History
Primary infection with herpes simplex viruses (HSVs) is clinically more severe than recurrent outbreaks. However, most primary HSV-1 and HSV-2 infections are subclinical and may never be clinically diagnosed.
Orolabial herpes
Herpes labialis (eg, cold sores, fever blisters) is most commonly associated with HSV-1 infection. Oral lesions caused by HSV-2 have been identified, usually secondary to orogenital contact. Primary HSV-1 infection often occurs in childhood and is usually asymptomatic.
Primary infection
Symptoms of primary herpes labialis may include a prodrome of fever, followed by a sore throat and mouth and submandibular or cervical lymphadenopathy. In children, gingivostomatitis and odynophagia are also observed. Painful vesicles develop on the lips, the gingiva, the palate, or the tongue and are often associated with erythema and edema. The lesions may progress to form pustules and ultimately ulcerate with a scalloped border, healing within 2-3 weeks.
Recurrences
The disease remains dormant for a variable amount of time. HSV-1 reactivation in the trigeminal sensory ganglia leads to recurrences in the face and the oral, labial, and ocular mucosae. Pain, burning, itching, or paresthesias usually precedes recurrent vesicular lesions that eventually ulcerate or form a crust. The lesions most commonly occur on the vermillion border, and symptoms of untreated recurrences last approximately 1 week. Recurrent erythema multiforme lesions have been associated with orolabial HSV-1 recurrences. A 2006 study reported that HSV-1 viral shedding had a median duration of 48-60 hours from the onset of herpes labialis symptoms. They did not detect any virus beyond 96 hours of symptom onset. [33]
Genital herpes
HSV-2 is identified as the most common cause of herpes genitalis. However, HSV-1 has been increasingly identified as a causative agent of primary genital herpes infections, and these are likely secondary to orogenital contact. HSV-1 accounts for 33% of primary genital herpes infections and is more common in patients younger than 30 years, those of white race, and men who have sex with men. [34] Recurrent genital herpes infections are almost exclusively caused by HSV-2.
Primary infection
Primary herpes genitalis occurs within 2 days to 2 weeks after exposure to the virus and has the most severe clinical manifestations. Symptoms of the primary episode typically last 2-3 weeks.
In men, painful, erythematous, vesicular lesions that ulcerate most commonly occur on the penis, but they can also occur on the anus and the perineum. In women, primary herpes genitalis presents as vesicular/ulcerated lesions on the cervix and as painful vesicles on the external genitalia bilaterally. They can also occur on the vagina, the perineum, the buttocks, and, at times, the legs in a sacral nerve distribution. Associated symptoms include fever, malaise, edema, inguinal lymphadenopathy, dysuria, and vaginal or penile discharge.
Females may also have lumbosacral radiculopathy, and as many as 25% of women with primary HSV-2 infections may have associated aseptic meningitis.
Recurrences
After primary infection, the virus may remain latent for months to years until a recurrence is triggered. Reactivation of HSV-2 in the lumbosacral ganglia leads to recurrences below the waist. Recurrent clinical outbreaks are milder and often preceded by a prodrome of pain, itching, tingling, burning, or paresthesia.
Individuals who are exposed to HSV and have asymptomatic primary infections may experience an initial clinical episode of genital herpes months to years after becoming infected. Such an episode is not as severe as a true primary outbreak.
More than one half of individuals who are HSV-2 seropositive do not experience clinically apparent outbreaks. However, these individuals still have episodes of viral shedding and can transmit the virus to their sexual partners.
Other HSV infections
Localized or disseminated eczema herpeticum is also known as Kaposi varicelliform eruption. Caused by HSV-1, eczema herpeticum is a variant of HSV infection that commonly develops in patients with atopic dermatitis, burns, or other inflammatory skin conditions. Atopic dermatitis is associated with a breakdown in the skin barrier and immune dysregulation, which can lead to cutaneous infections, such as, eczema herpeticum. Cutaneous infections in patients with atopic dermatitis lead to increased emergency department utilization, and both pediatric and adult patients have higher odds of an HSV infection. [35] Children are most commonly affected by eczema herpeticum, and it is more commonly associated with younger age and black or Asian race. [36] Eczema herpeticum can be diagnostically challenging, and the mean time to diagnosis is approximately 4 days. [37] Both primary and secondary HSV infections can lead to eczema herpeticum, and there is a 26.5% recurrence rate observed. [37] A retrospective study of 180 hospitalized patients with atopic dermatitis found that fever on admission, a rash on the neck, and a vesicular eruption were the clinical features associated with eczema herpeticum and these patients had a longer hospital length of stay. [38]
Additionally, HSV infection can complicate other cutaneous diseases associated with a breakdown in the skin barrier, such as pemphigus vulgaris. A hospital-based study of 60 patients with pemphigus vulgaris found that the presence of hemorrhagic crusting and linear erosions were associated with HSV infection. [39]
Herpetic whitlow, characterized by vesicular outbreaks on the hands and the digits, was most commonly due to infection with HSV-1. It usually occurred in children who sucked their thumbs and, prior to the widespread use of gloves, in dental and medical health care workers. The occurrence of herpetic whitlow due to HSV-2 is increasingly recognized, probably due to digital-genital contact.
Herpes gladiatorum is caused by HSV-1 and is seen as papular or vesicular eruptions on the face, arms, or torsos of athletes in sports involving close physical contact (classically associated with wrestling).
Disseminated HSV infection can occur in females who are pregnant and in individuals who are immunocompromised. These patients may present with atypical signs and symptoms of HSV, and the condition may be difficult to diagnose.
Herpetic sycosis, a follicular infection with HSV, may present as a vesiculopustular eruption on the beard area. This infection often results from autoinoculation after shaving through a recurrent herpetic outbreak. Classically caused by HSV-1, there have been rare reports of relapsing beard folliculitis caused by HSV-2. [40]
Neonatal HSV
HSV-2 infection in pregnancy can have devastating effects on the fetus. Neonatal HSV usually manifests within the first 2 weeks of life and clinically ranges from localized skin, mucosal, or eye infections to encephalitis, pneumonitis, disseminated infection, and demise.
Most women who deliver infants with neonatal HSV had no prior history, signs, or symptoms of HSV infection. Risk of transmission is highest in pregnant women who are seronegative for both HSV-1 and HSV-2 and acquire a new HSV infection in the third trimester of pregnancy.
Factors that increase the risk of transmission from mother to baby include the type of genital infection at the time of delivery (higher risk with active primary infection), active lesions, prolonged rupture of membranes, vaginal delivery, and an absence of transplacental antibodies. The mortality rate for neonates is extremely high (>80%) if untreated.
Physical Examination
Clinical herpes simplex virus (HSV) infections appear as clustered vesicles on an erythematous base. They often progress to pustular or ulcerated lesions with a scalloped border, and they eventually form a crust. HSV lesions tend to recur at or near the same location within the distribution of a sensory nerve. Systemic symptoms, such as fever, malaise, and acute toxicity, may accompany the lesions, especially in primary infections. Each condition has associated symptoms and clinical findings (see History).
Although HSV infections may occur anywhere on the body, 70-90% of HSV-1 infections occur above the waist. In contrast, 70-90% of HSV-2 infections occur below the waist.
Physical manifestations of HSV infections in patients who are immunocompromised are usually similar to those in healthy patients. However, larger lesions or necrotizing ulcers may occur, and widespread areas may be involved. Additionally, immunocompromised patients or those with HIV infection may present with vegetative tumorlike nodules. [41] HSV-2 is detected in 86% of mucocutaneous tumoral HSV and 97% of cases occur in the setting of immunosuppression. [42] The majority of these tumorlike HSV nodules occur in the anogenital region (76%) and they occur more frequently in men. [42]
Neonatal HSV may be difficult to diagnose because, often, no mucocutaneous lesions are present on physical examination. Respiratory distress, jaundice, and seizures may occur.
Complications
The most common complication of herpes simplex virus (HSV) infections is bacterial superinfection. In women with primary HSV-2 infection, aseptic meningitis is also common.
Significant complications, such as visceral and CNS dissemination and long-term sequelae, are rare and occur in patients who are immunocompromised or in cases of neonatal HSV.
Patients with AIDS who are treated with intravenous acyclovir may develop thymidine kinase–negative strains of HSV that are resistant to acyclovir. These patients may be successfully treated with intravenous foscarnet or cidofovir.
Babies born to mothers with genital HSV infection should be closely monitored for any signs of infection and promptly treated if signs of the disease develop. Preterm babies are at higher risk and HSV infection should be considered in preterm babies with a maternal history of HSV infection, prolonged rupture of membranes, and leukopenia. [43] Neonatal HSV infection has a mortality rate of more than 80% if untreated and a mortality/significant morbidity rate of approximately 50% even when treated.
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Characteristic cluster of vesicles on an erythematous base. Photo courtesy of Dr. John Reeves.
