David K. Hong and Charles G. Prober
Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) belong to a family of DNA viruses that include cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), and human herpes-viruses 6, 7, and 8 (Table 309-1). Following primary infection, herpes simplex viruses establish a latent state, in general, HSV-1 in the trigeminal ganglion and HSV-2 in the sacral ganglion. From time to time, the viruses may be reactivated, resulting in recurrent infections that may or may not be associated with symptoms. HSV-1 is usually transmitted in oral secretions, whereas HSV-2 is most often transmitted through sexual activity. HSV-1 infections occur most frequently during childhood and usually affect body sites above the waist (mouth, lips, eyes, face). HSV-2 infections occur most often during adolescence and adulthood, and involve body sites below the waist (genitalia, buttocks, thighs). Historically, the majority of infections in newborns is transmitted from the maternal genital tract and is usually caused by HSV-2.1 However, because the prevalence of genital infection with HSV-1 in the United States is increasing, a greater proportion of neonatal infections may be due to HSV-1.2,3
Humans are the only natural reservoirs of herpes simplex virus (HSV). Infections caused by HSV have no seasonal predilection; however, geographic location, socioeconomic status, age, and race influence the prevalence of infection. Children of lower socioeconomic classes and those from developing countries contract HSV-1 earlier in life than children of more affluent socioeconomic classes and children from developed countries. Increased direct person-to-person contact occurring in crowded living conditions probably accounts for these differences.
Primary infection with herpes simplex virus type 1 (HSV-1) usually occurs in infancy or childhood, whereas primary infection with herpes simplex virus type 2 (HSV-2) occurs after the onset of sexual activity. Acquisition of infection follows intimate mucocutaneous contact (eg, kissing, sexual intercourse) between a susceptible host and one shedding virus. The incubation period for most HSV infections ranges from 2 to 7 days. More recent seroepidemiologic studies reveal that the prevalence of HSV-1 in the general US population is around 60%, and the prevalence of HSV-2 is approximately 20%.3 In another more recent study, about 25% of children were infected with HSV-1 by the age of 12 years.4
The most devastating form of HSV infection in pediatric patients is neonatal herpes, occurring at an estimated rate of 1 in 3500 to 5000 deliveries. Genital HSV infection in pregnant women is the major source of virus for the newborn. Most infected infants contract HSV at the time of delivery through an infected birth canal.
PATHOGENESIS AND IMMUNITY
Herpes simplex viruses are 150 to 200 nm in diameter and consist of a core of linear double-stranded DNA surrounded by an icosahedral capsid, a fibrillous tegument, and a lipid envelope. There is extensive homology between HSV-1 and HSV-2, rendering serologic distinction difficult. There are at least 60 proteins specified by the virus. Mucocutaneous epithelial cells provide the presumed initial target for viral infection, whereas neural cells in trigeminal and sacral root ganglia constitute the site of latent infection.
Infection of the susceptible host results when herpes simplex virus (HSV) penetrates through abraded skin or mucosal surfaces. After minimal local replication at the site of inoculation, virus migrates along innervating axons to the sensory ganglia where infectious virus is synthesized. Visible lesions result after the virus returns to the inoculation site via peripheral sensory nerves. Vesicular lesions appear between epidermal and dermal layers and contain large amounts of virus, cell debris, and inflammatory cells. When the host is unable to limit viral replication, such as in newborns and the immunocompromised, viremia may result in multiorgan involvement.
Establishment of latency, punctuated by episodes of recrudescence, characterizes infections caused by HSV. During latency, the HSV genome is maintained in a repressed, noninfectious, “static” state. Periodic reactivation of HSV and spread down the neuraxis is associated with the development of recurrent lesions or asymptomatic viral excretion. A number of stimuli, including direct trauma to ganglia, exposure to ultraviolet lights, stress, hormonal changes, administration of immunosuppressive agents, and serious infection, may precipitate recurrent infections.5
The specific immunologic factors that influence the clinical course of HSV infections are not completely understood. Humoral, cell-mediated, and innate immune responses are important in influencing the acquisition of disease, severity of infection, and frequency of recurrences. The important role of antibody in HSV infections is evident by investigations of neonates exposed to HSV at the time of delivery; those exposed to virus in the presence of transplacentally acquired neutralizing antibodies are significantly less likely to contract infection. Humoral immunity also influences the course of HSV infections beyond the neonatal period. For example, antibodies against herpes simplex virus type 1 (HSV-1) reduce the risk of contracting herpes simplex virus type 2 (HSV-2) infection by about 50%, and a first episode of genital infection caused by HSV-2 is less severe in patients with preexisting HSV-1 antibodies than in patients without antibodies.
Table 309-1. Infections Caused by Human Herpes Viruses
Cellular immunity is also critical for the control of HSV infections. Clinically severe HSV infections are more common among patients with compromised cellular immunity than among normal hosts, especially in those with impairment of CD4 T cells.
Patients with genetic defects in specific components of their innate immune system, namely, Toll-like receptor 3 and UNC93-B, have been found to be susceptible to herpes encephalitis.6,7 The recognition of these patients underscores the importance of these immune mechanisms in controlling herpes virus.
Most herpes simplex virus (HSV) infections in normal children are asymptomatic or of mild-to-moderate severity. When associated with symptoms, primary infections tend to be more severe than recurrent infections. In contrast, HSV infections in immunocompromised children, even if recurrent, may result in extensive local disease with substantial attendant morbidity.
Herpes labialis is the most common herpes simplex virus (HSV) infection of childhood, with peak incidence at 1 to 5 years of age. Oral herpes infections are usually caused by herpes simplex virus type 1 (HSV-1); however, oral-genital sexual practices may result in herpes simplex virus type 2 (HSV-2) infection in the oral cavity. Most primary oral infections are subclinical, although careful examination may detect a few oral ulcers (Fig. 309-1). When symptomatic, the severity and sites of lesions vary: buccal mucosa, tongue, palate, and face may be affected; the gums may also be inflamed and bleed readily. Spread of infection from the oral mucosa to the lips, skin around the mouth, and eyes may occur. Children who frequently suck their fingers may develop concomitant infections of their digits (herpetic whitlow). Submandibular adenopathy, high fever, and irritability often accompany symptomatic oral infection. The most common reason for hospital admission is dehydration resulting from reduced eating and drinking.
The lips are the most common site of oral HSV-1 recurrences. Factors associated with recurrent bouts of herpes labialis (cold sores or fever blisters) include intense exposure to sun and/or wind (eg, skiing) and stressful life events. Labial herpes is commonly heralded by a burning sensation or itching 1 to 2 days before lesions develop. In the compromised host, the lips and adjacent facial areas may be involved for prolonged periods. The usual differential diagnosis of herpes labialis includes aphthous stomatitis, herpan-gina, infectious mononucleosis, and impetigo. Pharyngitis, which cannot be distinguished clinically from other viral and bacterial causes of infection, is a common manifestation of primary HSV infection in older children.
Primary and recurrent herpes simplex virus (HSV) infections may cause skin vesicles and ulcers on almost any part of the body. Primary skin infections may be accompanied by deep burning pain, edema, lymphadenopathy, and fever. Vesicles may appear singly or in clusters; they tend to become pustular, crust over, and heal within a week, usually leaving no scars. Herpetic whitlow is an eruption that typically occurs on the fingers (Fig. 309-2). It is often painful, and it is easily confused with bacterial infection. Herpes gladiatorum develops in skin area abraded during the course of wrestling after contact with someone who has oral HSV infection. Skin infections also have resulted from other contact sports such as rugby.
HSV cutaneous infection can be particularly severe among patients with burns, diaper rash, or underlying eczema (eczema herpeticum). Erythema multiforme may be associated with either primary or recurrent HSV. The lesions of erythema multiforme can recur with each recrudescence of herpetic infection.
HSV infections of the skin are sometimes difficult to diagnose, particularly when the patient is not seen until the lesions are crusted or pustular, or when the affected skin area is denuded. When HSV skin lesions assume a dermatomal distribution they may be mistaken for herpes zoster.
FIGURE 309-1. Herpes simplex with multiple oral ulcers. (Source: Reproduced, with permission, from Bondi EE, Jegasothy BV, Lazarus GS, eds. Dermatology: Diagnosis & Treatment. Orginally published by Appleton & Lange. Copyright © 1991 by The McGraw-Hill Companies, Inc.)
FIGURE 309-2. Herpetic whitlow with pustules superimposed on erythema and edema of the finger. (Source: From McPhee SJ, Papadakis MA. Current Medical Diagnosis & Treatment 2010. 49th ed. http://www.accessmedicine.com. Copyright © The McGraw-Hill Companies, Inc. All rights reserved.)
Herpetic involvement of the eye is of particular concern because it can cause loss of vision. Primary infections may be accompanied by conjunctivitis and tender preauricular nodes, with or without associated keratitis. Conjunctivitis sometimes occurs with recurrent infection, but the most common recurrent form is herpetic keratitis. This entity is readily diagnosed clinically because of the characteristic dendritic, branched, fluorescent-staining corneal ulcers. Deeper ocular involvement, including stromal keratitis and iridocyclitis, occurs occasionally. Corticosteroids, in the absence of antiviral drugs, are contraindicated because they may contribute to deeper ocular involvement.
Genital herpes infection is a common sexually transmitted disease, and at least one third of these infections occur in people 19 years old or younger. Herpes simplex virus type 2 (HSV-2) remains the most common cause of genital herpes in the United States, but an increasing proportion is caused by herpes simplex virus type 1 (HSV-1). In some countries, HSV-1 has actually become the predominant cause of genital herpes infections. Seroepidemiologic studies show that 17% of adults in the United States are seropositive for HSV-2; however, only 10% to 25% of people with HSV-2 antibodies have a history of genital herpes. Thus, most genital herpes infections are asymptomatic. When associated with symptoms, primary infections are usually more severe than recurrent infections.8
Over approximately 10 days, genital lesions associated with primary infection evolve from vesicles and pustules to ulcers, and then crust and heal during the subsequent 10 days. Lesions are distributed over the labia majora, labia minora, mons pubis, vaginal mucosa, and cervix in women. In men, lesions are typically found on the penile shaft. Local symptoms of itching and pain may precede visible lesions by 1 to 2 days. Tender inguinal adenopathy typically appears during the second or third week of illness and tends to be the last sign to resolve. Constitutional symptoms, including headache, fever, myalgias, and backache, often accompany symptomatic primary genital herpes infection. Extragenital complications of primary HSV infections include aseptic meningitis, mucocutaneous lesions beyond the genital area, pharyngitis, and visceral dissemination.
Most recurrences of genital herpes are asymptomatic. About 50% of individuals with symptomatic recurrences have local prodromal complaints for several hours to 3 days before the appearance of visible lesions. Sparse genital lesions typically increase in size over the first 3 days, reach a plateau at 6 days, and resolve rapidly. Factors implicated in precipitating recurrences include emotional stress, menses, and sexual intercourse. Of note, about 1% of individuals previously infected with HSV-2 have active viral shedding without symptoms on any given day.9
Herpes simplex virus (HSV) infections are associated with a variety of neurologic manifestations, including encephalitis, meningitis, radiculitis, and myelitis. HSV is the most important cause of life-threatening sporadic encephalitis; almost 75% of patients die if untreated. Beyond the newborn age group, HSV encephalitis is caused by herpes simplex virus type 1 (HSV-1).
Infections in Patients with Compromised Immunity
Herpes simplex virus (HSV) infection may cause severe localized disease, contiguous infection (eg, esophagitis or pneumonia in those with oral infection), or, rarely, disseminated infection in immunologically impaired persons, such as those with malignancy, congenital immunologic deficiencies, or AIDS, and in severely malnourished children. The basic defect common to these conditions has not been ascertained, although a common denominator may be a defect in cellular immunity.
Infections in the Neonate
Herpes infections in the neonate may be localized or disseminated. At onset, about 40% of infections are localized to the skin, eyes, and mucosa (SEM), 35% are localized to the central nervous system (CNS), and 25% are disseminated.
Neonatal SEM infection typically presents during the first 1 to 2 weeks of life. Skin lesions characteristically evolve rapidly from macules to vesicles on a red base, but rapid ulceration and skin denudation may confuse the diagnosis. Skin lesions tend to appear at sites of trauma such as the site of attachment of fetal scalp electrodes, the margin of the eyes, or over the presenting body part. Herpes simplex virus (HSV) infection should be considered whenever any vesicle appears on a neonate. Lesions of mucous membranes other than the eye are not common initial sites. Involvement of the eye may be unilateral or bilateral. Conjunctivitis, keratitis, or chorioretinitis may occur. Outcome of SEM disease is excellent if diagnosis is made promptly and antiviral therapy is administered. However, if untreated, SEM infection can progress to encephalitis or disseminated disease in 75% of cases. Recurrent skin lesions commonly occur periodically throughout the first 1 to 2 years of life.
Patients with HSV encephalitis often present with fever, lethargy, irritability, and seizures. Untreated, CNS disease has a mortality of 50%. Although high-dose acyclovir therapy has resulted in a marked decrease in mortality, many surviving infants have significant neurologic impairment.
Disseminated HSV infection is associated with sepsis and coagulopathy. It is often indistinguishable from neonatal bacterial sepsis. In addition to hypoxemia, coagulopathy, and hepatitis, significant respiratory compromise can occur. Chest radiographs are characterized by a diffuse, interstitial pattern that can progress to hemorrhagic pneumonitis.10 Despite high-dose acyclovir therapy, mortality is still ∼30%.
The definitive diagnosis of herpes simplex virus (HSV) is made by viral culture. HSV can be readily isolated in a number of tissue-culture systems, and cytopathic effects can be detected within 1 to 2 days. The presence of intranuclear inclusions and multinucleated giant cells seen in Papanicolaou-stained smears, or in Tzank preparations of cells obtained by scraping the base of a suspicious lesion, support the diagnosis of HSV infection. However, because these morphologic tests are only about 67% as sensitive as virologic methods, they should not be relied on in the management of potentially life-threatening infections. Immunofluorescence methods are much more sensitive than histologic methods for diagnosing HSV infection and are more rapid than viral culture.
Polymerase chain reaction (PCR) is a very sensitive technique for amplifying HSV DNA from cerebrospinal fluid and other body secretions. Laboratory standardization and false-positive reactions are potential challenges to the interpretation of polymerase chain reaction results.
Many serologic assays demonstrate antibodies to HSV. A primary infection is diagnosed by finding no HSV antibodies in the acute serum and a detectable HSV titer in the convalescent serum obtained after at least 1 week. A fourfold rise in titer may be observed with recurrent infections, and does not distinguish between primary and recurrent infection. IgM or IgA antibodies cannot be used to diagnose primary HSV infection because such antibodies also can be found with recurrent infections.
The similarity of herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) proteins produces extensive cross-reactivity of antibodies to these viruses in older serologic assays. However, more recently the US Food and Drug Administration (FDA) approved glycoprotein G-based type-specific assays, which reliably distinguish HSV-1 and HSV-2 antibodies. Because the clinical diagnosis of genital herpes is unreliable, these newer serologic tests are a useful tool in confirming infection with HSV.11
PREVENTION AND TREATMENT
Certain preventive measures can be used to reduce the likelihood of contracting herpes simplex virus (HSV) infection. For example, exposure of neonates to active maternal genital HSV infection may be reduced by cesarean delivery, especially if performed before or soon after rupture of membranes. Precautions should also be taken to prevent postnatal contact between a neonate and caregivers with nongenital herpetic lesions. Infants with suspected neonatal herpes should be isolated.
Treatment with antiviral agents for herpes simplex infections depends on the severity of infection and underlying host factors. Dosages for common treatment scenarios can be found in Table 245-1. In general, primary herpes simplex infections are more serious and may require more aggressive treatment. Recurrences are usually self-limited, although treatment can reduce duration of symptoms and viral shedding. Mild gingivostomatitis requires no therapy other than maintenance of proper oral hygiene and perhaps the application of a topical anesthetic. If these infections are severe, antiviral therapy with acyclovir may be indicated. Orally administered acyclovir, valacyclovir, or famciclovir is effective in the treatment and prevention of genital HSV infections. In addition, these agents can be used for treatment and suppression of recurrent genital lesions.12 Consultation with an ophthalmologist is advisable for children with ocular herpes. Systemic administration of high-dose acyclovir has been shown to reduce the mortality and morbidity of HSV encephalitis and neonatal herpes. Similarly, HSV infections in immunocompromised hosts should be treated with intravenous acyclovir.