Herpes Simplex

After completing this article, readers should be able to: HSV causes a contagious infection that affects approximately 60% to 95% of adults worldwide. HSV1 and HSV2 primarily infect human populations. HSV1 is associated chiefly with infections of the mouth, pharynx, face, eye, and central nervous system (CNS), and HSV2 is associated primarily with infections of the anogenital region, although both serotypes may infect any area. (1)Most adults are infected with HSV and carry latent viruses, but the serotype, severity of symptoms, and mode of transmission vary with age. Children are infected primarily with orolabial HSV1 by 5 years of age, with infection rates of 33% in populations that are of lower socioeconomic status and 20% in those who have improved socioeconomic status. By adulthood, HSV1 affects 70% to 80% in the lower socioeconomic population and 40% to 60% in the higher socioeconomic population. (1) Globally, the prevalence of HSV1 increases consistently with age, reaching 40% by age 15 years and increasing to 60% to 90% in older adults. (2) In the United States, the prevalence of HSV1 increases consistently with age, from 26.3% in 6- to 7-year-old children and 36.1% in 12- to 13-year-old children to 90% among those older than 70 years. (2)(3) Of note, the overall prevalence of HSV1 in the United States has been shown to be decreasing over time. (3)Worldwide, the prevalence of HSV1 infection is greater than HSV2 infection in most geographic areas. HSV2 primarily is sexually transmitted and, therefore, is not as common in young children. However, HSV2 can be transmitted from mother to neonate during pregnancy, with a neonatal incidence between 1 in 3,000 and 1 in 20,000 live births and approximately 1,500 new cases in the United States annually. Approximately 2% of women acquire genital herpes during pregnancy, and about 20% to 30% of pregnant women are seropositive for HSV2. (4) The prevalence of HSV2 varies across country, sex, and age. HSV2 prevalence is highest in areas of sub-Saharan Africa and parts of Central and South America. The prevalence usually is lower in western and southern Europe than in northern Europe and North America. The lowest rates of HSV2 prevalence are found in Asia.Generally, the prevalence is higher in women than in men and increases with age from negligible levels in children younger than 12 years to 20% to 40% by the age of 40 years and as high as 80% among higher-risk populations. (1)(2)(5)(6) In the United States, the prevalence of HSV2 infection in African Americans is much higher than in whites or Mexican Americans. Although time trends in HSV prevalence are limited, most studies suggest that the prevalence of HSV2 has increased over the past few decades in countries such as the United States from 16.0% in the late 1970s to 20.8% in the early 1990s; in other populations, HSV2 prevalence has either remained stable or decreased. (2)As stated previously, HSV2 is associated primarily with infections of the anogenital region, whereas HSV1 is found extragenitally. Recent studies, however, have shown a 30% increase in the prevalence of HSV2 infection, (7) with HSV2 being as common as HSV1 in the extragenital regions except for the orofacial area. Furthermore, HSV1 appears to be increasing in prevalence in the anogenital region, previously known to be infected predominantly by HSV2.There are more than 80 herpesviruses, eight of which are capable of infecting humans. In addition to HSV1 and HSV2, varicella-zoster virus (VZV), cytomegalovirus, Epstein-Barr virus, human herpesviruses (HHV6 and HHV7), and Kaposi sarcoma-associated herpesvirus (HHV8) can infect humans. All herpesviruses are enveloped, double-stranded DNA viruses that have highly organized genomes encoding more than 84 polypeptides. (6) Although the DNA sequences of HSV1 and HSV2 are very similar, the proteins within the envelope allow serologic distinction between the two.Infection is transmitted primarily through exposure to mucous membranes or skin that have active lesions or to mucosal secretions of an individual who has an active HSV infection. The virus is transmitted most easily through saliva and can remain stable outside of the host for short periods of time, allowing transmission for some time after direct mucocutaneous contact with the virus. HSV also can be transmitted through respiratory droplets or by exposure to mucocutaneous secretions from an asymptomatic person who is shedding virus. Shedding refers to the presence of viruses outside of the cells on the skin surface, despite the absence of clinical signs. (1) The initial or primary HSV1 or HSV2 infection usually has an incubation period of approximately 4 days, but can range from 2 to 12 days. This is followed by an active viral shedding period that lasts at least 1 week and up to several weeks. Most patients who are primarily infected with HSV are asymptomatic. Therefore, the virus still can be actively transmitted during the period of incubation and viral shedding without the occurrence of active skin lesions. (1) After initial infection, the virus usually remains latent, persisting within the sensory ganglia of the autonomic nervous system, and the infection can be considered incurable. Within the autonomic ganglia, the virus replicates while evading detection by the host immune system. (1)(6) HSV1 resides most commonly within the trigeminal ganglion, due to its primary target site in and around the oral areas; HSV2 primarily remains in sacral ganglia after infection of the genital region. Once triggered to reactivate by an internal or external stimulus, including stress, exposure to sunlight, fever, and menstruation, the virus can travel along the sensory nerve and reactivate in the same mucocutaneous region as the initial infection. Symptoms normally last for a shorter period of time than for the initial infection, and viral shedding only lasts 3 to 4 days. On average, reactivation of HSV occurs during approximately 1% of the days in the life of patients infected previously. (8)Several methods are employed to diagnose the presence of HSV infection, each having varying degrees of selectivity, sensitivity, cost, and utility. The main clinical method for diagnosing primary HSV1 infection is recognizing the classic presentation of herpetic lesions in or around the oral cavity. Monomorphous, grouped vesicles on an erythematous base evolve into coalescing, crusted papules and plaques within 1 to 3 days. The lesions have a propensity to erode or ulcerate. Initial infection can lead to an extensive gingivostomatitis. In contrast to HSV1, the initial diagnosis for HSV2 can be more difficult because the classic signs of genital herpes, herpetic ulcers in and around the genital area, may not be present. In neonates, the presence of vesicular lesions should raise high suspicion for HSV infection.Laboratory evaluations can be used to confirm an initial diagnosis or further investigate a suspicion of HSV infection. The gold standard for laboratory diagnosis is the viral culture. The viral culture technique can be employed only with active lesions and is obtained best by vigorously swabbing the base of an unroofed vesicle. The swab is inoculated into a prepared cell culture, and the inoculated cells are observed for characteristics of HSV infection, including multinucleated giant cells and desquamated epithelial cells with intranuclear inclusions. Such findings usually are observed within 2 to 7 days after inoculation and can confirm the presence of HSV infection. If the inoculated cell culture is devoid of characteristic signs of HSV infections for more than 15 days, the sample is reported as negative. Although this method offers a relatively rapid and effective method of diagnosing HSV infection, it can be limited by the quality of swabbing and culture techniques. The Tzanck smear is a rapid and reasonably priced diagnostic test that can confirm the presence of HSV infection. Cells scraped from the base of a freshly opened vesicle are stained and evaluated for the characteristic cytopathology of HSV infected cells, including multinucleated giant cells and eosinophilic intranuclear inclusions (Fig. 1). Although the test can confirm the presence of HSV or VZV, it cannot differentiate between the two herpes serotypes and, therefore, cannot diagnose HSV1 or HSV2 infection definitively. In addition, the sensitivity and specificity of the test are highly variable, depending on the evaluator. An experienced clinician, such as an infectious disease specialist or pathologist, should interpret test results because the findings may be subtle. With the increasing availability of the direct fluorescent antibody (DFA) technique, the Tzanck smear has decreased in popularity as a diagnostic alternative. DFA testing is an immunohistochemistry technique that uses a specific antibody to identify the presence of viral antigens. The antibody is tagged with fluorescent agent and forms an antigen-antibody complex with HSV antigens present within a tissue or smear specimen. The process can be performed with cytologic preparations, such as the Tzanck smear, as well as virally inoculated cell cultures. In addition, DFA may be employed to serotype the HSV infection. Because DFA testing is rapid, sensitive, inexpensive, and virally selective, it often is used to substantiate clinical suspicion and determine serotype.A punch, shave, or wedge tissue biopsy also may be used to detect the presence of HSV infection and is especially helpful when a suspicious lesion is old or atypical. The biopsied cells are observed microscopically to detect degenerative cytopathologic changes commonly associated with the infection. The degenerative changes present in cells infected with HSV1 and HSV2 also are observed in cells infected with VZV. Thus, the specificity of the technique is low, and the test cannot be used to serotype the infection.Amplification of viral DNA using polymerase chain reaction (PCR) is another method for detecting the putative presence of viral DNA. This method is particularly useful for detecting the presence of HSV in the cerebrospinal fluid (CSF) of patients suspected of having herpes encephalitis. As HSV PCR becomes more readily available and less expensive, it has the potential to become the most widely used means of detecting HSV for all types of infection because it is rapid, highly reliable, and valid.Serologic assays are employed to detect the presence of HSV antibodies when other techniques are impractical or ineffective. Such assays take longer to complete than other techniques and should be considered primarily for diagnosing recurrent infections, in the presence of healing lesions and the absence of active lesions, or when partners of persons who have clinical herpes are at risk. Sera are collected at two separate times; acute serum is obtained within 3 to 4 days after the onset of the initial symptoms and convalescent serum is gathered several weeks after the symptoms have abated. To confirm a diagnosis of primary HSV infection, the acute sample should be devoid of HSV-positive antibodies due to the delayed humoral response, and the convalescent sample should demonstrate the presence of both immunoglobulin G and M antibodies to HSV proteins. If any quantities of antibodies are observed in the acute sample, primary infection is ruled out and the diagnosis is recurrent herpes infection. The absence of antibodies in both samples indicates a negative test, which should be verified later by another serologic assay. In the absence of herpetic lesions, traditional serologic assays cannot determine the serotype or whether the site of infection is oral or genital. However, newer type-specific serologic assays can be performed to test for antibodies to both HSV1 and HSV2 proteins.Several transport media are available for effective viral transport after collection of the specimen, including swabs, liquid media, and cell cultures. Studies suggest that although there are slight differences in the survivability of both HSV1 and HSV2 in different media, most media are effective as long as the temperature is tightly controlled, preferably at 39.2°F (4.0°C), and transport times are kept to a minimum, preferably less than 24 hours and no greater than 48 hours. (9) Survival of the virus at temperatures greater than 39.2°F (4.0°C) and transport times greater than 48 hours for all transport media is variable and more dependent on viral concentration and accurate laboratory techniques.The clinical presentation of HSV infection is variable and dependent on method of transmission, age, and immunocompetency of the host. Cutaneous lesions usually consist of small, monomorphous vesicles on an erythematous base that rupture into painful, shallow, gray erosions or ulcerations with or without crusting. (10) The skin lesions typically are preceded by prodromal symptoms such as burning and paresthesia at the site, lymphadenopathy, fever, malaise, myalgia, loss of appetite, and headaches. Most initial infections are subclinical and may be unrecognized. Recurrent infections due to reactivation of the latent viruses in the dorsal root ganglia are more localized, milder, and shorter in duration. They tend to occur following triggers such as stress, menstruation, exposure to sunlight, and fatigue. Both primary and recurrent HSV infections can manifest on any mucocutaneous surface. Table 1 summarizes the clinical manifestations, differential diagnoses, and recommended treatments of herpetic infections occurring after the neonatal period.Herpetic gingivostomatitis presents as multiple round ulcers or superficial erosions commonly affecting the palate, tongue, and gingivae. It is caused much more commonly by HSV1. Patients may present with the typical prodromal symptoms, followed by classic vesiculoulcerative lesions. Children may present with diffuse erythema and swelling of the gingiva, drooling, foul-smelling breath, and anorexia. Such nonspecific signs and symptoms can be caused by a wide range of conditions, including Coxsackievirus infections, erythema multiforme, pemphigus vulgaris, acute necrotizing ulcerative gingivitis, and most commonly, aphthous stomatitis. Aphthous stomatitis can be differentiated from herpetic gingivostomatitis by the absence of a vesicular stage, prodrome, and systemic signs and symptoms. The major complication of herpetic gingivostomatitis is dehydration in children whose painful lesions result in poor fluid intake. Thus, pain control and sufficient rehydration comprise the mainstay of management.Herpes labialis is the most common manifestation of HSV1 infection. Because most initial infections are asymptomatic and may be unrecognized, recurrent orofacial herpes (commonly called fever blisters or cold sores) typically is the initial manifestation in children and young adults. The outer vermilion border is a common location, and the crusted lesions often are confused with staphylococcal or streptococcal impetigo (Figs. 2, 3). Secondary bacterial infections with Staphylococcus or Streptococcus also may occur and are characterized by honey-colored crusting on of the classic herpetic lesions. with oral can be effective within 1 to 2 days of prodromal symptoms. with an oral can the of and is recommended for patients who or more is in and, therefore, is not herpes (Fig. most commonly is caused by HSV2, although the due to HSV1 has been increasing (1) This sexually transmitted infection is associated with such as lower socioeconomic and (1) other such as and and such as infection, herpes and be suspected in children who genital and The of the to the is but two are including the and direct from mucocutaneous through the with oral can be effective patients least with an oral is HSV infection is the most common infectious of worldwide. HSV1 is the followed by or of the along with and herpes to is recommended to such as bacterial infection, and with HSV may have associated systemic or of both and oral presents with and vesiculoulcerative lesions on the of the of the (Fig. This infection occurs commonly in patients who have primary oral or genital herpes to and In contact is the most common of herpetic In and contact is more HSV2 the infectious agent of herpetic bacterial or and (10) are and are used in extensive occurs in those in contact such as and It most commonly affects areas such as the face, and HSV1 is more to be the agent than HSV2, due to the of contact and Patients who have herpes should contact during the culture results are negative. to transmission also should be and for active lesions and from and with for at least 15 of contact time between The that not be to the are and If the lesions have not crusted over or the are not the is high that the still is to the should be performed after the are and The of an be and to is to be but about such are and the to be of this the of can be a manifestation of primary or recurrent Patients present with nonspecific symptoms such as and HSV is characterized by with and cells in the HSV also is to a of of recurrent of and fever that pain trigeminal and is less effective in older adults than in children. Therefore, the recommended for adults for also is recommended for patients who have herpes infections of the herpes occurs in 1 in 3,000 to 20,000 live births and affects approximately 1,500 to in the United In addition, 40% to of to with primary genital lesions are with only 2% to of those to women (10) to 70% of who have neonatal herpes are to asymptomatic to the in diagnosing this herpes in the 4 weeks after and of different types on clinical eye, and with and and lesions are on the mouth, and eye, the skin into contact with the genital lesions (Fig. infection presents with signs such as and for 60% of the lesions also are can up to 40% of neonatal HSV is a manifestation that is associated with a of at least present with and multiple system differential diagnosis of neonatal HSV infection bacterial and viral infections such as and and and cell also may present with vesicles and be differentiated from HSV by using the diagnostic techniques is transmitted most commonly during but also can be transmitted in or through contact with the mother or other It is not transmitted through human of transmission are associated with younger age of the the presence of genital lesions during and Because of high rates of and diagnosis and of are high of suspicion is in who have vesicular skin lesions, with negative culture fever, and particularly are present. Because of the of the and the it is to culture results suspicion also is although there is no on the who are and have seropositive partners should be to those who acquire primary genital HSV during late pregnancy, the some and However, for those who have a of recurrent genital a found to the of HSV an HSV2 infection of the that has often in However, those that to typically present with vesicular lesions, and on HSV in can be differentiated from neonatal HSV by the absence of signs of systemic and in the as well as the presence of both and antibodies differential diagnostic and is to that for neonatal although the is and all also is known as Kaposi It is characterized by HSV infections of skin from an caused by and (1) The lesions tend to into superficial erosions and often are (Figs. and infected lesions. for bacterial infection, and (10) Most such as in areas of systemic has been However, the of is in infections in such as those who have immune and tend to have higher of and longer of and are less to (10) and The skin lesions often are and can be or The differential diagnosis herpes and conditions, depending on the of the with is erythema is a complication of HSV that erythema skin lesions. Patients commonly present with target or lesions on the with a for and The lesions occur within days of oral or genital HSV reactivation (Figs. and (1) This to without However, patients may from of HSV infections often both and of Because of the infectious of the virus and the it to the neonate and of is and should be in of transmission is the in the of HSV Patients should be the of the transmission through and and asymptomatic shedding of the virus. Patients who have active lesions on the skin should direct contact with the of or other methods during for genital the of contact and of who have active lesions, and of with after for herpes and the of or for pregnant women who are whose partners are seropositive to primary HSV infections during the of the The multiple that stress, exposure to sunlight, fever, menstruation, and to the such as should be with a contact should be by all for all patients infected with HSV except for those whose infections are limited to and the with a when using at all times; after and during direct contact with a or in the of HSV infections not result in but can the of the clinical and the of treatments and and pain control and Such is particularly for children with herpes labialis and gingivostomatitis. Because of patients may to or in control with and oral or rehydration may be oral for children is and although in children not been by the United States and as of is in primary genital HSV infection when is within days of disease onset and can the by 3 to 5 days. In HSV oral within 2 days of onset the only by an of 1 The recommended is of 80 for 7 to days in initial infections and for 5 days in with oral is for patients of or HSV infection that or more The recommended is 80 in with a of for a of 12 has shown that at a of a can in most of HSV be suspected in patients disease despite particularly in is the recommended in this is for cases having the potential for Such any neonate who has HSV infection, mucocutaneous HSV infections in and HSV encephalitis. The recommended is for days in who have disease and days in other neonatal HSV infections and HSV is known to Therefore, it is to the on the and and serum commonly by such as are not recommended to most mucocutaneous HSV lesions because such not the severity or of infections in is recommended in patients because it has been shown to the healing of including 1% and are for of HSV and neonatal HSV with