed HSV of the toe, because Mom affectionately bit his nails to cut them.  You get the idea.

This posting addresses laboratory diagnosis of mucocutaneous HSV.  Visceral HSV disease, like encephalitis, hepatitis, keratitis, etc., is another ballgame (a bad one at that).

There are 3 possible categories of HSV presentation:

  • Primary: First time you get the virus. It can be severe, lasting up to 2 weeks. Primary stomatitis can flood the mouth with painful blisters. Women with primary genital HSV have been hospitalized for urinary retention.
  • Recurrent: Mild outbreaks, lasting 4-5 days. Mostly just an annoyance, but may be psychologically afflicting due to appearance (orolabial) or sexual distress (genital).
  • Non-Primary First Genital Episode: First-ever occurrence, that’s mild. Usually due to pre-existing presence of HSV-1 antibodies, that attenuate the clinical response. Can also be a true HSV-2 recurrence, after an asymptomatic primary sero-conversion. Can’t tell without serological testing, & doesn’t make any difference.

Most of the time, we diagnose HSV clinically.  That can be perilous, since up to 20% of such “diagnoses” may be wrong.  There have been successful malpractice lawsuits, when couples have divorced due to Herpes, only to later discover the diagnostic error.

Does that mean we always have to draw labs?  No, but we do need to couch what we say.  Suppose a patient presents on the 3rd or 4th day with a cluster of genital ulcers that feel tingly, and began as vesicles.  There were 2 or 3 prior episodes.  I tell them,

“It’s probably Herpes.  Herpes is real common; in cities, 1 out of 5 adults have it.  Many may never get symptoms, but can still pass it to others [i.e. don’t blame your partner, who might have been asymptomatic].  I can test a specimen now, but after the first day, results may be false-negative.  A blood test might help, but can also be inconclusive.”

Then I discuss treatment options. transmission prevention, the fact that partner’s infection was likely acquired years ago (i.e. no recent infidelity), etc.  But what about those tests?

Swabs of Lesions

There are 4 different tests that can be done.  Primary HSV yields positive results much longer than recurrences do.

1.  Viral Culture. This is 100% accurate & specific if positive.  It can distinguish HSV-1 from HSV-2.  Problem is, the yield drops dramatically after the first day in recurrent HSV.  So a negative culture doesn’t prove anything.

2.  Direct Fluorescent Antibody tests. Here again, the yield depends on the type of lesion, which depends on the day of presentation.  A 1987 study found 97% sensitivity from genital vesicles, 79% from pustules, but only 45% from ulcers, & 17% from crusts.  Up to 25% of specimens may lack adequate cells to perform the test.

3.  Nucleic Acid Amplification (PCR) performs well, but is expensive. The CDC touts this as a preferred method because of its high sensitivity.  Some commercial labs don’t offer it due to lack of standardization.  I couldn’t find any literature about its specificity, and PCR tests in general always run a risk of false-positives (which can be more problematic than false-negatives).

PCR tests have been used in studies to detect viral shedding.  So in late pregnancy, a positive PCR might warrant C-section.  However, I don’t know if there’s evidence that PCR-positivity determines infectiousness; the test is so powerful, it might detect viral particles that wouldn’t even transmit.  More on HSV & pregnancy down below.

4.  Tzanck Smear. Rarely performed any more, not at all sensitive, but available at point-of-care for anybody with a microscope.  The appearance of “multinucleated giant cells” (which look just as they sound) is pathognomonic for either HSV or Varicella-Zoster virus (distinguished by the clinical syndrome).  Specimens must be obtained  by unroofing a vesicle, which limits utility.

Serology

Antibody testing can identify both HSV-1 and HSV-2 separately.  Since each HSV type remains latent forever, a positive test generally proves that a person is infected, and a negative antibody proves they’re not.  The only caveat is that in primary HSV, time is required to seroconvert, so a negative antibody proves nothing (the “window period”).

But there are problems.  For one, a positive antibody test doesn’t identify the cause of a given outbreak of genital lesions.  Many sero-positive people are and will remain asymptomatic; they do shed virus occasionally, but much more so during outbreaks.  So if a patient has vague symptoms that come and go, they may have nothing to do with HSV even if serology is positive.

Some asymptomatic couples might seek testing much as they do for HIV or other STDs, to establish their status once a relationship seems serious (i.e. the time to forego condoms).  But this may not be so advisable.  The question is, what will they do if they’re discordant: one’s HSV-2 positive, the other negative.  I can imagine several options, all unattractive:

  • Break up (that’d be sad)
  • Use condoms always, forever
  • The infected partner takes ongoing daily suppressive therapy, even if asymptomatic

Problem with the last option is it may not work.

One large study did find that continuous daily valacyclovir over 8 mos. decreased transmission (2% vs. 3.6% with placebo).  But what that means is, 1) some couples transmitted anyway; and 2) we’d expect even more transmission during the many future 8-month increments of time.

Then there’s the general and under-appreciated problem for all tests we perform: when we screen people with low likelihood of disease, most of the “positive” results we detect are really false-positives! (see our blurb about Screening Low-Prevalence Populations — DON’T!).  Say a couple is establishing a relationship, each of them had only had 1 or 2 partners previously, & mostly used condoms.  Neither has a history compatible with HSV-2 outbreaks.  What’s the likelihood one or both of them are latently infected?  Maybe not much.  So if one tests “positive,” might it be false?  No way to know.

Of course, for anyone with a history suggestive of HSV-2, serology could confirm the impression.  Then they should avoid sex during outbreaks or prodromal symptoms.  But that’s different from the never-been-symptomatic person.

The one time that asymptomatic shedding from a sero-positive person really matters is during pregnancy.  And it’s not the woman!  See below under “Pregnancy”.

A Case

A 30-year old woman in a monogamous relationship with one man presented with first-ever episode of fulminant oral ulcers.  They had a history of recent oral sex.  She received empiric acyclovir, a culture returned positive for “Herpes simplex,” but [for whatever reason] the lab never typed to distinguish HSV-1 from HSV-2.

The possibilities: 1) she had primary oral HSV-2 (most likely); 2) she had primary oral HSV-1 (not very likely); or 3) she had another viral stomatitis (Coxsackie virus, etc.), which provoked viral shedding from latent oral HSV-1 acquired (as usual) in childhood.  Serology would only be definitive if positive for only one HSV type, not both.  The patient was lost to follow-up.

Does it matter?  Probably not.  However, the rare but really serious HSV diseases, like keratitis and encephalitis, occur when virus that’s latent in the trigeminal ganglion migrates down a nerve to the eye or brain, instead of the mouth (where it causes a cold sore).  It tends to always be HSV-1, since that’s what gets acquired orally.

So if this woman had oral HSV-2, which is several times more virulent than HSV-1, and (genitally, at least) causes more frequent recurrences than HSV-1, & was unlucky enough to get eye or brain involvement, it could be really catastrophic.  Should she begin suppressive therapy?  Probably not, though I’d have a low threshold for offering it were she to have a few oro-labial recurrences, especially since they could well be more uncomfortable than the typical HSV-1 cold sore.

Pregnancy

Neonatal HSV, though quite rare, is devastating.  Mortality is high, and survivors invariably suffer serious neurological sequelae.  The standard preventive measure is to question women about a history of genital Herpes, then culture any suspicious lesions near term.  Positives are delivered by Caesarian section.

In the past, blind serial vaginal cultures were obtained; some practices may still do this.   Some give acyclovir suppression, which might cut the rate of viral shedding in half, but doesn’t stop it.

None of this may make sense.

The vast majority of afflicted neonates happen to be born to mothers who develop either primary or first-episode HSV in the last half of pregnancy.  In other words, these are women who’d never had a history of genital Herpes.  Their HSV-2 serology is negative.

Women who test positive for HSV-2 antibodies pass them transplacentally to their fetuses.  The neonates are protected by passive immunization.  Imagine that!

So actually, maybe women who’d never had Herpes should have antibodies drawn.  Whoever’s negative should have her partner(s) tested.  But that’s not going to happen, especially since neonatal HSV is too rare.

Most importantly, ask your pregnant patients if their partners might have a history compatible with genital HSV.  Test those women for HSV-2 antibodies:

  • Those who are negative should abstain from genital sex after 20 weeks, since asymptomatic viral shedding can occur in the absence of a frank outbreak.  Might sound drastic, but would certainly be prudent.
  • Another option would be to test their partners for HSV-2 antibody.  If negative, nothing to worry about.

Do NOT test for HSV-1 antibodies.  Even though HSV-1 causes some few cases of genital Herpes, anyone who’d ever been infected orally (i.e. the majority of the people) will be positive.

And that’s it for our discussion of Herpes simplex virus (derived from Greek for “creeping;” hope it wasn’t to creepy).

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2 responses to “Herpes Simplex — Laboratory Diagnosis

  1. very interesting!

  2. Pingback: Type I Herpes – Neonatal Concerns from Previous Post … | Herpes Survival Kit

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