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HSV-1 and HSV-2 affect all populations. HSV-1 is transmitted primarily through contact with infected oral secretions; HSV-2 is acquired primarily through contact with infected genital secretions. In developed countries, urban poor populations acquire HSV-1 at a younger age (70%-80% seropositive by age 20 years) than do the rest of the population (30%-40%) (829Whitley R, Kimberlin DW, Roizman B. Herpes simplex viruses. Clin Infect Dis 1998;26:541-53.). In a large U.S. study, HSV-1 seroprevalence in children aged 6-13 years was 31% and increased with age, from 26% in 6- to 7-year-olds to 36% in 12- to 13-year-olds, and varied by race/ethnicity, birthplace, and poverty levels (higher in non-Hispanic blacks, children born in Mexico, and children living below poverty level) (830Xu F, Lee FK, Morrow RA, et al. Seroprevalence of herpes simplex virus type 1 in children in the United States. J Pediatr 2007;151:374-7.). The seroprevalence of HSV-1 approaches 60% among the general older adult population (831Xu F, Sternberg MR, Kottiri BJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA 2006;296:964-73.). HSV-2 seroprevalence in persons aged 14-49 years was 17% and increased with age, from 2% in 14- to 19-year-olds to 26% in 40- to 49-year-olds. HSV-2 seroprevalence was higher in non-Hispanic blacks, persons with large numbers of sex partners, and females and varied by birthplace and poverty level (831Xu F, Sternberg MR, Kottiri BJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA 2006;296:964-73., 832Fleming DT, McQuillan GM, Johnson RE, et al. Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med 1997;337:1105-11.).

An HSV-infected mother can transmit HSV to her infant, resulting in neonatal infection. In older children and adults, classic HSV transmission is person to person through direct contact with infected oral secretions or lesions. Neonatal HSV infection rate is 1 case per 2000-15,000 deliveries (833Whitley R, Davis EA, Suppapanya N. Incidence of neonatal herpes simplex virus infections in a managed-care population. Sex Transm Dis 2007;34:704-8.). Neonatal transmission occurs primarily through exposure of the infant to HSV-infected maternal genital fluids during passage through the birth canal; by ascending infection; or through use of invasive procedures, such as fetal scalp monitoring, that disrupt fetal skin integrity during labor (834Prober CG, Corey L, Brown ZA, et al. The management of pregnancies complicated by genital infections with herpes simplex virus. Clin Infect Dis 1992;15:1031-8.). Congenital (in utero) HSV acquisition is rare but can result in devastating cutaneous, ocular, and CNS damage.

Maternal HSV antibody status before delivery influences both the severity and likelihood of transmission to the infant (834Prober CG, Corey L, Brown ZA, et al. The management of pregnancies complicated by genital infections with herpes simplex virus. Clin Infect Dis 1992;15:1031-8.). The risk for neonatal HSV infection is greatest in an infant born to a woman with primary HSV infection (range: 30%-50%) (829Whitley R, Kimberlin DW, Roizman B. Herpes simplex viruses. Clin Infect Dis 1998;26:541-53.). The risk is much lower (0%-5%) for infants born to women shedding HSV caused by reactivated infection (589Mostad SB, Kreiss JK, Ryncarz A, et al. Cervical shedding of herpes simplex virus and cytomegalovirus throughout the menstrual cycle in women infected with human immunodeficiency virus type 1. Am J Obstet Gynecol 2000;183:948-55.). Genital shedding of HSV at delivery increases risk for transmission, and prolonged rupture of membranes (>6 hours) increases the risk, probably because of ascending HSV infection from the cervix. Cesarean delivery substantially lowers the risk for transmission (829Whitley R, Kimberlin DW, Roizman B. Herpes simplex viruses. Clin Infect Dis 1998;26:541-53., 834Prober CG, Corey L, Brown ZA, et al. The management of pregnancies complicated by genital infections with herpes simplex virus. Clin Infect Dis 1992;15:1031-8., 835Brown ZA, Wald A, Morrow RA, et al. Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant. JAMA 2003;289:203-9.). Importantly, many mothers of neonates with HSV-related illness will have pregnancy histories void of either past HSV infection or primary lesions (834Prober CG, Corey L, Brown ZA, et al. The management of pregnancies complicated by genital infections with herpes simplex virus. Clin Infect Dis 1992;15:1031-8.). In the United States, 75% of neonatal infections are caused by genital herpes, HSV type 2, and the remainder by HSV type 1.

In a study of seroprevalence among pregnant U.S. women, overall HSV-1 seroprevalence was 63%; HSV-2 seroprevalence, 22%; and infection with both HSV-1 and 2, 13% (836Xu F, Markowitz LE, Gottlieb SL, et al. Seroprevalence of herpes simplex virus types 1 and 2 in pregnant women in the United States. Am J Obstet Gynecol 2007;196:43.e1-6.). HSV seroprevalence differed by race/ethnicity and number of lifetime sex partners. HSV-2 infection rates might be higher in HIV-infected than HIV-uninfected women. Women infected with HIV, particularly those with low CD4 count, shed HSV from the vulva and cervix more commonly than do HIV-uninfected women; most of this shedding is asymptomatic (589Mostad SB, Kreiss JK, Ryncarz A, et al. Cervical shedding of herpes simplex virus and cytomegalovirus throughout the menstrual cycle in women infected with human immunodeficiency virus type 1. Am J Obstet Gynecol 2000;183:948-55., 837Augenbraun M, Feldman J, Chirgwin K, et al. Increased genital shedding of herpes simplex virus type 2 in HIV-seropositive women. Ann Intern Med 1995;123:845-7.). Among HIV-uninfected women, the rate of HSV reactivation is approximately 25% during the last month of pregnancy, but 2%-3% will be shedding on the day of delivery (838Catalano PM, Merritt AO, Mead PB. Incidence of genital herpes simplex virus at the time of delivery in women with known risk factors. Am J Obstet Gynecol 1991;164:1303-6.). In comparison, in women coinfected with HIV and HSV, an estimated 10% have cervical shedding of HSV on the day of delivery (839Hitti J, Watts DH, Burchett SK, et al. Herpes simplex virus seropositivity and reactivation at delivery among pregnant women infected with human immunodeficiency virus-1. Am J Obstet Gynecol 1997;177:450-4.). The risk for genital HSV reactivation and shedding increases as HIV-related immunosuppression progresses (837Augenbraun M, Feldman J, Chirgwin K, et al. Increased genital shedding of herpes simplex virus type 2 in HIV-seropositive women. Ann Intern Med 1995;123:845-7., 839Hitti J, Watts DH, Burchett SK, et al. Herpes simplex virus seropositivity and reactivation at delivery among pregnant women infected with human immunodeficiency virus-1. Am J Obstet Gynecol 1997;177:450-4.). No evidence indicates that in utero HSV infection of the infant occurs more frequently in HIV-infected pregnant woman or whether infants born to women coinfected with HIV and HSV-2 are at increased risk for perinatal (intrapartum) HSV infection. However, HSV infection may increase the risk for mother-to-child HIV transmission. In a study in Kenya of women receiving zidovudine prophylaxis, the presence of HSV-2 - related genital ulcers in late pregnancy was associated with increased plasma HIV RNA levels and increased risk for intrapartum HIV transmission, even after adjustment for plasma HIV RNA levels (840Drake AL, John-Stewart GC, Wald A, et al. Herpes simplex virus type 2 and risk of intrapartum human immunodeficiency virus transmission. Obstet Gynecol 2007;109(2 Pt 1):403-9.).

Recurrent or persistent HSV infection is the AIDS-indicator condition in approximately 6% of children with AIDS. In a study in HIV-infected children in the United States during the HAART era, the incidence of systemic HSV infection was 0.9 per 100 child-years and was most common among children with reduced CD4 percentage (<25%) (3Gona P, Van Dyke RB, Williams PL, et al. Incidence of opportunistic and other infections in HIV-infected children in the HAART era. JAMA 2006;296:292-300.). As in HIV-infected adults, HIV-infected children have more frequent and severe episodes of HSV reactivation. Five percent to 10% of children with AIDS and primary gingivostomatitis develop frequent recurrences, which can be associated with severe ulcerative disease and symptoms similar to primary infection (841Salvini F, Carminati G, Pinzani R, et al. Chronic ulcerative herpes simplex virus infection in HIV-infected children. AIDS Patient Care STDS 1997;11:421-8.). HIV-infected children also can shed virus longer with both primary and reactivation HSV infection than can HIV-uninfected children.

Neonatal HSV can appear as disseminated multiorgan disease (approximately 25% of neonates with HSV infection); localized disease of the CNS (approximately 35% of neonates); or CNS disease localized to the skin, eyes, and mouth (approximately 40% of neonates) (842Kimberlin DW, Lin CY, Jacobs RF, et al. Natural history of neonatal herpes simplex virus infections in the acyclovir era. Pediatrics 2001;108:223-9.). Infants with disseminated disease usually present at age 9-11 days; encephalitis occurs in 60%-75% of these infants. Vesicular rash occurs in approximately 80% of children with localized disease of the skin, eyes, and mouth, but in only approximately 60% of children with CNS or disseminated disease (842Kimberlin DW, Lin CY, Jacobs RF, et al. Natural history of neonatal herpes simplex virus infections in the acyclovir era. Pediatrics 2001;108:223-9., 843Kimberlin DW. Herpes simplex virus infections of the newborn. Semin Perinatol 2007;31:19-25.). Localized disease usually presents by the 10th day of life, and even with treatment, neonates with skin lesions commonly have cutaneous recurrences during the first 6 months after treatment (842Kimberlin DW, Lin CY, Jacobs RF, et al. Natural history of neonatal herpes simplex virus infections in the acyclovir era. Pediatrics 2001;108:223-9.). Infants with localized CNS disease, or CNS disease with skin, eyes, and mouth involvement, usually are ill by day 16-19 of life (843Kimberlin DW. Herpes simplex virus infections of the newborn. Semin Perinatol 2007;31:19-25.). Although treatment has reduced morbidity and mortality, infants with neonatal HSV infection remain at risk for neurologic sequelae, with the most severe neurologic sequelae seen in those with CNS disease. Two percent to 6% of infants with localized skin, eye, or mucus membrane disease have later neurologic sequelae after apparently successful treatment (844Gutierrez K, Arvin AM. Long term antiviral suppression after treatment for neonatal herpes infection. Pediatr Infect Dis J 2003;22:371-2., 845Kimberlin DW, Powell D, Gruber W, et al. Administration of oral acyclovir suppressive therapy after neonatal herpes simplex virus disease limited to the skin, eyes and mouth: results of a phase I/II trial. Pediatr Infect Dis J 1996;15:247-54.).

After the neonatal period, the most common appearance of HSV infection in children is orolabial disease. Fever; irritability; tender submandibular lymphadenopathy; and superficial, painful ulcers in the gingival and oral mucosa and perioral area characterize primary HSV gingivostomatitis. HIV-infected children who experience primary infection when they are immunocompromised can have severe local lesions or, more rarely, disseminated HSV with visceral involvement and generalized skin lesions with primary infection. Other sites of involvement among HIV-infected children with severe immunocompromise include the esophagus, CNS, and genitals and disseminated disease involving the liver, adrenals, lung, kidney, spleen, and brain.

HSV genitalis is the more common manifestation of HSV-2 infection. Painful, ulcerative lesions on the perineum and on vaginal and urethral mucosal surfaces are common during primary infection. Local symptoms include pain and pruritis. Mucosal disease usually is accompanied by dysuria, or vaginal or urethral discharge; inguinal lymphadenopathy, particularly in primary infection, is common with perineal disease (846Corey L, Adams HG, Brown ZA, et al. Genital herpes simplex virus infections: clinical manifestations, course, and complications. Ann Intern Med 1983;98:958-72.).

Among HIV-infected persons, HSV keratitis, neonatal HSV, HSV encephalitis, and herpetic whitlow are similar in presentation and treatment to diseases in HIV-uninfected persons but might be more severe. HSV retinitis occurs as acute retinal necrosis, occasionally in patients with HSV encephalitis. HSV encephalitis occurs among HIV-infected persons, but no evidence indicates it is more severe or common than among HIV-uninfected persons.

Clinical diagnosis is based on the typical appearance of vesicles and ulcers. The virus can be isolated in culture and usually can be detected in tissue culture cells within 1-3 days. HSV DNA by PCR also can be used to establish the presence of HSV infection in skin lesions or infected mucosal sites of perinatally exposed newborns. To diagnose neonatal HSV infection, specimens for HSV culture or HSV DNA PCR should be obtained from blood and skin vesicles, mouth or nasopharynx, eyes, urine, and stool or rectum; positive cultures from any of the latter sites >48 hours after birth indicate viral replication rather than contamination after intrapartum exposure. CSF should be tested for HSV DNA by PCR amplification of an HSV DNA sequence common to both HSV-1 and HSV-2. Direct immunofluorescence for HSV antigen can be conducted on cells collected from skin, conjunctiva, or mucosal lesion scrapings. Giemsa staining (Tzanck preparation) of lesion cell scrapings might show multinucleated giant cells and eosinophilic intranuclear inclusions, but this test is insensitive, nonspecific, and not routinely recommended.

Among children with suspected HSV encephalitis, cultures of the CSF for HSV usually are negative. Detection of HSV DNA by PCR in the CSF has replaced brain biopsy as the diagnostic test of choice for such patients. The reported sensitivity of the CSF PCR in neonatal CNS HSV disease is 75%-100%, with the specificity 70%-100% (847). During therapy for HSV-proven encephalitis, the CSF HSV PCR remains positive for a mean of 10 days (848Kimura H, Aso K, Kuzushima K, et al. Relapse of herpes simplex encephalitis in children. Pediatrics 1992;89(5 Pt 1):891-4.).

Definitive diagnosis of HSV esophagitis requires endoscopy with biopsy (histologic evidence of multinucleated giant cells with intranuclear viral inclusion) and culture.

Antiviral prophylaxis after exposure to HSV, or to prevent initial episodes of HSV disease among persons with latent infection, is not recommended (DIII).

Acyclovir is excreted primarily by the kidney; as a result, dose adjustment based on creatinine clearance is needed in patients with renal insufficiency or renal failure. Primary toxicities of acyclovir are phlebitis, renal toxicity, nausea, vomiting, and rash. Toxicities are similar for valacyclovir. In infants receiving high-dose acyclovir for neonatal disease, the major side effect was neutropenia (e.g., absolute neutrophil count <1000/mm³) (857Kimberlin 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;108:230-8.). Grade 3 or higher nephrotoxicity was observed in 6%. For infants and children receiving high-dose IV acyclovir, monitoring of complete blood counts and renal function is recommended at initiation of treatment and once or twice weekly for the duration of treatment, particularly for those with underlying renal dysfunction or those receiving prolonged therapy.

Management of acyclovir-resistant herpes with foscarnet is associated with decreased renal function; ≤30% of patients experience increases in serum creatinine levels. Renal toxicity and foscarnet binding to divalent metal ions such as calcium leads to metabolic abnormalities in approximately one third of patients, and serious electrolyte imbalances (including abnormalities in calcium, phosphorus, magnesium, and potassium levels) and secondary seizures, or cardiac dysrhythmias can occur. Abnormal liver transaminases and CNS symptoms also can occur. For patients receiving foscarnet, complete blood counts, serum electrolytes, and renal function should be monitored twice weekly during induction therapy and once weekly thereafter.

Atypical lesions that may have a delayed response to therapy have been reported in adults initiating HAART and attributed to IRIS (856Strick LB, Wald A, Celum C. Management of herpes simplex virus type 2 infection in HIV type 1-infected persons. Clin Infect Dis 2006;43:347-56.).

Treatment failure related to resistance to antiviral drugs should be suspected if lesions do not indicate signs of resolution within 7-10 days after initiation of therapy. In immunocompromised patients with suspected acyclovir-resistant HSV, a lesion culture should be obtained and, if virus is isolated, susceptibility testing performed to confirm drug resistance (858Balfour HH, Jr. Antiviral drugs. N Engl J Med 1999;340:1255-68.).

The treatment of choice for acyclovir-resistant HSV is IV foscarnet (AI) (858Balfour HH, Jr. Antiviral drugs. N Engl J Med 1999;340:1255-68., 865Balfour HH, Jr, Benson C, Braun J, et al. Management of acyclovirresistant herpes simplex and varicella-zoster virus infections. J Acquir Immune Defic Syndr 1994;7:254-60.). All acyclovir-resistant HSV strains are resistant to valacyclovir, and most are resistant to famciclovir. Topical trifluridine or cidofovir also have been used successfully for lesions on cutaneous surfaces, although prolonged application for 21-28 days or longer might be required (866Lateef F, Don PC, Kaufmann M, et al. Treatment of acyclovir-resistant, foscarnet-unresponsive HSV infection with topical cidofovir in a child with AIDS. Arch Dermatol 1998;134:1169-70.). IV cidofovir has been used to treat a child with acyclovir and foscarnet resistant HSV (867Blot N, Schneider P, Young P, et al. Treatment of an acyclovir and foscarnet-resistant herpes simplex virus infection with cidofovir in a child after an unrelated bone marrow transplant. Bone Marrow Transplant 2000;26:903-5.).

Administration of oral acyclovir prevented cutaneous recurrences of HSV after neonatal disease of the skin, eyes, and mouth. However, the effect of such therapy on neurologic outcome needs assessment, and additional investigation is necessary before routine use of suppressive therapy can be recommended for children (845Kimberlin DW, Powell D, Gruber W, et al. Administration of oral acyclovir suppressive therapy after neonatal herpes simplex virus disease limited to the skin, eyes and mouth: results of a phase I/II trial. Pediatr Infect Dis J 1996;15:247-54.).

Because episodes of HSV disease can be treated successfully, chronic therapy with acyclovir is not required after lesions resolve. However, children who have frequent or severe recurrences (e.g., four to six severe episodes a year) can be administered daily suppressive therapy with oral acyclovir (AI) (864Eksborg S. The pharmacokinetics of antiviral therapy in paediatric patients. Herpes 2003;10:66-71.). Valacyclovir or famciclovir also are options for older children (AI). Effective HAART may decrease recurrences.

Not applicable, secondary prophylaxis not usually recommended in children.