Pathogenesis

The transmission of herpes simplex virus (HSV) infection is dependent upon intimate, personal contact of a susceptible seronegative individual with someone excreting HSV. Virus must come in contact with mucosal surfaces or abraded skin for infection to be initiated. With viral replication at the site of primary infection, either an intact virion or, more simply, the capsid is transported retrograde by neurons to the dorsal root ganglia where, after another round of viral replication, latency is established (Fig. 32.1(a), left panel). The more severe the primary infection, as reflected by the size, number, and extent of lesions, the more likely it is that recurrences will ensue. Although replication sometimes leads to disease and, infrequently, results in life-threatening infection (e.g., encephalitis), the host-virus interaction leading to latency predominates. After latency is established, a proper stimulus causes reactivation; virus becomes evident at mucocutaneous sites, appearing as skin vesicles or mucosal ulcers (Fig. 32.1(b), right panel).

Fig. 32.1

(a) Primary infection. (b) Recurrent infection.

Infection with HSV-1 generally occurs in the oropharyngeal mucosa. The trigeminal ganglion becomes colonized and harbors latent virus. However, it has been increasingly common to detect evidence of HSV-1 in the genital tract, usually the consequence of oral-genital sex. When such occurs, recurrences of HSV-1 in the genital tract are uncommon. Acquisition of HSV-2 infection is usually the consequence of transmission by genital contact. Virus replicates in the genital, perigenital or anal skin sites with seeding of the sacral ganglia (Fig. 32.2). As is the case of HSV-1’s ability to infect the genital tract, HSV-2 can infect the mouth. Recurrences at this site are uncommon.

Fig. 32.2

Sites of HSV infection and disease (Whitley, 2001).

Operative definitions of the nature of the infection are of pathogenic relevance. Susceptible individuals (namely, those without pre-existing HSV antibodies) develop primary infection after the first exposure to either HSV-1 or HSV-2. A recurrence of HSV is known as “recurrent infection.” Initial infection is when an individual with pre-existing antibodies to one type of HSV (namely, HSV-1 or HSV-2) can experience a first infection with the opposite virus type (namely, HSV-2 or HSV-1, respectively). Primary infection has, more recently, been labeled first-episode disease because some individuals present with what appears to be a clinically severe primary infection but have pre-existing antibodies to the causative type. This observation indicates that individuals may have a well-established latent infection before the first episode of clinically evident disease occurs.

Reinfection with a different strain of HSV can occur, albeit extremely uncommon in the normal host and is called exogenous reinfection. Cleavage of DNA from an HSV isolate by restriction endonuclease enzymes yields a characteristic pattern of subgenomic products. Analyses of numerous HSV-1 and HSV-2 isolates from a variety of clinical situations and widely divergent geographic area demonstrates that epidemiologically unrelated strains yield distinct HSV DNA fragment patterns. In contrast, fragments of HSV DNA derived from the same individual obtained years apart, from monogamous sexual partners, or following short and long passages in vitro, have identical fragments after restriction endonuclease cleavage (Buchman et al., 1978). Utilizing endonuclease technology, exogenous reinfection is exceedingly low in the immune competent host.

Unique biologic properties of HSV that influence pathogenesis

HSV-1 and HSV-2 exhibit two unique biologic properties that influence pathogenesis and subsequent human disease. Both viruses have the capacity to invade and replicate in the CNS and the capacity to establish a latent infection in dorsal root ganglia (Roizman and Pellett, 2001).

The term, neurovirulence, encompasses both neuroinvasiveness from peripheral sites and replication in neuronal cells. When paired isolates (brain and lip) from patients with HSV encephalitis are evaluated by PFU/LD₅₀ ratios following direct intracerebral inoculation in mice, the encephalitis isolates have lower PFU/LD₅₀ ratios than isolates from lip lesions. Neurovirulence appears to be the function of numerous genes (Roizman and Knipe, 2001). In fact, deletion of virtually any of the genes dispensable for viral replication in cell culture reduces the capacity of the virus to invade and replicate in CNS. Mutations affecting neuroinvasiveness have also been mapped in genes encoding glycoproteins. Access to neuronal cells from usual portals of entry into the body requires postsynaptic transmission of virus and, therefore, a particularly vigorous capacity to multiply and to direct the virions to appropriate membranes. In addition, since neuronal cells are terminally differentiated and do not make cellular DNA, they lack the precursors for viral DNA synthesis that are also encoded by the viral genes dispensable for growth in cell culture. Of particular interest, however, is the role of γ₁34.5 gene in neurovirulence (Chou et al., 1990; Chou and Roizman, 1986; Hesselgesser and Horuk, 1999; Whitley et al., 1993). Although γ₁34.5 deletion mutants multiply well in a variety of cells in culture, they are among the most avirulent mutants identified to date in vivo.

Latency has been recognized biologically since the beginning of the century (Baringer and Swoveland, 1973; Bastian et al., 1972; Stevens and Cook, 1971) and has been extensively reviewed (Roizman and Knipe, 2001; Nahmias and Roizman, 1973; Roizman and Sears, 1987). The molecular basis for latency is addressed in Chapter 33. Following entry, both HSV-1 and HSV-2 infect nerve endings and translocate by retrograde transport to the nuclei of sensory ganglia. The virus multiplies in a small number of sensory neurons, which are ultimately destroyed. In the vast majority of the infected neurons, the viral genome remains for the entire life of the individual in an episomal state. In a fraction of individuals, the virus reactivates and is moved by anterograde transport to a site at or near the portal of entry. Reactivations occur following a variety of local or systemic stimuli.

Patients treated for trigeminal neuralgia by sectioning a branch of the trigeminal nerve develop herpetic lesions along the innervated areas of the sectioned branch (Carton and Kilbourne, 1952; Cushing, 1905; Goodpasture, 1929; Pazin et al., 1978). Reactivation of latent virus appears dependent upon an intact anterior nerve route and peripheral nerve pathways. Latent virus can be retrieved from the trigeminal, sacral, and vagal ganglia of humans either unilaterally or bilaterally (Bastian et al., 1972). The recovery of virus by in vitro cultivation of trigeminal ganglia helps explain the observation of vesicles that recur at the same site in humans, usually the vermilion border of the lip. Recurrences occur in the presence of both cell-mediated and humoral immunity. Recurrences are spontaneous, but there is an association with physical or emotional stress, fever, and exposure to ultraviolet light, tissue damage, and immune suppression. Recurrent herpes labialis is three times more frequent in febrile patients than in non-febrile controls (Baringer and Swoveland, 1973; Roizman and Sears, 1987; Selling and Kibrick, 1964).

Little is known regarding the mechanisms by which the virus establishes and maintains a latent state or is reactivated. There are in fact disagreements on the fate of neurons in which latent virus became reactivated. The relevant issues may be summarized as follows.

1. Sensory neurons harboring virus contain nuclear transcripts arising from approximately 8.5 kbp of the sequences flanking the U_L sequence. These transcripts are known as the latency associated transcripts or LATs. A shorter region is more abundantly represented in the nuclei. The RNA transcribed from this region forms two populations 2 kbp and 1.5 kbp, respectively, and represents stable introns of an unknown, and relatively unstable transcript. The abundant 2.5 and 1.5 kbp RNA play no role in the establishment or maintenance of the latent state although they may play a role in reactivation. These LATs may have an apoptotic function, which might explain the higher efficiency of reactivation of viruses expressing LATs.
   The source of genetic functions required for the establishment or maintenance of the latent state remains unknown. All of the deletion mutants tested to date establish latency but not all reactivate. Whereas establishment or maintenance of latency are functions expressed by dorsal root neurons, the activation of viral gene expression that leads to viral replication does require a full complement of viral gene.
2. Usually, replication of HSV-1 and HSV-2 destroys the infected cell, but reactivation of latent virus may not destroy neurons harboring the virus. This suggestion is based on the observation that patients do not suffer from local anesthesia at the site of frequent, multiple recurrences. An alternative explanation is that nerve endings from adjacent tissues innervated by other neurons extend into the site of the healed lesion (Roizman and Knipe, 2001; Roizman and Sears, 1987).

Pathology

The histopathologic characteristics of a primary or recurrent HSV (Fig. 32.3) reflect viral-mediated cellular death and associated inflammatory response. Viral infection induces ballooning of cells with condensed chromatic within the nuclei of cells, followed by nuclear degeneration, generally within parabasal and intermediate cells of the epithelium. Cells lose intact plasma membranes and form multinucleated giant cells. With cell lysis, a clear (referred to as vesicular) fluid containing large quantities of virus appears between the epidermis and dermal layer. The vesicular fluid contains cell debris, inflammatory cells, and often multinucleated giant cells. In dermal substructures there is an intense inflammatory response, usually in the corium of the skin, more so with primary infection than with recurrent infection. With healing, the vesicular fluid becomes pustular with the recruitment of inflammatory cells and scabs. Scarring is uncommon. When mucous membranes are involved, vesicles are replaced by shallow ulcers.

Fig. 32.3

Histopathology of herpes simplex virus infection (Whitley, 2001).

Pathology of central nervous system disease

HSE results in acute inflammation, congestion and/or hemorrhage, most prominently in the temporal lobes and usually asymmetrically in adult (Boos and Esiri, 1986) and more diffusely in the newborn. Adjacent limbic areas show involvement as well. The meninges overlying the temporal lobes may appear clouded or congested. After approximately 2 weeks, these changes proceed to frank necrosis and liquefication, as shown in Fig. 30.4. Microscopically, involvement extends beyond areas that appear grossly abnormal. At the earliest stage, the histologic changes are not dramatic and may be non-specific. Congestion of capillaries and other small vessels in the cortex and subcortical white matter is evident; other changes are also evident, including petechiae. Vascular changes that have been reported in the area of infection include areas of hemorrhagic necrosis and perivascular cuffing (Fig. 32.5(a), (b)). The perivascular cuffing becomes prominent in the second and third weeks of infection. Glial nodules are common after the second week (Boos and Kim, 1984; Kapur et al., 1994). The microscopic appearance becomes dominated by evidence of necrosis and, eventually, inflammation; the latter is characterized by a diffuse perivascular subarachnoid mononuclear cell infiltrate, gliosis, and satellitosis-neuronophagia (Boos and Esiri, 1986; Garcia et al., 1984). In such cases, widespread aras of hemorrhagic necrosis, mirroring the area of infection, become most prominent. Oligodendrycytic involvement and bliosis (as well as astrocytosis) are common, but these changes develop very late in the disease. Although found in only approximately 50% of patients, the presence of intranuclear inclusions supports the diagnosis of viral infection, and these inclusions are most often visible in the first week of infection. Intranuclear inclusions (Cowdry type A inclusions) are characterized by an eosinophilic homogeneous appearance and are often surrounded by a clear, unstained zone beyond which lies a rim of marginated chromatin, as shown in Fig. 32.6.

Fig. 32.4

Gross pathologic findings in HSE, illustrating hemorrhagic necrosis of the inferior medial portion of the temporal lobe (Whitley, 2001).

Fig. 32.5

(a) Hemorrhagic necrosis on microscopic examination (Whitley, 2001). (b) Perivascular cuffing on histopathologic examination of a patient with HSE (Whitley, 2004).

Fig. 32.6

Intranuclear inclusions (Whitley, 2004).

Impact of host response to infection on disease

The pathogenesis of HSV infections is influenced by both specific and non-specific host defense mechanisms (Lopez et al., 1993). With the appearance of non-specific inflammatory changes, paralleling a peak in viral replication, specific host responses can be quantitated but vary from one animal system to the next. In the mouse, delayed-type hypersensitivity responses are identified within 4–6 days after disease onset, followed by a cytotoxic T-cell response and by the appearance of both IgM- and IgG-specific antibodies. Host responses in humans are delayed, developing approximately 7–10 days later. Immunodepletion studies have identified the importance of cytotoxic T-cells (CTLs) in resolving cutaneous disease. Adoptive transfer of CD8⁺ or HSV-immune CD4⁺ T cells also reduces viral replication or protection from challenge.

T-cell lymphocyte subsets have been examined for host susceptibility to infection, including those cells responsible either for H2-restricted cytotoxicity or for in vitro or adoptive transfer of delayed-type hypersensitivity (Kohl et al., 1989). These latter cells have a requirement for both the IA and H2 K/D regions (Nash et al., 1981). Studies utilizing a specific infected cell polypeptide product (ICP4) have identified its requirement for mediation of T-cells (Martin et al., 1988). Prior immune responses to HSV-1 infection have a protective effect on the acquisition of HSV-2 infection (Mertz et al., 1992). Polyclonal antibody therapy will decrease mortality rates in the newborn mouse (Brown et al., 1991). In addition, administration of these antibodies can limit progression of both neurologic and ocular disease. Protection can be achieved with monoclonal antibodies to specific viral polypeptides, especially the envelope glycoproteins. Such results have been accomplished with both neutralizing and non-neutralizing antibodies. Antibody-dependent cell-mediated cellular cytoxic host responses also correlate with improved clinical outcome, as will be noted below for neonatal HSV infections.

Numerous reports have incriminated or refuted HLA associations with human HSV infections. For recurrent fever blisters, these studies have included HLA-A1, HLA-A2, HLA-A9, HLA-BW16, and HLA-CW2. Recurrent ocular HSV infections have been associated with HLA-A1, HLA-A2, HLA-A9, and HLA-DR3. These conflicting associations can be faulted by population selection bias.

Humoral immune responses of humans parallel those following systemic infection of mice and rabbits. IgM antibodies appear transiently and are followed by IgG and IgA antibodies, which persist over time. Neutralizing and antibody-dependent cellular cytotoxic antibodies generally appear 2–6 weeks after infection and persist for the lifetime of the host. Immunoblot and immunoprecipitation antibody responses have defined host response to infected cell polypeptides and correlated these responses with the development of neutralizing antibodies (Bernstein et al., 1985; Eberle et al., 1981). After the onset of infection, antibodies appear which are directed against gD, gB, ICP-4, gE, gG-1 or gG-2, and gC. Both IgM and IgG antibodies can be demonstrated, depending upon the time of assessment.

Lymphocyte blastogenesis responses develop within 4–6 weeks after the onset of infection and sometimes as early as 2 weeks (Corey et al., 1978; Russell, 1974; Sullender et al., 1987). With recurrences, boosts in blastogenic responses can be defined promptly; however, these responses, as after primary infection, decrease with time. Non-specific blastogenic responses do not correlate with a history of recurrences.

Host response of the newborn to HSV differs from that of older individuals. Impairment of host defense mechanisms contributes to the increased severity of some infectious agents in the fetus and the newborn. Factors which must be considered in defining host response of the newborn include the mode of transmission of the agent (viremia vs mucocutaneous infection without blood-borne spread), and time of acquisition of infection.

Humoral immunity does not prevent either recurrences or exogenous reinfection. Thus, it is not surprising that transplacentally acquired antibodies from the mother are not totally protective against newborn infection (Kohl et al., 1989; Sullender et al., 1987). The quantity of neutralizing antibodies is higher in those newborns who do not develop infection when exposed to HSV at delivery (Prober et al., 1987). Transplacentally acquired neutralizing antibodies either prevent or ameliorate infection in exposed newborns, as do antibody-dependent cell-mediated cytotoxic antibodies (Prober et al., 1987). Nevertheless, the presence of antibodies at the time of disease presentation does not necessarily influence the subsequent outcome (Whitley et al., 1988; Whitley et al., 1980).

Infected newborns produce IgM antibodies (as detected by immunofluorescence) specific for HSV within the first 3 weeks of infection and increase rapidly during the first 2–3 months, being detectable for as long as 1 year after infection. The most reactive immunodeterminants are the surface viral glycoproteins, particularly gB and gD (Sullender et al., 1987).

Newborns infected by HSV have a delayed T-lymphocyte proliferative response as compared to that of older individuals (Sullender et al., 1987). Most infants have no detectable T-lymphocyte responses to HSV 2–4 weeks after the onset of clinical symptoms (Sullender et al., 1987; Rasmussen and Merigan, 1978). These delayed responses may be associated with disease progression (Sullender et al., 1987).

Infected newborns have decreased α-interferon production in response to HSV antigen as compared to adults with primary HSV infection (Sullender et al., 1987). Lymphocytes from infected babies also have decreased responses to α-interferon generation (Sullender et al., 1987).

Orolabial infection

Genital infection

Keratoconjunctivitis

Herpes simplex virus is a major cause of ocular scarring and visual loss (Simmons, 2002). It is estimated that in excess of 300 000 cases of HSV eye infections are diagnosed each year in the United States (Whitley et al., 1998). Beyond the neonatal period, the majority of these infections are caused by HSV-1. Infection may be unilateral or bilateral, beginning with follicular conjunctivitis associated with pain, photophobia, and tearing and followed by chemosis, periorbital edema, and preauricular lymphadenopathy (Pavan-Langston, 1990). Progressive infection may result in sight-threatening corneal ulcers, characterized by pathognomonic branching dendritic lesions. Healing may be slow, requiring more than 1 month. About one-third of individuals develop recurrences during the ensuing 5 years.

Cutaneous infections

HSV can infect virtually any part of the skin or mucosa. One of the most common cutaneous sites for HSV-1 or HSV-2 infection is the pulp or nail bed of the finger. This is referred to as herpetic whitlow and most commonly occurs in medical and dental professionals, in whom it results from digital contamination with genital or oral secretions (Feder and Long, 1983). When a young child develops herpetic whitlow, it may result from autoinoculation during primary oral herpes infection or when an infected adult trims the child’s nails by biting (Feder and Long, 1983). The typical clinical course of whitlow involves the initial appearance of discrete vesicular or pustular lesions over the distal phalynx which subsequently coalesce over several days. Pain often is associated with a tingling or burning sensation. Fever, lymphangitis, and tender swelling of local lymph nodes may be present. The diagnosis of herpetic whitlow is most often confused with bacterial cellulitis.

Close contact between abraded skin and oral secretions results in cutaneous infections caused by HSV-1 among participants in certain contact sports including wrestlers (herpes gladiatorum) and rugby players (scrum-pox) (Becker et al., 1988; Stacey and Atkins, 2000). In descending order, the most common sites of infection among wrestlers are the head, extremities, and trunk (Belongia et al., 1991). About 40% of infected athletes have associated sore throat and 25% have fever, chills, and headache (Belongia et al., 1991). Herpes infections also can result in severe cutaneous infection when they occur on skin damaged by diaper dermatitis, burns, or atopic dermatitis (Jenson and Shapiro, 1987; Wheeler and Abele, 1966; McMill and Cartotto, 2000). Finally, HSV is the most common precipitating factor for recurrent erythema multiforme (Orton et al., 1984).

Central nervous system infections

Herpes simplex viruses cause a variety of peripheral and CNS illnesses of infectious and post-infectious nature (Simmons, 2002; Schmutzhard, 2001). HSV-1 is the most common cause of sporadic severe encephalitis in the United States, accounting for an estimated 10 to 20% of all cases (Lakeman et al., 1995). Without treatment, more than 70% of infected patients die and virtually all survivors have severe sequelae (Whitley, 2001). Encephalitis can result from a primary or, more commonly, a reactivated HSV infection.

Patients typically present with altered state of consciousness, bizarre behavior, and focal neurologic findings, referable to the temporal lobe. Typical abnormalities in the cerebrospinal fluid (CSF) of patients with HSV encephalitis include a few hundred white blood cells/mm³, with a predominance of lymphoid cells (75% to 100%) and an increased number of red blood cells (Koskiniemi et al., 1984). 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 common (Koskiniemi et al., 1984). Virus rarely is isolated from CSF but the presence of HSV DNA, identified by polymerase chain reaction (PCR), is sensitive and specific for the diagnosis of HSV encephalitis (Lakeman et al., 1995; Tang et al., 1999).

Typical findings on electroencephalography include focal spike and slow-wave abnormalities, with characteristic paroxysmal lateralizing epileptiform discharges. Focal edema associated with hemorrhagic necrosis may be present on neurodiagnostic images; abnormalities tend to be evident earlier on magnetic resonance imaging than computed tomography.

Other neurologic syndromes associated with HSV infection include recurrent aseptic meningitis (Mollaret’s meningitis), brainstem encephalitis, ascending myelitis, post infectious encephalomyelitis, a variety of movement disorders and atypical pain syndromes, and temporal lobe epilepsy (Simmons, 2002; Schmutzhard, 2001).

Neonatal infection

Over 90% of neonatal infections caused by HSV are contracted at the time of delivery (intrapartum infection) but about 5% are contracted in utero (congenital infection). Manifestations of congenital infection include skin lesions and scars, chorioretinitis, microcephaly, hydranencephaly, and microphthalmia (Hutto et al., 1987).

Neonates infected perinatally present with a range of manifestations, categorized as localized to the skin eye and mouth (SEM) or the CNS, or as disseminated infection. In a recent cohort of 79 neonates with HSV infection who were enrolled into a clinical study between 1989 and 1997, 13% had SEM, 35% had CNS, and 52% had disseminated infection (Kimberlin et al., 2001).

Neonates with SEM disease usually present during the first 2 weeks of life; occasionally skin lesions are evident in the delivery room. The cutaneous lesions first appear where there has been trauma, such as the site of attachment of fetal scalp electrodes, the margin of the eyes, or over the presenting body part. Initially the lesions appear as macules but they rapidly evolve to vesicles. Outcome of SEM disease is excellent if diagnosis is considered, and antiviral therapy administered, in a timely fashion (Kimberlin et al., 2001).

Neonatal HSV infection involving the CNS usually results in fever and lethargy, first appearing between the second and third weeks of life. The sign most specific for HSV infection is the presence of skin lesions. However, approximately one-third infants with CNS disease due to HSV infection do not have skin lesions at the time of clinical presentation (Kimberlin et al., 2001). A common but not as specific sign of neonatal HSV infection of the CNS is the sudden onset of seizures that tend to be focal and difficult to control. Usual CSF abnormalities include a mononuclear pleocytosis (<100 white blood cells/mm³), slightly reduced glucose, and modestly to markedly elevated protein concentration. The electroencephalogram typically is diffusely abnormal and magnetic resonance imaging reveals either temporal or diffuse cerebral disease. If untreated, most neonates with CNS infection caused by HSV die and almost all survivors are left severely neurologically impaired.

Signs of disseminated infection caused by HSV may mimic severe bacterial infection with onset during the first week of life. Common clinical manifestations include vascular instability, hepatomegaly, jaundice, bleeding, and respiratory dysfunction. Approximately 60% of patients develop skin lesions during their illness, but lesions may be absent at the onset of symptoms (Kimberlin et al., 2001). Progression of infection is rapid, with death resulting from shock, liver failure with bleeding, respiratory failure, or neurologic compromise.

Infection in compromised hosts

The likelihood of complicated HSV, with attendant substantial morbidity, parallels the degree of compromise of cellular immune function (Rand et al., 1977). The most frequent complication of HSV infections among immunocompromised patients is slowly progressive and chronic mucocutaneous infections, accompanied by extensive tissue damage and necrosis (Whitley et al., 1984; Whitley, 2004). Contiguous mucosal spread resulting in esophageal, tracheal, pulmonary involvement or visceral dissemination also can occur but fatal infections are not common. Organ transplant recipients, particularly human stem cell transplant recipients, and individuals with HIV/AIDS are at particular risk for both severe and frequently recurrent infections.

Acknowledgment

This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract (NO1-AI -65306, NO1-AI-15113, NO1-AI-62554, NO1-AI-30025), the General Clinical Research Unit (RR-032), and the State of Alabama.

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