Herpes Simplex Virus

Herpes Simplex Virus

PART III  Etiologic Agents of Infectious Diseases SECTION B  Viruses 204 Herpes Simplex Virus David W. Kimberlin and Charles G. Prober 1056 Herpes...

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PART III  Etiologic Agents of Infectious Diseases SECTION B  Viruses

204 Herpes Simplex Virus

David W. Kimberlin and Charles G. Prober

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Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) belong to the Alphaherpesvirinae subfamily of herpesviruses.1 The large DNA viruses have a short reproductive cycle, rapidly produce lytic infection in tissue culture, and remain latent in sensory neural ganglia. After infection of the oral mucosa, usually by HSV-1, the virus becomes latent in the trigeminal ganglia. After genital infection by HSV-2 or HSV-1, the latent virus remains in the sacral ganglia. In common with other herpesviruses, the HSV core of linear, doublestranded DNA is contained within an icosahedral capsid that consists of 162 capsomeres. The capsid is surrounded by a tightly adherent membrane of tegument protein and a phospholipid-rich envelope. The complete virion has an approximate diameter of 110 to 120 nm. Complete DNA sequencing demonstrates a greater than 90% homology between HSV-1 and HSV-2. The HSV genome encodes at least 84 different polypeptides. They include glycoproteins embedded in the viral envelope; capsid proteins; DNA polymerase, protein kinase, and other viral enzymes; DNA-binding proteins involved in viral replication; and many other proteins with poorly understood biologic functions.2 Attachment of HSV to cell surface receptors initiates infection. After attachment, the HSV envelope fuses to the plasma membrane, allowing the viral capsid to be transported to the nucleus, where the viral DNA is released. Transcription, DNA synthesis, capsid assembly, DNA packaging, envelopment, and release of new viral progeny ensue in infected cells.2 Several viral surface glycoproteins are important determinants of virulence. For example, glycoprotein B (gB) and gC mediate cellular attachment, gD is required for viral entry into cells, and gE is required for efficient expression of late genes, and with gI, it forms a potent Fc receptor.2 The first set of viral gene products to be synthesized includes the six immediate early (IE) proteins; five of the IE proteins regulate the reproductive cycle of the virus, and one blocks the presentation of antigenic peptides on the cell surface. The second set of proteins produced comprises the early proteins. These proteins, which include thymidine kinase and DNA polymerase, primarily are responsible for viral nucleic acid synthesis and are the main targets of the antiviral therapeutic drugs. The third set of proteins, known as late proteins, assembles to form the capsid and tegument. These proteins ultimately facilitate viral envelopment.

in multiorgan involvement. Disseminated clinical infection occurs most often in neonates and patients with compromised immune systems, including pregnant women, but it also occurs rarely in immunocompetent hosts. Establishment of lifelong latency, interrupted by periods of recrudescence, is an important feature of HSV infections. Maintenance of the latent state probably depends on several factors, including the number of neurons infected during the primary episode, the number involved with each reactivation, and the possible incremental involvement of additional neurons with each recurrent episode.5 During latency, the HSV genome is maintained in a repressed, noninfectious, static state. Transcriptional latency patterns of HSV-1 and HSV-2 are similar.6 The molecular basis of latency and reactivation involves the active expression of only a single diploid gene encoding latency-associated transcripts.7 Maintenance of the virus in this nonreplicating state does not compromise the survival and normal function of host ganglion cells. Periodic reactivation of HSV and centrifugal spread down the neural axon are associated with the development of recurrent lesions (i.e., clinically apparent disease) or asymptomatic viral excretion (i.e., asymptomatic infection). Several stimuli can precipitate reactivation from a latent state, including manipulation of nerve roots, direct trauma to ganglia or the skin or mucosa innervated by peripheral nerves, exposure to ultraviolet light, stress, hormonal changes such as those accompanying menses, administration of immunosuppressive agents, and illness from another cause. The likelihood of viral reactivation is related to virus type and the interaction between the virus and the host’s immunologic systems. Viral reactivation from latency is common after primary orolabial infection with HSV-1 and after genital infection with HSV-2. In contrast, when primary orolabial infection is caused by HSV-2 or primary genital infection is caused by HSV-1, recurrences are less common, reflecting the adaptation achieved by these two viruses for their usually preferred areas of the body. For example, less than 25% of people have recurrences after first-episode infections of the genital tract caused by HSV-1, whereas more than 60% have recurrences after genital HSV-2 infections.7,8 The likelihood that recurrences are associated with symptoms depends on the quantity of reactivated virus, virus-cell interactions, and host immune factors.

PATHOPHYSIOLOGY

IMMUNITY

Infection of the susceptible host occurs when virus penetrates through abraded skin or mucosal surfaces. It is hypothesized that HSV enters cutaneous neurons after minimal replication at the site of inoculation and then migrates along innervating axons to the sensory ganglia, where infectious virus is produced.3 Visible lesions result when virus subsequently travels back to the inoculation site through peripheral sensory nerves, replicates, and destroys epithelial cells.4 Histology of skin lesions shows sequential changes of balloon degeneration of infected cells, with condensation of nuclear chromatin, degeneration of cell nuclei and plasma membranes, and formation of multinucleated giant cells. Initially, vesicular lesions appear between epidermal and dermal layers and contain large amounts of virus, cell debris, and inflammatory cells. As additional inflammatory cells are recruited, pustular lesions replace vesicles, and healing ensues. Mucosal membrane lesions are more ulcerative than skin lesions, because the thin layer of epithelium in mucosal lesions ruptures readily. Histologic changes observed in primary infection usually are more severe than those of recurrent episodes. Occasionally, spread occurs beyond the dorsal root ganglia or the localized mucocutaneous eruption, leading to generalized infection. When the host is unable to contain viral replication, viremia can result

The immune response to HSV is initiated as a containment strategy and continues as a curative strategy.9 The usual result in normal hosts is the localization of virus to a limited anatomic area with neutralization of infectivity, followed by establishment of latency. Despite extensive investigation, specific immunologic factors that modulate the clinical course and outcome of HSV infections remain incompletely understood. Although HSV infections tend to be more severe in patients with cellular rather than humoral immunodeficiencies, both antibody- and cellmediated responses are important in influencing the acquisition of disease, the severity of infection, and the frequency of recurrences.10 The important role of antibody in HSV infections is evident from investigations of neonates exposed to HSV at the time of delivery. Those exposed to HSV-2 in the presence of transplacentally acquired neutralizing antibody are significantly less likely to contract infection11 and, if infected, usually have localized disease manifesting later in the neonatal period.12 Titers of antibodies that mediate antibody-dependent cellular cytotoxicity (ADCC) correlate inversely with severity of neonatal infection.13 Humoral immunity also seems to be relevant to the pathogenesis of HSV infections beyond the neonatal period. For example, HSV-1

Herpes Simplex Virus

seropositive stem cell transplant recipients who have HSV-1 seropositive donors have shorter and less frequent episodes of HSV-1 infection than do those who have HSV-1 seronegative donors.14 Low levels of mononuclear cell ADCC activity in patients with leukemia correlate with greater susceptibility to HSV infections.15 Antibodies against HSV-1 provide partial protection against HSV-2 infection. Prior HSV-1 infection reduces the risk of contracting HSV-2 infection by about 50%,16 and a first episode of genital infection caused by HSV-2 is less severe if people have preexisting HSV-1 antibodies.17 Investigations focused on local defense mechanisms have identified the protein targets of antibodies to HSV and their appearance in mucosal secretions.18 These studies underscore the role of humoral immune response in HSV infections. It is well established that the cellular immune response is critical for the control of HSV infections, but which HSV antigens are the most important inducers of protective responses remains unknown. Substantially diminished HSV antigen-stimulated lymphocyte proliferation and reduced interferon production are observed in infected neonates and postpartum women compared with responses in nonparturient adults.19

EPIDEMIOLOGY Most infections caused by HSV are asymptomatic or nonspecific. Defining the epidemiology of HSV has depended on seroepidemiologic studies, which initially were confounded by extensive antigenic similarities between HSV-1 and HSV-2. The development over the past 2 decades of commercially available, type-specific assays for antibodies unique to HSV-1 and HSV-2 has provided a means of reliably determining prior infection with each virus.20 Beyond the neonatal period, primary infection with HSV-1 usually occurs in infancy or childhood, whereas primary infection with HSV-2 occurs after the onset of sexual activity. HSV infections occur throughout the world, with humans serving as the only reservoir. Acquisition of virus follows intimate mucocutaneous contact between a susceptible host and a person who is shedding virus during primary infection or reactivation. Because HSV infection results in lifelong latency, the prevalence in any population is cumulative. Because transmission and acquisition of virus usually occur in the absence of symptoms, the spread of infection throughout a population can be silent. These factors account for worldwide endemic HSV infection. Infections caused by HSV have no seasonal predilection, but geographic location, socioeconomic status, age, and race influence the prevalence of infection in most studies.3 Data from the United States and other industrialized countries document a decline in HSV-1 seroprevalence among adolescents over the past 1 to 2 decades due to improvements in living conditions, better hygiene, and less crowding.21–25 Despite these declines, HSV-1 infection remains more common among non-Hispanic US blacks and Mexican Americans than among non-Hispanic US whites and among respondents with lower than higher incomes.26,27 Approximately one third of children from lower socioeconomic populations and 20% from middle-income populations have serologic evidence of HSV infection by 5 years of age. Prevalence rises in lower socioeconomic populations to more than three fourths by adolescence, although not in middle-income populations until the second or third decade of life. Beginning in the mid-1960s, population-based studies of genital herpes revealed a rising incidence of clinically evident genital disease, with most first infections occurring in those 18 to 36 years of age.28 Estimating the prevalence of HSV-2 infection on the basis of clinically apparent genital disease has major limitations of misclassifying HSV-1 genital infections29–32 and missing most HSV-2 infections, which are inapparent.33 Population-based serosurvey studies, which have used type-specific assays that reliably detect antibodies to HSV-2, demonstrated an increase of more than 30% in the prevalence of HSV-2 infections between the late 1970s and the early 1990s.34 Subsequently, HSV-2 seroprevalence in the United States has decreased, and the current seroprevalence of HSV-2 among young adults is 10% to 20%.22 Age, race, sex, and history of other sexually transmitted infections (STIs) affect seroprevalence rates. HSV-2 infection rates are comparatively higher among blacks, women, and persons attending STI clinics.34 Seroprevalence of HSV-2 among pregnant women has ranged consistently from 15% to 30%.35

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Transmission of HSV-2 typically results from contact with an asymptomatic sexual partner. In one study evaluating contacts of 66 people who had genital herpes, only one third of source partners reported recent genital herpetic lesions, one third described genital symptoms that were atypical of genital herpes, and one third had no prior symptoms.36 In another prospective study evaluating 144 heterosexual partners in whom one partner was seronegative and the other had symptomatic, recurrent genital HSV, 70% of all transmissions resulted from contact during periods of asymptomatic viral shedding.37 The reported risk of acquisition of infection in these cohorts is approximately 10% per year.37,38

CLINICAL SYNDROMES Orolabial Infection Primary Infection Most HSV infections occurring above the waist are caused by HSV-1 and are localized to the mouth and oropharynx (Fig. 204.1). Limited data suggest that only about 10% to 30% of cases of perioral HSV infections in children are associated with signs and symptoms of illness.39,40 The classic clinical presentation of primary herpetic gingivostomatitis as extensive orolabial HSV lesions with primary HSV infection in the young child is an unusual manifestation. When symptomatic disease occurs, high fever, irritability, tender submandibular lymphadenopathy, and mucocutaneous eruption evolve after a mean incubation period of 3 to 4 days. Detection of HSV DNA in the blood by polymerase chain reaction (PCR) occurs in about one third of symptomatic children.41 Vesiculoulcerative lesions can involve the palate, gingiva, tongue, lip, and facial area.42,43 Intraoral edema and pain are associated with lesions that evolve from vesicles to shallow ulcers on an erythematous base. The most common reason for hospital admission with primary gingivostomatitis is dehydration resulting from impaired eating and drinking. The duration of symptoms in primary gingivostomatitis ranges from 2 to 3 weeks. Pharyngitis is a common manifestation of primary HSV infection in older children and adults. HSV has been isolated from the posterior pharynx of 5% to 24% of college students with pharyngeal symptoms.44,45

FIGURE 204.1  Toddler with 3 days of high fever and poor intake has typical herpes simplex virus vesicoulcerative lesions on the tongue and cluster of vesiculobullous lesions below the lip. (Courtesy of J.H. Brien ©.)

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PART III  Etiologic Agents of Infectious Diseases SECTION B  Viruses

HSV pharyngitis cannot be distinguished clinically from other viral and bacterial infections. Common manifestations of illness are pharyngeal erythema, exudative or ulcerative lesions on the posterior pharynx and tonsils, enlarged cervical lymph nodes, and fever.44,45

Reactivation of Infection Reactivation of HSV from the trigeminal ganglia usually is not associated with clinical findings. It is estimated that silent excretion of virus in healthy, previously infected people occurs on about 1% of days for children and 5% to 10% of days for adults.46 Reactivation of infection commonly follows manipulation of the trigeminal nerve route,47 dental procedures,48 or stimuli such as fever, ultraviolet radiation, or exposure to the sun.49,50 The frequency of recurrences varies, but on average, approximately one third of people with prior infection have clinically evident recurrences.51 Signs and symptoms associated with clinical recurrences usually are mild.52 Many patients have prodromal symptoms of pain, burning, or tingling that precede the eruption by 1 to 2 days. The most common site of recurrent orolabial lesions is the outer edge of the vermilion border. On average, three to five lesions are seen. Lesions begin as vesicles, evolve into pustules or ulcers in 1 to 2 days, and heal completely within 8 to 10 days. Pain is greatest at the onset of eruption and resolves within 4 to 5 days. Unilateral clusters of lesions can occur on skin along trigeminal nerve distribution, with or without conjunctivitis (see Fig. 82.1 in Chapter 82). Viral excretion and infectivity last only 2 to 3 days; the titer of virus varies from less than 10 plaque-forming units (PFUs)/mL in the prodromal phase to almost 105 PFUs/mL in the vesicular phase.

Genital Infection Familiarity with the serologic classification of genital herpes infection is important for understanding of the biologic and clinical features of the disease.53 When a person with no prior HSV-1 or HSV-2 antibody acquires either virus in the genital tract, a first-episode primary infection results. If a person with preexisting HSV-1 antibody acquires HSV-2 genital infection, a first-episode nonprimary infection ensues. Viral reactivation from latency and subsequent antegrade translocation of virus to skin and mucosal surfaces produces a recurrent infection, which presupposes preexisting homologous antibody to the reactivating HSV. Historically, most first-episode genital herpes infections were caused by HSV-2. However, an increasing proportion, especially among young adults, is caused by HSV-1.29–32 Whereas only 5% to 10% of adults in the United States have a history suggesting prior genital herpes infection, seroepidemiologic studies show that approximately one in five people 30 to 39 years of age and one in four persons 40 to 49 years of age have been infected with HSV-2.22 Seroprevalence rates exceed 40% among attendees of US STI clinics, with comparatively higher rates for women and blacks.54

First-Episode Primary Infection About 40% of men and 70% of women seeking medical care for primary genital herpes have constitutional symptoms. Headache, fever, myalgia, and backache develop after a mean incubation period of 7 days. Symptoms peak within 4 days of onset of lesions and gradually abate over 7 to 10 days. Local symptoms such as itching and pain usually precede visible lesions by 1 to 2 days. New lesions appear over 7 to 8 days. Lesions evolve from vesicles and pustules to wet ulcers over approximately 10 days and then crust and heal during the ensuing 10 days. Lesions are distributed over the labia majora, labia minora, mons pubis, vaginal mucosa, and cervix in women. In men, lesions typically occur over the shaft of the penis. About 85% of women have vaginal discharge, and 25% of men have urethral discharge. More than 80% of women and more than 40% of men have dysuria for 7 to 10 days. Tender inguinal lymphadenopathy typically appears during the second or third week of illness in about 80% of both sexes and usually is the last sign to resolve. Mean duration of viral shedding is 11 days. Extragenital complications of primary HSV infections include aseptic meningitis, mucocutaneous lesions beyond the genital area, pharyngitis, and visceral dissemination. These complications are more common in women than in men.17

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First-Episode Nonprimary Infection Almost one half of people with their first clinical outbreak of genital herpes have preexisting antibodies to the heterologous herpes virus. Presumably as a result of the preexisting immunity to shared HSV antigens, these people have lower frequencies of systemic symptoms and extragenital complications, fewer lesions, shorter duration of pain, and more rapid healing than patients with primary infections.17

Recurrent Infection Most recurrences of genital herpes are asymptomatic. About 1% of people previously infected with HSV-2 have active viral shedding without symptoms on any given day.55 Shedding of HSV from the genital tract occurs in people seropositive for HSV-2, even if they have no prior history of genital herpes.56 Average duration of episodes of asymptomatic viral shedding is 1.5 days, but it can be as short as a few hours.57 Recurrent clinical genital herpes usually is mild, with constitutional symptoms in only 5% of men and 10% of women. Of those who have symptoms, more than 40% of women and more than 50% of men have local prodromal symptoms for several hours to 3 days.17 Genital lesions, which usually are few and confined, typically increase in size over the first 3 days, reach a plateau at 6 days, and resolve rapidly. Mean time to complete healing is 9 to 10 days, and duration of viral shedding is 4 days. Tender lymphadenopathy, dysuria, vaginal discharge, and systemic complications occur less commonly. Factors implicated in precipitating recurrences include emotional stress, menses, and sexual intercourse. Genital shedding of HSV-2 in women as determined by PCR is increased in the setting of hormonal use, bacterial vaginosis, and high-density vaginal colonization with group B Streptococcus.58

Keratoconjunctivitis Ocular herpes infection beyond the neonatal period usually is caused by HSV-1. Approximately 300,000 cases of HSV infection of the eyes are diagnosed each year in the United States.3 Infection involves one or both eyes, with a typical course of follicular conjunctivitis associated with pain, photophobia, and tearing and followed by chemosis, periorbital edema, and preauricular lymphadenopathy.59 Periocular skin involvement can occur. As infection progresses, diffuse punctate lesions occur on the cornea, followed within days by the appearance of serpiginous ulcers. Pathognomonic branching dendritic lesions (see Figs. 82.1, 82.2, and 82.3 in Chapter 82) of the cornea appear and are associated with blurred vision. Deeper stromal structures can be injured, especially after injudicious use of topical corticosteroids. Healing can require more than 1 month. After primary ocular HSV infection, recurrences are observed in about one third of people during the ensuing 5 years. Recurrences can include reappearance of dendritic ulcerations or deep stromal injury that can threaten sight.

Cutaneous Infections HSV can infect skin outside the perioral and genital areas. Infection of the pulp or nail bed of the finger is a typical site and is referred to as herpetic whitlow. Whitlow is most common in medical and dental professionals, in whom it results from digital contamination with genital and oral secretions, respectively.60,61 Young children have herpetic whitlow as a result of autoinoculation of HSV-1 during primary oral herpes infection or when an infected adult inoculates the virus while trimming the child’s nails by biting them62 (Fig. 204.2). In adolescents and adults, herpetic whitlow usually follows autoinoculation from genital secretions during first-episode HSV-2 infection.63 Discrete vesicular or pustular lesions arise over the distal phalanx and coalesce over several days, frequently appearing purplish and dusky. Infection is associated with local tingling, burning pain, erythema, and edema, and it can be accompanied by fever, lymphangitis, and tender swelling of related lymph nodes. Lesions often are confused with bacterial cellulitis. Surgical intervention is contraindicated. Crusting of the lesions occurs after about 10 days and is followed by healing and reappearance

Herpes Simplex Virus

FIGURE 204.2  Herpetic whitlow due to herpes simplex virus type 1 (HSV-1) in an infant whose mother trimmed his nails with her teeth. (Courtesy of S.S. Long.)

of normal skin. Lesions recur but at rates lower than those observed with oral or genital disease. HSV-1 causes cutaneous infection among athletes participating in contact sports, such as wrestling and rugby, referred to as herpes gladiatorum and scrum-pox, respectively.64,65 Viral inoculation results from close contact between oral secretions and abraded skin.66 Surveys of athletic trainers suggest that this infection is endemic among young competitive wrestlers.67 In the largest outbreak of herpes gladiatorum reported, infection was diagnosed in 60 high school wrestlers68; 73% of infected wrestlers had lesions on the head, 42% on the extremities, and 28% on the trunk. About 25% of the infected boys had fever, chills, and headache, and 40% had sore throat. Herpes infections of skin damaged by diaper dermatitis, thermal burns, or atopic dermatitis/eczema (i.e., eczema herpeticum) can be particularly severe.69–71 Rapidly spreading eruptions and visceral dissemination can occur. HSV is the most commonly recognized precipitating factor for recurrent erythema multiforme and is identified as the precipitant in about one fourth of cases.72 In one study, HSV type-common glycoprotein antigen (i.e., crude antigen) was found in 12 of 16 skin biopsy specimens of erythema multiforme lesions.73

Central Nervous System Infections HSV causes a variety of central nervous system (CNS) illnesses during and after infection. Self-limited aseptic meningitis occurs after firstepisode genital infection. HSV is the most common cause of sporadic fatal encephalitis, accounting for approximately 10% to 20% of viral encephalitis cases in developed countries.74,75 Beyond the neonatal period, HSV encephalitis typically is caused by HSV-1. Encephalitis has a biphasic age predilection, with about one third of cases occurring in people younger than 20 years of age and approximately one half of cases occurring in people older than 50 years of age. Encephalitis can occur as a result of primary (~25%– 33% of cases) or recurrent infection (~67%–75% of cases).76–78 Typically, patients have fever, altered consciousness, unusual behavior, and focal neurologic abnormalities, with signs and symptoms consistent with temporal lobe involvement. Although antiviral therapy has resulted in a dramatic decrease in mortality rates, a substantial number of survivors are left with various degrees of neurologic impairment, including cognitive deficits, behavioral disorders, and recurrent seizures. Patients with HSV encephalitis may have an increased number of red blood cells in cerebrospinal fluid (CSF); counts greater than1000/mm3 are common, and counts greater than 25,000/mm3 have been observed.70 This “hemorrhagic encephalitis” historically suggested HSV encephalitis and was related to HSV’s propensity to cause damage across tissue planes,

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including across blood vessel walls. With earlier diagnosis of HSV encephalitis due to heightened awareness and improved diagnostic testing, CSF red blood cells are seen less often than in the 1970s and 1980s. The CSF usually has a few hundred white blood cells (WBCs)/mm3, with a predominance of lymphoid cells (75% to 100%). However, pleocytosis varies from a few to more than 1000 WBCs/mm3, and occasionally neutrophils predominate; 10% to 20% of CSF specimens can be acellular, especially if obtained early in the disease.79 Protein concentration is normal in about one half of CSF specimens obtained during the first week of illness, but thereafter, concentrations as high as 500 to 1200 mg/ dL are observed.79 Production of HSV-specific antibody in the CNS occurs by the second week of illness, resulting in an increased ratio of CSF-to-serum concentration of HSV antibody.79 Virus can be isolated from culture of CSF in approximately 4% of cases.77 The finding of HSV DNA in CSF, identified by PCR testing, is sensitive and specific for the diagnosis of HSV encephalitis80 and has revolutionized confirmation of infection by eliminating the need for brain biopsy. However, CSF obtained before the third day of illness can be falsely negative by PCR.81,82 If the index of suspicion remains high for HSV encephalitis, a repeat lumbar puncture for CSF analysis by PCR should be performed. Electroencephalography typically reveals focal spike and slow-wave abnormalities early in the course of HSV encephalitis. A characteristic finding is paroxysmal lateralizing epileptiform discharges (PLEDs). Neurodiagnostic images can be normal at the onset of infection, followed within days by development of edema associated with focal infection or hemorrhagic necrosis. Magnetic resonance imaging is a more sensitive early test than computed tomography (Fig. 204.3).83 Several unusual CNS manifestations attributed to HSV have been described. They include recurrent aseptic meningitis (i.e., Mollaret meningitis), brainstem encephalitis, ascending myelitis, parainfectious encephalomyelitis (i.e., acute disseminated encephalomyelitis), and encephalomyeloradiculitis.84 HSV has been implicated in the pathogenesis of several other neurologic syndromes, including Bell palsy, atypical pain syndromes, trigeminal neuralgia, vestibular neuritis, and temporal lobe epilepsy.

Other Infections Unusual clinical manifestations of HSV have been described in immunocompetent hosts. They include visceral dissemination, esophagitis, tracheobronchitis, pneumonitis, and hepatitis. Viremia with visceral dissemination can result in infection of any organ. Beyond the neonatal period, disseminated infection is more common in adults, especially pregnant women, than in children. Isolated esophageal involvement has been described in some patients, with a mean age of 35 years.85 Most infections were caused by HSV-1, and most were primary. Symptoms suggesting esophageal HSV include retrosternal chest pain and odynophagia. Necrotizing and exudative tracheobronchitis due to HSV can precipitate bronchospasm, often necessitating mechanical ventilation. Most reported cases have involved elderly adults or immunocompromised hosts.86 HSV pneumonitis can result from spread down the tracheobronchial tree, extension from esophageal involvement, or hematogenous dissemination. Hepatic infection caused by HSV rarely occurs in normal hosts but rather affects neonates, pregnant women, and persons with underlying conditions.87 Infection usually is fulminant in nature, with death commonly ensuing as a result of severe hepatic necrosis and consequent uncontrolled liver failure and coagulopathy. Acute retinal necrosis can occur as a reactivation-immunologic event. It has been reported as long as 9 years after a perinatally acquired infection.88

Intrauterine and Perinatal Infections Congenital (in utero) infection due to intrauterine exposure to HSV is rare.89–91 Manifestations of congenital infection usually include the triad of cutaneous manifestations (e.g., active skin lesions, scarring from old lesions), ocular involvement (e.g., chorioretinitis, microphthalmia), and CNS abnormalities (e.g., microcephaly, hydranencephaly). Hydrops

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A

illness with onset after this time is unlikely to be caused by perinatally acquired HSV. Approximately 25% of neonatal HSV infections involve visceral organs (e.g., liver, lungs, bone marrow) with or without brain involvement (i.e., disseminated disease), whereas the other two manifestations by definition do not have dissemination. They are brain involvement with or without skin lesions (i.e., CNS disease), occurring in approximately 30% of neonatal HSV cases, and infection limited to the skin, eyes, and mouth (i.e., SEM disease), occurring in approximately 45% of cases.95 SEM disease (see Fig. 204.4) typically manifests during the first 2 weeks of life. Skin lesions tend to appear at sites of trauma, such as the site of attachment of fetal scalp electrodes, the bulb syringe trauma site on palatal mucosa, the margin of the eyes, or at a circumcision site or over the presenting body part. Lesions evolve rapidly from macules to vesicles on an erythematous base. HSV infection should be considered whenever any vesicle appears on a neonate. The outcome of SEM disease is excellent if the diagnosis is made promptly and antiviral therapy is initiated. When the disease is not treated, about 80% of cases progress to disseminated or CNS disease.95,96 HSV infection of the CNS tends to manifest slightly later in the neonatal period than other categories of neonatal HSV infection. Typically, fever and lethargy appear between 2 and 3 weeks of age, followed by the onset of seizures, which can be focal and difficult to control; skin lesions exist in about 35% to 40% of cases at the time of presentation. Some infants who come to medical attention quickly have only nonspecific signs and symptoms. In 8 of 8 cases, patients were younger than 14 days of age in one retrospective study,97 and 15 of 16 were younger than 21 days of age in another.98 CSF examination usually reveals a mild pleocytosis (50–400 WBCs/ mm3, predominantly mononuclear), a slightly reduced glucose level, and a modestly to markedly elevated protein concentration (500–1000 mg/ dL). The electroencephalogram typically is abnormal diffusely. Computed tomography can be normal early in the course of CNS disease; magnetic resonance imaging is a more sensitive study. Temporal lobe involvement is typical, but diffuse infection can occur. Without therapy, one half of neonates with CNS HSV infection die, and most survivors sustain severe neurologic impairment.99 Disseminated neonatal HSV infection often mimics severe bacterial infection, with onset typically occurring during the first 2 weeks of life. Common clinical findings include cardiovascular instability, hepatomegaly, jaundice, bleeding, and respiratory dysfunction. Almost 60% of patients have skin lesions at some time during their illness, but lesions often are absent at the onset of symptoms. Progression of infection is rapid, with death caused by unremitting shock, progressive liver failure, bleeding, respiratory failure, or neurologic deterioration.96

Infection in Compromised Hosts B FIGURE 204.3  (A) Axial T2-weighted magnetic resonance imaging (MRI) of a 27-day-old infant with herpes simplex virus type 2 (HSV-2) encephalitis. The image shows edema with necrosis of the temporal lobes bilaterally, with less involvement of parietal lobes. The mother had only a distant history of genital HSV more than 15 years before this pregnancy and no clinical recurrence within recent years. (B) Coronal T1-weighted MRI of a 13-year-old adolescent with acute onset of leftsided seizures due to HSV-1 encephalitis. Notice the right-sided temporal lobe necrosis and edema. (A, Courtesy of S.S. Long. B, Courtesy of J.H. Brien ©.)

fetalis has been reported as a rare manifestation.92 Neonates with in utero HSV infection have disease manifestations apparent within the first 24 to 48 hours of life (Fig. 204.4). Most neonatal HSV infections are perinatally acquired; they result from exposure to virus in the maternal genital tract at delivery.93 The risk of neonatal infection is largely influenced by the HSV antibody status of the mother. About 50% to 60% of neonates exposed to maternal primary infection acquire HSV infection, whereas infection occurs in approximately 2% of those exposed to recurrent infection at delivery.11,94 In neonates, HSV infection manifests in three ways (Table 204.1). Signs of neonatal infection are invariably evident by 4 to 6 weeks of age, and

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HSV infection in immunocompromised hosts is a frequent source of morbidity but is uncommonly fatal. Risk of severe HSV parallels the extent of compromise of cellular immune responses. The most frequent complication of HSV infections among these patients is severe ulcerations that develop on keratinized and nonkeratinized mucosal surfaces.100 Oral and genital lesions progress slowly, with accompanying tissue damage and necrosis. Healing takes an average of 6 weeks. Local cutaneous dissemination can occur. Contiguous mucosal spread of infection can result in esophageal, tracheal, or pulmonary involvement or in visceral dissemination.101

LABORATORY FINDINGS AND DIAGNOSTIC TECHNIQUES Identification of Virus Culture.  Culture is the most specific method for diagnosing an active HSV infection. Samples from skin lesions should be obtained by aspiration of the contents of intact skin lesions, swabbing of the bases of denuded skin lesions, or swabbing of the mucosal sites of prior outbreaks. Premoistened cotton swabs are preferred for collection of specimens for culture because calcium alginate–impregnated swabs inhibit virus isolation.102 If direct inoculation onto culture media at the time of collection

Herpes Simplex Virus

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A

B

C

D

E

F

FIGURE 204.4  Mucocutaneous manifestations of herpes simplex virus (HSV) in the neonate. (A and B) Clusters of vesicular lesions are seen at the scalp electrode site and on the face of an infant. (C) Early skin vesicles are seen in another infant. (D) An infant was discharged from the nursery at 2 days of age with the diagnosis of chemical conjunctivitis. He returned at 8 days of age with keratoconjunctivitis. HSV-2 was isolated from the conjunctiva. (E and F) Infant who was born at 25 weeks’ gestation and 72 hours after rupture of the membranes (i.e., footling presentation) had onset of raised vesiculobullous lesions on day 4 of life, with rapid spread down the leg and ulceration. HSV-2 was recovered from mucocutaneous sites, and polymerase chain reaction (PCR) testing was positive for blood and cerebrospinal fluid samples. (A, B, and C, Courtesy of J.H. Brien ©. D, Courtesy of S.S. Long. E and F, Courtesy of S.G. Pinniti, K.N. Feja, M. Hiatt, and R.W. Tolan, Jr., The Children’s Hospital at Saint Peter’s University Hospital, New Brunswick, NJ.)

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TABLE 204.1  Characteristics of Neonatal Herpes Simplex Virus Infections Feature

Skin, Eye, and Mucous Membrane Infection

Central Nervous System Infection

Disseminated Infection

Usual age at onset

7–14 days

14–21 days

5–12 days

Clinical findings

Vesicles on an erythematous base; conjunctivitis

Lethargy, irritability, fever, seizures

Shock, hepatomegaly, jaundice, bleeding, respiratory distress

Diagnostic testing

Culture of skin lesions, with or without PCR; DFA of skin lesions

Culture of skin lesions, if present, with or without PCR; DFA of skin lesions; indices and PCR on CSF; EEG; neuroimaging studies

Cultures of skin lesions, if present, with or without PCR; DFA of skin lesions; culture of nasopharynx, axillae, rectum

Mortality rate if treated

0%

5%

30%

Sequelae rate if treated

0%

30%

15%

CSF, cerebrospinal fluid; DFA, direct fluorescent antibody test; EEG, electroencephalogram; PCR, polymerase chain reaction.

is not feasible, specimens should be placed into 1 to 2 mL of medium for viral transport. Specimens transported to reference laboratories at room temperature within 3 days yield adequate recovery of HSV.103 For prolonged storage, specimens should be maintained at −70°C. Freezing at −20°C before processing and multiple cycles of freezing and thawing reduce the viability of HSV. The typical cytopathic effect of HSV in vitro is foci of enlarged, refractile cells in the monolayer of a variety of cell culture lines. The time required to observe a cytopathic effect after incubation depends on the concentration of virus in the sample; a cytopathic effect is evident within 24 hours if the sample contains high concentrations of virus and within 4 to 5 days if there is a low concentration. Timing of specimen collection is critical; HSV can be recovered from more than 90% of genital herpes lesions sampled during the vesicular stage but from only about 25% sampled during the crusted stage.104 The availability of HSV-specific monoclonal antibody has facilitated the confirmation of virus isolated and the specification of viral type.105 Specificity of these reagents corresponds well with typing of isolates by restriction enzyme analysis.106 Immunofluorescence.  Rapid, reliable direct methods have been developed to detect HSV in specimens obtained from mucocutaneous lesions. The most commonly used method is direct immunofluorescent staining.106 The best method for specimen collection consists of unroofing a lesion to expose its base, removing cells with the blunt end of a cotton applicator stick, and streaking the sample onto a glass slide. With the use of fluorescein-conjugated monoclonal HSV antibody, direct staining of samples from lesion scrapings is 80% to 90% as sensitive as tissue culture isolation, with few false-positive reactions.105,107 The Papanicolaou stain or Tzanck test no longer should be used to demonstrate cytologic changes in specimens obtained from suspected HSV lesions because these methods are less sensitive and nonspecific.96 Polymerase Chain Reaction.  PCR amplification of HSV DNA is a sensitive and specific diagnostic technique. The most important application of HSV PCR testing is in the diagnosis of HSV encephalitis. First reported in 1990,108 subsequent studies from several laboratories confirmed the utility of PCR for the diagnosis of HSV encephalitis, with sensitivity and specificity consistently exceeding 90%.80,109,110,111,112,113 PCR testing is considered the gold standard for the laboratory diagnosis of HSV CNS disease.80 PCR testing also is applied increasingly to blood or swab specimens collected from skin or mucosal sites. In one study of 63 infants, 83% had HSV DNA detected in blood, including 64% with CNS disease and 78% with SEM disease.114 Performance characteristics for specimens collected from genital swabs are well defined,115,116 but utility for skin and mucous membrane specimens from neonates suspected of having HSV has not been delineated.117

Serology Before 2000, commercially available serologic assays were unable to distinguish between HSV-1 and HSV-2 antibodies, severely limiting their utility. Several type-specific serologic assays that reliably distinguish between immunoglobulin G (IgG) directed against HSV-1 and HSV-2

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have since been approved by the US Food and Drug Administration. Many of these products are sold as kits that are used by clinical laboratories throughout the United States. Monoclonal antibodies to the unique glycoprotein G (gG) of HSV-2 are used to capture protein from an HSV-infected cell sonicated in a solid-phase enzyme immunoassay or to prepare immunoaffinity-purified antigen for use in a dot blot assay.118 Several additional tests that claim to distinguish between HSV-1 and HSV-2 antibody are available commercially, but high cross-reactivity due to the use of crude antigen preparations limit their utility,119 and their use is not recommended. Serologic tests that detect immunoglobulin G (IgG) antibodies cannot be used to diagnose recurrent HSV infection because a rise in antibody titer does not always occur. Primary infections can be confirmed by documenting seroconversion between acute and convalescent sera. A finding of IgM anti-HSV does not distinguish primary infection because reactivation can cause production of IgM antibody. HSV IgM assays also can have unacceptably high false-positive rates.

TREATMENT Acyclovir or a derivative is the drug of choice for most HSV infections (Table 204.2).120 Available formulations include topical ointment, oral tablets and liquid, and a preparation for intravenous delivery. The mechanisms of action, pharmacokinetics, dosages, and toxicities are detailed in Chapter 295.

Orolabial Infection In a study of 72 children with documented HSV primary herpetic gingivostomatitis, those who received oral acyclovir compared with placebo had a shorter duration of oral lesions (4 vs. 10 days) and earlier disappearance of fever, extraoral lesions, and drinking and eating difficulties. Duration of viral shedding also was significantly shorter in the group treated with acyclovir (1 vs. 5 days).121 Topical and oral acyclovir regimens have been evaluated in the treatment of recurrent herpes labialis. Topical acyclovir is not effective, and oral acyclovir, even when administered immediately at the onset of symptoms, affords marginal benefit in immunocompetent hosts.122,123 Prophylactic administration of oral acyclovir may be useful in persons with frequently recurrent herpes labialis. In one randomized, doubleblind, placebo-controlled study, 56 adults who previously experienced more than six recurrent episodes of herpes labialis in a year had a 53% reduction in clinical recurrences while receiving suppressive therapy with oral acyclovir.124 Oral acyclovir also has had some benefit in reducing the extent of herpes labialis outbreaks in people who are prone to recurrences as a result of precipitants such as ultraviolet light exposure49 and alpine skiing.50

Genital Infection Acyclovir is useful in the management of patients with genital herpes, affording greatest benefit in first-episode primary infections and least benefit in recurrent genital herpes.125,126 Valacyclovir and famciclovir, two

Herpes Simplex Virus

TABLE 204.2  Systemic Acyclovir Therapy for Herpes Simplex Virus Infections

acyclovir as prophylaxis against recurrent stromal keratitis appears to be effective at reducing long-term scarring from herpes infection.130

Type of Infection

Usefulness of Acyclovir Therapy

Cutaneous Infections

Orolabial

Possibly effective in severe, primary gingivostomatitis

Sparse data exist regarding the treatment of cutaneous HSV infections in the normal host beyond the neonatal period. One study of nine evaluable subjects with recurrent lesions on the hand caused by HSV-2 concluded that oral acyclovir therapy had a beneficial effect on the duration of symptoms, signs, and culture positivity.131 Treatment of cutaneous infections should be considered for burned patients or patients with eczema because infections in these hosts are potentially serious.

Marginally effective in recurrent infections Useful prophylactically in limited circumstances Genital

Effective in treatment of first episode and, to a limited extent, of recurrent infections Effective in suppressing frequently recurrent attacks

Keratoconjunctivitis

Topical therapy beneficial (i.e., vidarabine, trifluridine, or acyclovir)

Cutaneous

Possibly effective in severe eruptions in those with compromised integument (e.g., burns, eczema) Possibly effective in whitlow infections Possibly effective prophylactically in limited circumstances

Central nervous system

Effective in reducing mortality and morbidity of encephalitis

Neonates

Effective in reducing mortality and morbidity rates

Compromised hosts

Effective for therapy of localized and disseminated infections Effective prophylactically against recurrent infection Resistance can emerge during long-term therapy

antiviral agents with superior bioavailability for oral dosing compared with acyclovir, are safe and equally effective as acyclovir in the therapy of genital herpes. Intravenous and oral administrations of acyclovir are more effective than topical therapy for primary and nonprimary first clinical episodes of genital HSV infections.127 Oral administration is preferred for ambulatory patients because it is almost equal in efficacy to intravenous therapy. For primary infection, treatment reduces the duration of viral shedding and the time to complete healing by more than 1 week. In some studies, acyclovir therapy also shortens the duration of new lesion formation, pain, dysuria, and other symptoms. Treatment does not prevent the establishment of latency or reduce the frequency of subsequent recurrences. Acyclovir has a beneficial although less pronounced effect on the course of recurrent genital herpes, resulting in a reduction of viral shedding and time to healing by 1 to 2 days; the effect on pain and itching is less.127,128 Patients who tend to have more severe recurrent attacks, with multiple lesions persisting for more than 1 week, may benefit most from treatment. To ensure maximal benefit of therapy, patients may be provided a prescription for acyclovir tablets with instructions to begin the drug at the first indication of recurrence. Long-term suppressive therapy with acyclovir has substantial value for frequently recurrent genital herpes. Recurrences are reduced by more than 75%, and when lesions occur, they are more likely to be mild. Although the frequency of asymptomatic shedding of HSV is substantially reduced during long-term suppressive therapy, shedding is not eliminated, and sexual transmission of the virus still can occur.129

Keratoconjunctivitis Ocular infections caused by HSV usually are treated topically in conjunction with parenteral therapy in the neonate. Trifluridine or ganciclovir ophthalmic drops or ointment are used commonly (see Chapter 82). Oral

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Central Nervous System Infection In the first study that documented the efficacy of antiviral therapy of a CNS viral disease, vidarabine was shown to significantly improve the outcome of patients with HSV encephalitis.132 The mortality rate was reduced from 70% among placebo recipients to 44% among drug recipients. A subsequent controlled intervention trial determined acyclovir to be superior to vidarabine.76 The mortality rate was reduced from 54% among vidarabine recipients to 28% among acyclovir recipients. Survival was significantly affected by the age of the patient, the Glasgow Coma Scale score, and the duration of disease at onset of therapy. Age and the Glasgow score also significantly influenced morbidity observed 6 months after diagnosis. Outcome was best for those younger than 30 years of age with a Glasgow score greater than10 at the onset of therapy.76 A subsequent uncontrolled study of acyclovir therapy for HSV encephalitis in adults observed a worse long-term prognosis for subjects with a poor physiology score on hospitalization and for those for whom therapy was delayed more than 2 days after admission.133 A low Glasgow score (but not necessarily presence of seizures) and age younger than 3 years appear to predict a poor outcome of HSV encephalitis in children treated with acyclovir.112 Beyond the perinatal period, which is discussed later, acyclovir is given at a dose of 30 to 45 mg/kg/day in divided doses every 8 hours. Administration calculation as 500 mg/m2/dose every 8 hours may be superior, particularly to avoid excessive dosing and renal injury associated with weights less than 50 kg.134

Other Infections There are no controlled data regarding the effectiveness of antiviral therapy in patients with unusual manifestations of HSV infection. It is prudent to administer parenteral acyclovir to those with severe, lifethreatening infections.

Intrauterine and Perinatal Infections Antiviral therapy is beneficial for neonates with HSV infections. Vidarabine was the first agent with demonstrable benefit, reducing the mortality rate of disseminated or CNS infection from 70% among placebo recipients to 40% among vidarabine recipients. Acyclovir is now the drug of choice.135 An open-label evaluation of increasing dosages of intravenous acyclovir support the use of a 21-day course of 60 mg/kg/day to treat neonatal CNS and disseminated infection.117,136 A 14-day course of 60 mg/kg/day is recommended for infants with SEM infection, even if HSV is detected in blood by PCR. The best therapeutic results are obtained for localized SEM infection, with no deaths and with universally good neurodevelopmental outcomes.95 In contrast, approximately 30% of infants with disseminated infection die.136 There have been anecdotal reports of recovery from or survival of fulminant hepatic failure after liver transplantation and while receiving plasmapheresis of hemofiltration awaiting transplantation. About 5% of infants with CNS disease die despite therapy, and only 30% of survivors are normal at 1 year of age without additional suppressive therapy.135,136 Recurrence of CNS symptoms with abnormal CSF findings occurs in about 8% of survivors of disseminated or CNS disease.135 Six months of suppressive oral acyclovir (300 mg/m2 per dose, 3 times daily) begun immediately after initial therapy of CNS infection improves neurodevelopment outcome assessed at 12 months of age and decreases

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PART III  Etiologic Agents of Infectious Diseases SECTION B  Viruses

the number of skin recurrences in all disease classifications of neonatal HSV.137 Although neonates with proven HSV infections should receive acyclovir promptly, the role of empiric acyclovir therapy is not clear. The relative risks of drug exposure and potential prolongation of hospitalization are weighed against the risk of delayed therapy.138 Clinical settings in which empiric acyclovir therapy should be considered include the appearance of skin lesions typical of HSV while awaiting results of diagnostic tests, fever or other unexplained signs of infection in a neonate known to have been exposed to HSV at delivery, progressive clinical deterioration in an infant initially suspected to have bacterial sepsis for whom bacterial culture results are negative, and unexplained encephalitis in a neonate with unremitting seizures.95,139 When considering antiviral therapy in a neonate suspected of having HSV infection, the following specimens should be obtained: swab specimens from the mouth, nasopharynx, conjunctivae, and anus (i.e., surface cultures) for HSV culture and, if desired, for PCR testing; specimens of skin vesicles and CSF for HSV culture and PCR testing, respectively; whole blood for PCR testing; and serum samples for measuring alanine aminotransferase (ALT).117 Guidance is available from the American Academy of Pediatrics (AAP) for the evaluation and treatment of infants born to women with active genital lesions.140

Compromised Hosts Acyclovir is the drug of choice for the management of progressive mucocutaneous HSV in patients with compromised immune function. Therapy speeds healing of localized lesions and reduces the morbidity and mortality rates due to visceral dissemination.141 Emergence of HSV strains resistant to acyclovir is more common in the management of HSV infections in immunocompromised hosts than in normal hosts.142 The prevalence of acyclovir-resistant strains among immunocompromised hosts varies according to the type and degree of immunosuppression, but it usually ranges between 5% and 10%.143 HSV strains resistant to both acyclovir and foscarnet have been isolated from patients in whom sequential therapy with the two drugs failed.144

PREVENTION Several candidate HSV vaccines have been developed from extracts of infected cells or recombinant virus glycoproteins, and newer vaccine approaches include DNA-based vaccines and replication-impaired viruses.145–147 No tested vaccine has effectively prevented infection or establishment of latency,31,145 and prevention of HSV infection depends on reducing transmission, acquisition, and reactivation of the virus. Complete prevention of transmission of genital HSV infection requires sexual abstinence because most infections are subclinical; consistent condom use provides some protection. Reduction in the vertical transmission of HSV could be accomplished by reducing maternal infections or the likelihood of transmission to the neonate. Although suppressive acyclovir reduces clinical genital HSV reactivation, it does not eliminate asymptomatic viral shedding.129 Because most women infected with HSV-2 have no history of genital herpes, it is unlikely that this method will be a practical approach to reducing the risk of infection of neonates born to previously infected mothers. Development of neonatal HSV disease in infants born to women on suppressive antiviral therapy has been reported.148 Preventing the acquisition of new infections during pregnancy is complicated by the high proportion of genital infections transmitted from partners not known to be infected with HSV-2 and by the increasing incidence of genital HSV-1 infection. Strategies to identify women who are shedding virus at parturition and thereby prevent transmission by cesarean delivery have been confounded by the need to recognize clinical lesions before progression of labor. These strategies are further frustrated by the occurrence of asymptomatic viral shedding, even in primary episodes. Use of prenatal cultures fails to predict shedding of virus at delivery and is not recommended.149 Recognizing these limitations, the AAP has provided guidance for management of infants born to women with active genital lesions.140 Long-term suppressive therapy with acyclovir reduces reactivation of latent genital and orolabial HSV infections.124,129 Once-daily suppressive valacyclovir therapy, administered to the infected partner

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of immunocompetent, heterosexual, monogamous couples who are discordant for HSV-2 infection reduces transmission of HSV to the uninfected partner.150 Prophylactic acyclovir also has been used successfully in immunocompromised hosts, including those with bone marrow and renal transplants, cancer, and other immunodeficiencies. In these immunocompromised hosts, the frequency of HSV reactivation typically is reduced from 60% to 80% among placebo recipients to 0% to 10% among acyclovir recipients.151 Availability of rapid virus identification and specific serologic tests could inform a graded approach in the future. All references are available online at www.expertconsult.com.

Key Points: Diagnosis and Management of Neonatal Herpes Simplex Virus Infections EPIDEMIOLOGY • The rate of neonatal infection is 1 case per 1700 to 1 case per 12,500 live births in the United States; the most reliable incidence rate is 1 case per 3200 live births. • Infections acquired in utero (congenital) are rare, representing less that 5% of all cases. • Most infections result from exposure at delivery to mothers shedding virus in the absence of symptoms. • Maternal primary infection is associated with a much higher neonatal attack rate than maternal recurrent infection (50–60% vs. 2%). CLINICAL FEATURES • There are three classic presentations ■ Skin, eye, and mucous membrane (SEM) infection characterized by skin vesicles at sites of trauma, mucosal lesions, and conjunctivitis (45% of cases of neonatal herpes simplex virus [HSV] disease) ■ Disseminated infection resembling bacterial sepsis with shock, liver failure, bleeding diatheses, and respiratory failure (25% of cases of neonatal HSV disease) ■ Central nervous system infection with irritability, lethargy, and typified by seizures (30% of cases of neonatal HSV disease) • Usual age of onset is 5 to 21 days; SEM and disseminated infection typically is earlier (average, 10–12 days of life); central nervous system (CNS) infection typically is later (average, 17–19 days of life). • High (>70%) mortality rate for untreated disseminated disease • Reduced mortality rate with antiviral therapy but persistent morbidity, except for SEM infection DIAGNOSIS • Culture and direct fluorescent antibody test of skin lesions, with or without polymerase chain reaction (PCR) • Viral cultures of specimens obtained from skin and mucous membranes (i.e., surface sites), with or without PCR • Cerebrospinal fluid analysis, including PCR • Whole blood PCR • Serum alanine aminotransferase (ALT) level • Electroencephalography and brain imaging (i.e., computed tomography, magnetic resonance imaging, or cranial ultrasonography) TREATMENT • Intravenously administered acyclovir, 60 mg/kg/day in 3 divided doses for 14 days (SEM infection) to 21 days (disseminated and CNS infection) days; followed by orally administered acyclovir, 300 mg/m2/dose × 3 doses/day (900 mg/m2/day) for 6 months

KEY REFERENCES 22. Bradley H, Markowitz LE, Gibson T, et al. Seroprevalence of herpes simplex virus types 1 and 2—United States, 1999–2010. J Infect Dis 2014;209:325–333. 31. Belshe RB, Leone PA, Bernstein DI, et al. Efficacy results of a trial of a herpes simplex vaccine. N Engl J Med 2012;366:34–43. 32. Bernstein DI, Bellamy AR, Hook EW 3rd, et al. Epidemiology, clinical presentation, and antibody response to primary infection with herpes simplex virus type 1 and type 2 in young women. Clin Infect Dis 2013;56:344–351. 97. Curfman AL, Glissmeyer EW, Ahmad FA, et al. Initial presentation of neonatal herpes simplex virus infection. J Pediatr 2016;172:121–126. 98. Long SS, Pool TE, Vodzak J, et al. Herpes simplex virus infection in young infants during 2 decades of empiric acyclovir therapy. Pediatr Infect Dis J 2011;30:556–561. 114. Melvin AJ, Mohan KM, Schiffer JT, et al. Plasma and CSF herpes simplex virus levels at diagnosis and outcome of neonatal infection. J Pediatr 2015;166:827–833.

134. Rao SR, Abzug MJ, Carosone-Link P, et al. Intravenous acyclovir and renal dysfunction in children: a matched case control study. J Pediatr 2015;166:1462–1468. 135. Whitley R, Arvin A, Prober C, et al. A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection. N Engl J Med 1991;324:444–449. 136. Kimberlin DW, Lin CY, Jacobs RF, et al. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics 2001;108:230–238. 137. Kimberlin DW, Whitley RJ, Wan W, et al. Oral acyclovir suppression and neurodevelopment after neonatal herpes. N Engl J Med 2011;365:1284–1292. 138. Shah SS, Aronson PL, Mohamad Z, et al. Delayed acyclovir therapy and death among neonates with herpes simplex virus infection. Pediatrics 2011;128:1153–1160. 140. Kimberlin DW, Baley J. Guidance on management of asymptomatic neonates born to women with active genital herpes lesions. Pediatrics 2013;131:e635–e646. 148. Pinninti SG, Angara R, Feja KN, et al. Neonatal herpes disease following maternal antenatal antiviral suppressive therapy: a multicenter case series. J Pediatr 2012;161:134–138, e1-3.

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