Pathology of herpes simplex virus 2

It remains one of the most common sexually transmitted infections STI but continues to be underestimated, given the vague presentation of its symptoms. In addition to providing the reader with basic knowledge of the pathogen and clinical presentation of herpes genitalis, this review article discusses important aspects of the laboratory diagnostics, antiviral therapy, and prophylaxis.

This article is aimed at all health-care providers managing patients with herpes genitalis and attempts to improve the often suboptimal counseling, targeted use of laboratory diagnostics, treatment, and preventive measures provided to patients. 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.

Histopathology of herpes simplex virus infection Whitley, 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.

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. The perivascular cuffing becomes prominent in the second and third weeks of infection. Glial nodules are common after the second week Boos and Kim, ; Kapur et al. 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, ; Garcia et al.

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. 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.

The pathogenesis of HSV infections is influenced by both specific and non-specific host defense mechanisms Lopez et al. 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. 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.

Studies utilizing a specific infected cell polypeptide product ICP4 have identified its requirement for mediation of T-cells Martin et al. Polyclonal antibody therapy will decrease mortality rates in the newborn mouse Brown et al. 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. 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.

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. 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.

The quantity of neutralizing antibodies is higher in those newborns who do not develop infection when exposed to HSV at delivery Prober et al. Transplacentally acquired neutralizing antibodies either prevent or ameliorate infection in exposed newborns, as do antibody-dependent cell-mediated cytotoxic antibodies Prober et al.

Nevertheless, the presence of antibodies at the time of disease presentation does not necessarily influence the subsequent outcome Whitley et al. 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. Newborns infected by HSV have a delayed T-lymphocyte proliferative response as compared to that of older individuals Sullender et al. Most infants have no detectable T-lymphocyte responses to HSV 2—4 weeks after the onset of clinical symptoms Sullender et al.

These delayed responses may be associated with disease progression Sullender et al. Therefore, most infections are asymptomatic or associated with non-specific signs and symptoms. However, when symptoms do occur, they tend to be more severe with primary compared with recurrent infections. Also, whether accompanied by symptoms or not, viral excretion during primary infection is more prolonged than shedding during recurrent infection.

The most common sites of HSV infection include the skin and mucosal surfaces. HSV-1 and HSV-2 infections tend to be transmitted by different routes and infect different areas of the body but signs and symptoms of infection with either virus are similar Whitley and Roizman, However, over the last several decades considerable overlap in site of infection has evolved. The oropharynx is the most common site of infection caused by HSV Although most primary orolabial infections appear to be mild or asymptomatic, some young children develop extensive orolabial lesions accompanied by systemic symptoms.

A typical course of severe infection includes, high fever, irritability, tender submandibular lymphadenopathy, and a widespread mucocutaneous eruption. Vesiculo-ulcerative lesions involve the palate, gingiva, tongue, lip, and perioral area Kuzushima et al. Dehydration, due to impaired eating and drinking, is the most common reason for hospital admission Cesario et al. Symptomatic primary infection may evolve over 2 to 3 weeks.

Primary HSV infection in older children and adults can present as pharyngitis. In some individuals, viral reactivation, with or without associated symptoms occurs in association with fever, exposure to ultraviolet radiation or wind, non-specific stresses, manipulation of the trigeminal nerve root, or dental extraction Openshaw and Bennett, The outer edge of the vermilion border is the most common site of reactivation; on average three to five lesions are present.

The lesions usually begin as vesicles, evolve into pustules or ulcers after 1 to 2 days, and heal within 8 to 10 days. Prodromal symptoms including burning, itching, or tingling may precede the outbreak by several hours and pain, when evident, is maximum at the onset of eruption, resolving after 4 to 5 days Spruance et al.

The majority of primary genital herpes infections occur in the absence of symptoms. These symptoms peak during the first 4 days of infection and abate over the subsequent 7 to 10 days.

Itching and local pain often precede visible lesions by 1 to 2 days. Lesions erupt over 7 to 8 days and evolve from vesicles and pustules to wet ulcers over approximately 10 days; crusting and healing follows over the ensuing 10 days. Common sites for lesions in women are the labia majora, labia minora, mons pubis, vaginal mucosa, and cervix. Lesions in men typically are found on the shaft of the penis.

Tender inguinal adenopathy appears during the second to third week of illness and is generally the last sign to resolve.

Complications are more common in women than men and include aseptic meningitis, paraesthesias and dysaesthesias of the legs and perineum, mucocutaneous lesions beyond the genital area, pharyngitis, and visceral dissemination. Perianal infection and proctitis are common in men who have sex with men.

Importantly, when PCR is used to detect evidence of HSV excretion in the genital tract of women known to have genital herpes, infectivity increases by at least fourfold.

Thus, these women can be infectious as often as one out of four days. Genital lesions are few in number and localized; they typically evolve from vesicle to healing in 8 to 10 days.

The buttock, thighs and perianal mucosa may be unrecognized sites of recurrent infection. It has been suggested that herpes infection be considered in the differential diagnosis of unexplained recurrent itching, burning, blistering, or erythema at any site below the waist Simmons, Approximately one-third of patients will not have recurrent infections, one-third will have two recurrences per year, and one third will have more than six recurrences per year Whitley, Emotional stress, menses, and sexual intercourse have been some of the factors implicated in precipitating recurrences.

Herpes simplex virus is a major cause of ocular scarring and visual loss Simmons, It is estimated that in excess of cases of HSV eye infections are diagnosed each year in the United States Whitley et al. Beyond the neonatal period, the majority of these infections are caused by HSV 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, 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. HSV can infect virtually any part of the skin or mucosa. 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, 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.

In descending order, the most common sites of infection among wrestlers are the head, extremities, and trunk Belongia et al. 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, ; Wheeler and Abele, ; McMill and Cartotto, Finally, HSV is the most common precipitating factor for recurrent erythema multiforme Orton et al.

Herpes simplex viruses cause a variety of peripheral and CNS illnesses of infectious and post-infectious nature Simmons, ; Schmutzhard, 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 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.

Manifestations of congenital infection include skin lesions and scars, chorioretinitis, microcephaly, hydranencephaly, and microphthalmia Hutto et al. 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.

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.

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.

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. 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. In contrast, intradermal injection of HSV below the epidermal basement membrane did not cause disease.

To determine if the basement membrane restricts HSV spread in vitro, Vero cells were cultured in the lower well of a dual well system. The upper well was separated from the lower well by a filter coated with the artificial basement membrane, matrigel. Addition of virus to the upper well failed to result in either viral accumulation in the lower well or infection of the cells in the lower well.