Herpes Simplex Virus

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Chapter 244 Herpes Simplex Virus

The 2 closely related herpes simplex viruses (HSVs), HSV type 1 (HSV-1) and HSV type 2 (HSV-2), cause a variety of illnesses, depending on the anatomic site where the infection is initiated, the immune state of the host, and whether the symptoms reflect primary or recurrent infection. Common infections involve the skin, eye, oral cavity, and genital tract. Infections tend to be mild and self-limiting, except in the immunocompromised patient and newborn infant, in whom they may be severe and life threatening.

Primary infection occurs in individuals who have not been infected previously with either HSV-1 or HSV-2. Because these individuals are HSV seronegative and have no pre-existing immunity to HSV, primary infections can be severe. Nonprimary 1st infection occurs in individuals previously infected with 1 type of HSV (e.g., HSV-1) who have become infected for the 1st time with the other HSV type (in this case, HSV-2). Because immunity to one HSV type provides some cross protection against disease caused by the other HSV type, nonprimary 1st infections tend to be less severe than true primary infections. During primary and nonprimary initial infections, HSV establishes latent infection in regional sensory ganglion neurons. Virus is maintained in this latent state for the life of the host but periodically can reactivate and cause recurrent infection. Symptomatic recurrent infections tend to be less severe and of shorter duration than 1st infections. Asymptomatic recurrent infections are extremely common. They cause no physical distress, although patients with recurrent infections are contagious and can transmit the virus to susceptible individuals. Re-infection with a new strain of either HSV-1 or HSV-2 at a previously infected anatomic site (e.g., the genital tract) can occur but is relatively uncommon, suggesting that host immunity, perhaps site-specific local immunity, resulting from the initial infection affords protection against exogenous re-infection. This observation suggests that it might be feasible to develop effective HSV vaccines.

Epidemiology

HSV infections are ubiquitous, and there are no seasonal variations in risk for infection. The only natural host is humans, and the mode of transmission is direct contact between mucocutaneous surfaces. There are no documented incidental transmissions from inanimate objects such as toilet seats.

All infected individuals harbor latent infection and experience recurrent infections, which may be symptomatic or may go unrecognized, and thus are periodically contagious. This information helps explain the widespread prevalence of HSV.

HSV-1 and HSV-2 are equally capable of causing initial infection at any anatomic site but differ in their capacity to cause recurrent infections. HSV-1 has a greater propensity to cause recurrent oral infections, whereas HSV-2 has a greater proclivity to cause recurrent genital infections. For this reason, HSV-1 infection typically results from contact with contaminated oral secretions, whereas HSV-2 infection most commonly results from anogenital contact.

HSV seroprevalence rates are highest in developing countries and among lower socioeconomic groups, although high rates of HSV-1 and HSV-2 infections are found in developed nations and among persons of the highest socioeconomic strata. Incident HSV-1 infections are more common during childhood and adolescence but are also found throughout later life. Data from the U.S. population–based National Health and Nutrition Examination Survey (NHANES) conducted between 1999 and 2004 showed a consistent increase of HSV-1 prevalence with age, which rose from 39% in adolescents 14-19-yr of age to 65% among those 40-49 yr of age. HSV-1 seroprevalence was not influenced by gender but rates were highest in Mexican-Americans (80.8%), intermediate in non-Hispanic blacks (68.3%), and lowest in non-Hispanic whites (50.1%), The NHANES study found an overall HSV-2 prevalence of 17% with a steady increased with age from 1.6% in the 14-19 yr age group to 26.4% in the 40-49-yr group. The rate was higher among females than males (22.8% and 11.2%, respectively) and varied by race and ethnic group, with an overall seroprevalence of 41.7% in blacks, 13.6% in Mexican-Americans, and 13.0% in whites. Modifiable factors that predicted HSV-2 seropositivity included less education, poverty, cocaine use, and a greater lifetime number of sexual partners. Studies show that only about 10% of HSV-2–seropositive subjects report a history of genital herpes, emphasizing the asymptomatic nature of most HSV infections.

A 3-yr longitudinal study of Midwestern adolescent girls 12-15 yr of age found that 44% were seropositive for HSV-1 and 7% for HSV-2 at enrollment. At the end of the study, 49% were seropositive for HSV-1 and 14% for HSV-2. The attack rates, based on the number of cases per 100 person-years, were 3.2 for HSV-1 infection among all girls and 4.4 for HSV-2 infection among girls who reported being sexually experienced. Findings of this study indicate that sexually active young women have a high attack rate for genital herpes and suggest that genital herpes should be considered in the differential diagnosis of any young woman who reports recurrent genitourinary complaints. In this study, participants with pre-existing HSV-1 antibodies had a significantly lower attack rate for HSV-2 infection, and those who became infected were less likely to have symptomatic disease than girls who were HSV seronegative when they entered the study. Prior HSV-1 infection appears to afford adolescent girls some protection against becoming infected with HSV-2; in adolescent girls infected with HSV-2, the pre-existing HSV-1 immunity appears to protect against development of symptomatic genital herpes.

Neonatal herpes is an uncommon but potentially fatal infection of the fetus or more likely the newborn. It is not a reportable disease in most states, and therefore there are no solid epidemiologic data regarding its frequency in the general population. In King County, Washington, the estimated incidence of neonatal herpes per was 2.6 cases/100,000 live births in the late 1960s, 11.9 from 1978 to 1981, and 31 from 1982 to 1999. This increase in neonatal herpes cases parallels the increase in cases of genital herpes. The estimated rate of neonatal herpes is 1/3,000-5,000 live births, which is higher than reported for the reportable perinatally acquired sexually transmitted infections such as congenital syphilis and gonococcal ophthalmia. More than 90% of the cases are the result of maternal-fetal transmission. The risk for transmission is greatest during a primary or nonprimary 1st infection (30-50%) and much lower when the exposure is during a recurrent infection (<2%). Infants born to mothers dually infected with HIV and HSV-2 are also at higher risk for acquiring HIV than infants born to HIV-positive mothers who are not HSV-2 infected. It is estimated that approximately 25% of pregnant women are HSV-2 infected and that approximately 2% of pregnant women acquire HSV-2 infection during pregnancy.

HSV is a leading cause of sporadic, fatal encephalitis in children and adults. In the USA it is estimated that there are 1,250 cases annually of HSV encephalitis.

Pathogenesis

In the immunocompetent host the pathogenesis of HSV infection involves viral replication in skin and mucous membranes followed by replication and spread in neural tissue. Viral infection typically begins at a cutaneous portal of entry such as the oral cavity, genital mucosa, ocular conjunctiva, or breaks in keratinized epithelia. Virus replicates locally, resulting in the death of the cell, and sometimes produces clinically apparent inflammatory responses that facilitate the development of characteristic herpetic vesicles and ulcers. Virus also enters nerve endings and spreads beyond the portal of entry to sensory ganglia by intraneuronal transport. Virus replicates in some sensory neurons, and the progeny virions are sent via intraneuronal transport mechanisms back to the periphery, where they are released from nerve endings and replicate further in skin or mucosal surfaces. It is virus moving through this neural arc that is primarily responsible for the development of characteristic herpetic lesions, although most HSV infections do not reach a threshold necessary to cause clinically recognizable disease. Although many sensory neurons become productively infected during the initial infection, some infected neurons do not initially support viral replication. It is in these neurons that the virus establishes a latent infection, a condition in which the viral genome persists within the neuronal nucleus in a largely metabolically inactive state. Intermittently throughout the life of the host, undefined changes can occur in latently infected neurons that trigger the virus to begin to replicate. This replication occurs despite the host’s having established a variety of humoral and cellular immune responses that successfully controlled the initial infection. With reactivation of the latent neuron, progeny virions are produced and transported within nerve fibers back to cutaneous sites somewhere in the vicinity of the initial infection, where further replication occurs and causes recurrent infections. Recurrent infections may be symptomatic (with typical or atypical herpetic lesions) or asymptomatic. In either case, virus is shed at the site where cutaneous replication occurs and can be transmitted to susceptible individuals who come in contact with the site or with contaminated secretions. Latency and reactivation are the mechanisms by which the virus is successfully maintained in the human population.

Viremia, or hematogenous spread of the virus, does not appear to play an important role in HSV infections in the immunocompetent host but can occur in neonates, individuals with eczema, and severely malnourished children. It is also seen in patients with depressed or defective cell-mediated immunity, such as occurs with HIV infection or some immunosuppressive therapies. Viremia can result in dissemination of the virus to visceral organs, including the liver and adrenals. Hematogenous dissemination of virus to the central nervous system appears to only occur in neonates.

The pathogenesis of HSV infection in newborns is complicated by their relative immunologic immaturity. The source of virus in neonatal infections is typically but not exclusively the mother. Transmission generally occurs during delivery, although it is well documented to occur even with cesarean delivery with intact fetal membranes. The most common portals of entry are the conjunctiva, mucosal epithelium of the nose and mouth, and breaks or abrasions in the skin that occur with scalp electrode use or forceps delivery. With prompt antiviral therapy, virus replication may be restricted to the site of inoculation (the skin, eye, or mouth). However, virus may also extend from the nose to the respiratory tract to cause pneumonia, move via intraneuronal transport to the central nervous system to cause encephalitis, or spread by hematogenous dissemination to visceral organs and the brain. Factors that may influence neonatal HSV infection include the virus type, portal of entry, inoculum of virus to which the infant is exposed, gestational age of the infant, and presence of maternally derived antibodies specific to the virus causing infection. Latent infection is established during neonatal infection, and survivors may experience recurrent cutaneous and neural infections.

Clinical Manifestations

The hallmarks of common HSV infections are skin vesicles and shallow ulcers. Classic infections manifest as small, 2- to 4-mm vesicles that may be surrounded by an erythematous base. These may persist for a few days before evolving into shallow, minimally erythematous ulcers. The vesicular phase tends to persist longer when keratinized epithelia is involved and be brief, sometimes fleeting, when moist mucous membranes are the site of infection. Because HSV infections are common and their natural history is influenced by many factors, including portal of entry, immune status of the host, and whether it is an initial or recurrent infection, the typical manifestations are seldom classic. Most infections are asymptomatic or unrecognized, and nonclassic presentations such as small skin fissures and small erythematous nonvesicular lesions are common.

Acute Oropharyngeal Infections

Herpes gingivostomatitis most often affects children 6 mo to 5 yr of age but is seen across the age spectrum. It is an extremely painful condition with sudden onset, pain in the mouth, drooling, refusal to eat or drink, and fever of up to 40.0-40.6°C. The gums become markedly swollen, and vesicles may develop throughout the oral cavity, including the gums, lips, tongue, palate, tonsils, pharynx, and perioral skin (Fig. 244-1). The vesicles may be more extensively distributed than typically seen with enteroviral herpangina. During the initial phase of the illness there may be tonsillar exudates suggestive of bacterial pharyngitis. The vesicles are generally present only a few days before progressing to form shallow indurated ulcers that may be covered with a yellow-gray membrane. Tender submandibular, submaxillary, and cervical lymphadenopathy is common. The breath may be foul as a result of overgrowth of anaerobic oral bacteria. Untreated, the illness resolves in 7-14 days, although the lymphadenopathy may persist for several weeks.

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Figure 244-1 Clustered perioral vesicles and erosions in an infant with primary herpetic gingivostomatitis.

(From Schachner LA, Hansen RC, editors: Pediatric dermatology, ed 3, Philadelphia, 1988, Mosby, p 1078.)

In older children, adolescents, and college students, the initial HSV oral infection may manifest as pharyngitis and tonsillitis rather than gingivostomatitis. The vesicular phase is often over by the time the patient presents to a health care provider, and signs and symptoms may be indistinguishable from those of streptococcal pharyngitis, consisting of fever, malaise, headache, sore throat, and white plaques on the tonsils. The course of illness is typically longer than for untreated streptococcal pharyngitis.