Introduction: HSV virus

Herpes simplex viruses (HSV) are double stranded, enveloped DNA viruses of the Herpesviridae family. There are two distinct serotypes or “types” for short, HSV-1 and HSV-2. These two types share 40% sequence homology of their genome structure, which reaches 83% for their protein-coding regions, which explains antigenic cross-reactivity between them. Typically, due to tropism for specific anatomical sites, HSV-1 predominantly infects the mucus membranes and skin of the orolabial area. However, HSV-1 is now being seen more often in the genitalia due to the decreasing prevalence of orolabial HSV-1 in the young adult population and increase in frequency of oral sex. HSV-2 typically infects the genitalia. Despite this tropism for sites “above and below the umbilicus”, there is no absolute site for either virus, as there is mixing and matching of both viral subtypes .

Accordingly, statements that HSV-2 equals genital herpes and HSV-1 equals orolabial herpes should be avoided.

HSV infection and clinical presentation

HSV typically infects the epithelial cells of the skin and mucosa through minor breaks and then travels by retrograde transport along sensory nerves to the sensory root ganglia. Here there is viral replication. Establishment of latency occurs for the life of the host. Periodically there is reactivation from the latent state, with anterograde transfer from sensory ganglions to the periphery (skin or mucous membranes), where subclinical shredding as well as overt symptomatic and asymptomatic clinical lesions result.

Typical clinical lesions following primary infection occur only in the order of 10–25% of infections. The remainder of lesions are either undiagnosed, have a short lived atypical presentation or are asymptomatic. Hence, transmission occurs not only by penetrative sexual intercourse, but also through genital skin to genital skin contact with infected partners. These infected partners are shedding virus either during a clinically evident but not necessarily symptomatic, herpetic episode (clinical reactivation) or more commonly during an episode of asymptomatic infection, otherwise known as either subclinical shedding or asymptomatic shedding.

With a clinically overt lesion, even during the prodrome of erythema and papule formation, there is viral replication and infectivity, just as it occurs when a vesicle and ultimately an ulcer forms (see Fig. 1 ). In fact the peak viral titre occurs within the first 24 hours of lesion development. Once the lesions crust over, the viral titre falls. (See Fig. 2 ). The host immune response allows healing, which occurs rapidly, as HSV lesions are self-limiting. In the early phase of edema, erythema and fissuring, which may be painful or itchy, the diagnosis may not be readily realised until the development of typical blisters and ulcers are evident. (See Figs. 3 to 5 ). When a clinically overt lesion is evident, this may represent a primary infection or in fact, be the first episode of an infection acquired years before this manifestation. Differentiating an initial from recurrent disease can be difficult; however, initial disease more often presents bilaterally whereas recurrent outbreaks are often unilateral (men = 15% and female = 4% bilateral) .

Typical ulcerative HSV lesions noted bilaterally in a classic primary infection.

The time course of primary genital HSV infection from symptoms to lesion development .

Atypical presentation with labial oedema, pain, swelling and dysuria. Tell-tale lesions are noted on the upper thigh.

Atypical presentation of recurrent HSV lesions presenting in the sacral dermatome of the buttock.

Atypical presentation of a primary HSV presenting with labial oedema pain mimicking labial abscess (note patient went to surgery for drainage prior to diagnosis).

Subclinical HSV is more frequently detected by nucleic acid amplification techniques such as polymerase chain reaction assays (PCR), which in comparison to culture has a fourfold greater sensitivity at detecting virus. This shedding may occur with minimal or no symptoms and thus explaining how HSV infection is transmitted unintentionally to uninfected partners . Yet it is unknown if this increased detection of HSV by PCR translates to greater infectivity, which was presumed when viral culture was used to detect asymptomatic shedding. The minimal viral infecting dose is also not known.

HSV infection and clinical presentation

HSV typically infects the epithelial cells of the skin and mucosa through minor breaks and then travels by retrograde transport along sensory nerves to the sensory root ganglia. Here there is viral replication. Establishment of latency occurs for the life of the host. Periodically there is reactivation from the latent state, with anterograde transfer from sensory ganglions to the periphery (skin or mucous membranes), where subclinical shredding as well as overt symptomatic and asymptomatic clinical lesions result.

Typical clinical lesions following primary infection occur only in the order of 10–25% of infections. The remainder of lesions are either undiagnosed, have a short lived atypical presentation or are asymptomatic. Hence, transmission occurs not only by penetrative sexual intercourse, but also through genital skin to genital skin contact with infected partners. These infected partners are shedding virus either during a clinically evident but not necessarily symptomatic, herpetic episode (clinical reactivation) or more commonly during an episode of asymptomatic infection, otherwise known as either subclinical shedding or asymptomatic shedding.

With a clinically overt lesion, even during the prodrome of erythema and papule formation, there is viral replication and infectivity, just as it occurs when a vesicle and ultimately an ulcer forms (see Fig. 1 ). In fact the peak viral titre occurs within the first 24 hours of lesion development. Once the lesions crust over, the viral titre falls. (See Fig. 2 ). The host immune response allows healing, which occurs rapidly, as HSV lesions are self-limiting. In the early phase of edema, erythema and fissuring, which may be painful or itchy, the diagnosis may not be readily realised until the development of typical blisters and ulcers are evident. (See Figs. 3 to 5 ). When a clinically overt lesion is evident, this may represent a primary infection or in fact, be the first episode of an infection acquired years before this manifestation. Differentiating an initial from recurrent disease can be difficult; however, initial disease more often presents bilaterally whereas recurrent outbreaks are often unilateral (men = 15% and female = 4% bilateral) .

Typical ulcerative HSV lesions noted bilaterally in a classic primary infection.

The time course of primary genital HSV infection from symptoms to lesion development .

Atypical presentation with labial oedema, pain, swelling and dysuria. Tell-tale lesions are noted on the upper thigh.

Atypical presentation of recurrent HSV lesions presenting in the sacral dermatome of the buttock.

Atypical presentation of a primary HSV presenting with labial oedema pain mimicking labial abscess (note patient went to surgery for drainage prior to diagnosis).

Subclinical HSV is more frequently detected by nucleic acid amplification techniques such as polymerase chain reaction assays (PCR), which in comparison to culture has a fourfold greater sensitivity at detecting virus. This shedding may occur with minimal or no symptoms and thus explaining how HSV infection is transmitted unintentionally to uninfected partners . Yet it is unknown if this increased detection of HSV by PCR translates to greater infectivity, which was presumed when viral culture was used to detect asymptomatic shedding. The minimal viral infecting dose is also not known.

Infection terminology

Initial primary genital infection is defined as the acquisition of either HSV-1 or HSV-2 of the genital skin or mucosa in the absence of both HSV-1 and 2 serum antibodies (ie no previous exposure or infection).

Initial non-primary is defined as having pre-existing antibodies to HSV-1 or HSV-2 (IgG), but not necessarily from a previous clinically overt infection. For example, in the setting of someone who has had pre-existing HSV-2 (defined by IgG HSV-2), a new genital infection with HSV-1 can develop, since this person has had no pre-existing HSV-1 infection (as defined by HSV-1 IgG negative). In these settings, over time, there will be a serological response to the new subtype. One might expect to see an IgM response during a primary infection, but it is not conclusive as an initial primary infection since an IgM response can occur from reactivation.

Recurrent infection occurs when there are pre-existing antibodies to an HSV subtype (of the lesion infecting type). Meaning, there is pre-existing IgG to the specific infectious strain. For example, an individual with a clinically apparent HSV-2 infection also has IgG to HSV-2 (from pre-existing infection).

A first episode is the first clinical outbreak evident to the patient and is often the reason for seeking clinical consultation. Many first episodes are indeed recurrences with an initial infection that was either subclinical or atypical. Most patients with recurrences will have diagnosed themselves with a more socially acceptable diagnosis before seeking medical attention. This list is expansive and includes the following: vaginitis from candida, contact dermatitis (ie from topical medications, toilet paper, sanitary napkins, soaps, condoms or other menstrual products), trauma from lack of lubrication during sexual intercourse, frequent sexual intercourse, irritation from tight jeans, irritation from G-string, irritation from bicycle seat, urinary tract infection, vaginal dryness, shaving burns, reactions to hair removal products, haemorrhoids or anal fissures . All these conditions mimic the symptoms of HSV infection.

Sero-epidemiology

There have been changes in the patterns of acquisition of HSV-1 infection in the past few decades in developed populations. Seropositivity for HSV-1 has decreased from near 100% in the past resulting from extended family living. Now, family units are more nuclear and common, especially in higher socio-economic families. This provides less opportunity to acquire HSV-1 in childhood via the oral route . This has resulted in an increase in HSV-1 infections being acquired sexually and presenting as genital infections, which in some populations approaches nearly 50% of clinically evident primary genital infections. This change in epidemiology may also be related to more frequent oro-genital sexual practices in young individuals as a means of preventing unwanted pregnancies or an expansion of pleasurable or desired sexual activities. Hence, HSV-1 seropositivity varies from one community to another; it approaches 100% in childhood in poorer socio-economic groups.

Defining the type of an infecting HSV strain can help predict clinical patterns of the virus for the clinician and patient. For instance, HSV-1 is less likely to recur in the genital tract than HSV-2. Clinical recurrences occurring within 1 year of symptomatic genital lesions occur in 20–50% for HSV-1, whereas for HSV-2 it occurs in 70–90% of cases .

Seropositivity for HSV-2 increases with the onset of sexual activity. It varies by populations too, with the worldwide range in the order of 10–40%. High risk behaviours populations have higher prevalence rates. It is also higher in HIV positive populations (60–95%) compared to general population, women compared to men, and MSM compared to heterosexual men. The prevalence in Australia is in the order of 13% , whereas in the US, it is higher in the order of 25% .The age-adjusted prevalence for HSV-2 In British Columbia, Canada is 17.3% (95% CI, 15.2-19.4). Prevalence ranges from 7.1% (ages, 15-19 years) to 28.1% (ages, 40–44 years), with the largest increase after the age of 24 years .

Viral shedding

In recent studies of symptomatic and asymptomatic patients with past infection of HSV-2 (as defined by positive serology for HSV-2 by Western Blot) where data collection included intense daily swabbing (intravaginally, labial, perennial, perianal swabs) and patient diary entries, symptomatic patients were found to shed 20% of the time, whilst asymptomatic patients only shed 10% of the time . Of note the quantity of shedding was not different for either group, despite the different rates. When even more intensive screening was performed, (4 times daily), it was noted that shedding is very frequent, although usually short lived, with most shedding being less than 24 hours . In general, shedding is greater for those with more clinical recurrences, than those without symptoms. However, there was no significant differences in gender, sexual preferences, serotype positivity or age .

In further sophisticated studies where patients swabbed at different anatomical sites, shedding was found to be widespread throughout the genital tract. Moreover, when biopsies were performed in areas of reactivation and viral shedding, it was apparent that shedding was rapidly cleared by the local immunological responses, as measured by local CD8 resident memory cells . Thus there is a local, chronic immune response, which contributes in part to the increased susceptibility of HIV acquisition (in the order of 2-3 fold) . This may also be the explanation of why suppressive antiviral therapy for HSV-2 does not decrease HIV acquisition.