Sections

Pediatric Herpes Simplex Virus Infection

Sections Pediatric Herpes Simplex Virus Infection
Overview
Presentation
DDx
Workup
Treatment
Guidelines
Medication
Questions & Answers
Media Gallery
References

Overview

Practice Essentials

Herpes simplex virus (HSV) infections are ubiquitous and have a wide range of clinical manifestations (see the images below). Beyond the neonatal period, most primary HSV-1 infections occur in infancy and childhood and are transmitted primarily by contact with infected saliva. Primary HSV-2 infections are acquired after onset of sexual activity, and genital herpes infections are among the most common sexually transmitted infections.

Primary herpes simplex virus (HSV) gingivostomatitis in an infant is shown. This same patient also had concomitant herpes whitlow as shown in the following image.

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Herpes whitlow in an infant.

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Signs and symptoms

HSV causes myriad clinical presentations, as follows:

Orolabial infection
Genital infection
Intrauterine and perinatal infection (herpes neonatorum)
Central nervous system infection
Infection in immunocompromised hosts
Other infections: Herpetic whitlow, herpes gladiatorum, keratoconjunctivitis, Mollaret meningitis, erythema multiforme

Clinical features of orolabial HSV infection include the following^[1]:

Abrupt onset of illness
Fever
Listlessness or irritability
Inability to eat and/or drink
Gingivitis (with markedly swollen, erythematous, and occasionally bleeding gums)
Increased drooling in infants due to pain on swallowing
Vesicular lesions on the tongue, buccal mucosa, and palate with extension, at times, to the lips and face (these may rupture and coalesce to form large, ulcerated areas)
Tender submandibular or cervical adenopathy
In recurrent cases, a prodrome of pain, burning, tingling, and itching

Clinical features of genital HSV infection may include the following:

In first episodes, severe constitutional symptoms (eg, fever, malaise, myalgias^[2])
Initial itching and pain, followed by more troublesome signs and symptoms
Lesions that evolve from vesicles to pustules to wet ulcers and heal by crusting
Painful inguinal lymphadenopathy, dysuria, and vaginal discharge
Paresthesias of the legs and perineum
Urinary retention

Herpes neonatorum may be categorized as follows^{[3, 4, 5, 6, 7]}:

Skin, eye, and mucous membrane (SEM) disease
Disseminated infection
CNS infection

Clinical features of HSV CNS infection may include the following:

Insidious or abrupt onset
Headache, altered consciousness, and focal neurologic abnormalities at presentation
Symptoms of aseptic meningitis (headache, fever, stiff neck, photophobia)
Symptoms of autonomic nervous system dysfunction and transverse myelitis (eg, hyperesthesia or anesthesia of the lower back, perineum, or sacral region)

See Clini cal Presentation for more detail.

Diagnosis

Measures for diagnosing HSV infection in children include the following:

PCR assay (preferred for CNS infection^{[8, 9, 10]}and possibly valuable for disseminated disease)
Isolation of the virus in tissue cultures (most common confirmation method)
Histologic analysis of scrapings or punch biopsy specimens
Cytologic evaluation via a Tzanck preparation
Serologic testing (only for determining past HSV exposure)
Lumbar puncture and cerebrospinal fluid analysis
Immunofluorescent microscopy
Brain biopsy
Imaging studies: Computed tomography, magnetic resonance imaging

See Workup for more detail.

Management

Specific medical therapy for pediatric HSV infection involves antiviral medications. For neonates born either vaginally or by Caesarian section to infected mothers, determination of primary vs reactivation disease in the mother is necessary to guide duration of therapy. Antiviral agents used include the following:

Oral acyclovir (most common)
Oral famciclovir (a prodrug that is converted to penciclovir)
Oral valacyclovir (a prodrug that is converted to acyclovir)
IV acyclovir (for encephalitis, neonatal disease, severe infection in immunocompromised patients, occasional cases of severe orolabial or genital disease,^{[11, 12, 13, 14]}, and recurrent genital HSV infections)

Inpatient management is often indicated for pediatric patients with HSV infections. Suggested criteria include the following:

Many children with severe HSV gingivostomatitis who are dehydrated
Neonates with disseminated or CNS disease
Older patients with encephalitis who may be very ill at presentation
HSV infection in immunocompromised patients

Measures to prevent or minimize transmission of genital HSV infection include the following:

Avoid contact with individuals excreting the virus (difficult, because they are often asymptomatic)
Start oral antiviral therapy at the first symptom or sign of genital HSV disease
Promote condom use
Provide appropriate evaluation, counseling, and education

Measures to prevent transmission of HSV to newborns include the following:

Reassure women with recurrent disease that risk of neonatal infection is low
Perform cesarean delivery if a mother has active lesions during delivery^[15]
Observe infants delivered vaginally by mothers with active genital herpes. At approximately 24 hours, obtain screening laboratory testing as per American Academy of Pediatrics guidelines (see Guidelines Summary)^[16]
In pregnant women with symptomatic genital herpes, consider antiviral suppressive treatment initiated at the time of diagnosis

See Treatment and Medication for more detail.

Background

Herpes simplex virus (HSV) is a double-stranded, enveloped, DNA virus. Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) belong to the family Herpesviridae, subfamily Alphaherpesvirinae. Following initial infection, the herpes viruses become latent in the sensory neural ganglia (the trigeminal and/or sacral ganglion in HSV-1 infection^[17]and usually the sacral ganglion in HSV-2 infection^[18]). Herpes simplex virus infections are ubiquitous and cause a wide range of infections from isolated mucocutaneous lesions to disseminated infection in all age groups. Neonatal herpes simplex virus disease is associated with high morbidity and mortality.^[19]Herpes simplex virus infections are among the few non-HIV viral infections amenable to antiviral therapy. Available antiviral chemotherapy can be used to treat infection, shorten the clinical course, and, in certain circumstances, prevent infection with herpes simplex virus.

Pathophysiology

Infection occurs in a susceptible host following exposure of abraded skin or mucosal surfaces to the virus. After inoculation, the virus travels to the sensory ganglion, where it replicates and establishes latency. Recurrence occurs when the virus subsequently migrates along the peripheral sensory nerve, replicates, and produces a typical local lesion.^{[20, 21]}Lifelong latency and periodic recurrences are hallmarks of herpes simplex virus infection. These reactivations can follow exposure to ultraviolet light, stress, hormonal changes, immunosuppression, and other infection.^{[22, 23]}Histology of skin lesions shows cellular balloon degeneration, condensation of nuclear chromatin, and formation of multinucleated giant cells.^[21]

Disseminated infection occurs when the host is unable to control viral replication leading to viremia and multiorgan involvement. It is usually seen in neonates and immunocompromised individuals (and very rarely in immunocompetent hosts). Specific immunologic factors responsible for immunity to herpes simplex virus are not completely understood. Both antibody and cell-mediated immunity influence the severity and frequency of recurrences. Herpes simplex virus is also believed to suppress innate immunity by suppressing the production of interferon-alfa and interferon-beta.^[24]Additionally, titers of antibodies that mediate antibody-dependent cellular cytotoxicity inversely correlate with severity of neonatal infection.^[25]

United States statistics

Herpes simplex virus infections occur throughout the world, with humans serving as the only reservoir. The infection is acquired by intimate mucocutaneous contact between a susceptible host and a symptomatic or asymptomatic host shedding virus during primary infection or reactivation. Because the infection results in lifelong latency, the prevalence in any population is cumulative. An estimated 90% of all people worldwide have one or both viruses.^[26]

Beyond the neonatal period, most primary HSV-1 infections occur in infancy and childhood and are transmitted primarily by contact with infected saliva. Primary HSV-2 infections are acquired after onset of sexual activity and genital herpes infections are among the most common sexually transmitted infections (STIs).

The prevalence of herpes simplex virus infections depends on socioeconomic status, age, race, and geographic location. For example, approximately 33% of children from lower socioeconomic backgrounds have serologic evidence of herpes simplex virus disease by age 5 years compared with 20% of middle-class individuals. Greater person-to-person contact in crowded living conditions is believed to account at least in part for the role of socioeconomic status in prevalence, though multiple additional factors may also be responsible.^[27] The importance of daycare attendance is likely but not well studied.

In the United States, HSV-2 seroprevalence increases from about 20-30% in patients aged 15-29 years to 35-60% in patients aged 60 years. This change represents a 30% increase compared with data from 1976-1980. Factors that increase the frequency of HSV-2 infection in older adolescents and adults include gender (more women than men), race (more blacks than whites), marital status (more divorced individuals than single or married individuals), and place of residence (more city residents than suburban residents).^{[28, 29]}

The seroprevalence rate of HSV-2 in pregnant women ranges from 15-30%.^[30] Approximately 10% of pregnant women who are HSV-2 seronegative have a sexual partner who is HSV-2 seropositive and are, therefore, at risk of contracting a primary HSV-2 infection during pregnancy. Transmission typically results from contact with an asymptomatic sexual partner with a reported risk of acquisition of approximately 10%.^{[31, 32]} Overall, approximately 2% of women acquire herpes simplex virus during pregnancy.

International statistics

Herpes simplex virus has worldwide distribution. The prevalence of genital herpes in developing countries is 2-74% and varies among countries.^{[33, 34]} In African countries that are experiencing HIV epidemics, HSV-2 infection is highly prevalent (≥70%).^[35] Evidence suggests that genital herpes simplex virus infection increases the risk of HIV infection and that persons infected with both viruses are more likely to transmit HIV.^{[36, 37, 38]}

A meta-analysis of Canadian studies by AlMukdad et al suggests that the seroprevalence of HSV-1 and the proportion of genital herpes cases in which HSV-1 is detected are on the rise. The pooled mean proportion of genital herpes cases in which HSV-1 was detected was 37.4%, and the proportion was highest among women and among adolescents and young adults.^[39] A meta-analysis of studies in Australia and New Zealand by the same researchers found that the pooled mean proportion of HSV-1 detection in genital herpes was 30.5% and was highest among young persons.^[40]

Race-, sex-, and age-related demographics

Race

Although the risk of herpes simplex virus infection is not related to race, infection rates in the United States vary according to race because of various factors, such as racial and ethnic differences in the prevalence of poverty and low socioeconomic status, access to health care, sexual and health-related behavior, and illicit drug use.

By age 5 years, more than 35% of Black children are infected with HSV-1 compared with 18% of White children. Through adolescence, the prevalence of antibodies to HSV-1 in Blacks is approximately twice the rate among Whites. By comparison, the estimated prevalence of antibodies to HSV-1 in Mexican American teenagers is between that of Blacks and Whites.^[27] By age 40 years, HSV-1 seroprevalence is similar among Blacks and Whites. The prevalence of HSV-2 antibodies among Blacks is 3-4 times higher than that among Whites.

Seroprevalence among women of childbearing age in the late 1970s was estimated to be 50% for Blacks and 20% for Whites. By the late 1980s, rates of infection had increased to approximately 60% for Blacks and 35% for Whites. As shown in two nationwide surveys of HSV-2 seroprevalence in the last 2 decades, the cumulative lifetime incidence of HSV-2 reaches 25% in White women, 20% in White men, 80% in black Women, and 60% in Black men.^[41] Studies have indicated that the seroprevalence of HSV-2 among Hispanics ranges from 17-22.3%.

Infants born to non-Hispanic White women may be at higher risk of herpes simplex virus infections. This is a result of a greater likelihood that these women are herpes simplex virus seronegative and therefore at risk of acquiring a primary HSV-1 or HSV-2 infection in late pregnancy.

Sex

Infection rates with HSV-1 tend to be similar in both sexes during early childhood. However, through adolescence, the prevalence of antibodies to HSV-1 is slightly higher among females than among males. Rates of HSV-2 infection are higher in women than in men.^[42] Nationwide surveys of HSV-2 seroprevalence over the last 2 decades have demonstrated cumulative lifetime incidences of 25% in White women and 80% in Black women. This compares with rates of 20% in White men and 60% in Black men.

Age

Beyond the neonatal period, most childhood herpes simplex virus infections are caused by HSV-1. The seroprevalence of HSV-1 antibodies increases with age, and its rate is 20% by age 5 years. Between the ages of 14-19 years, HSV-1 seroprevalence in the general population increases to 35%,^[27] and by 20-40 years of age 40-60% of individuals are likely to be seropositive for HSV-1. As a reflection of the association between infection and sexual activity, many HSV-2 infections occur around puberty and early adolescence, including gingivostomatitis from orogenital contact. A progressive increase in HSV-2 infections occurs in all populations beginning in adolescence.^[42] In the United States, HSV-2 seroprevalence increases from approximately 20-30% in those aged 15-29 years to 35-60% in those aged 60 years. Most neonatal infections are caused by HSV-2, but increasing proportions are being caused by HSV-1.^{[19, 43]}

Prognosis

Herpes simplex virus infections beyond the fetal and neonatal period are usually associated with increased morbidity but are not life threatening.

Herpes simplex virus encephalitis is a serious disease that can result in clinically significant neurologic impairment or death. The mortality rate is approximately 70% in untreated patients and 19% in treated patients.^[19] Even after treatment, survivors have some neurologic impairment (impaired learning, dysnomia) noted upon detailed clinical cognitive testing.

Even with antiviral therapy, neonatal herpes simplex virus infection is associated with significant morbidity and mortality. Death typically does not occur after skin, eye, and mucus membrane (SEM) disease is treated, but 12-month mortality rates approach 4% with neonatal CNS disease and 29% with disseminated disease. Among neonates treated with antivirals, 2% of children with SEM disease, 69% of children with herpes simplex virus–related CNS disease, and 17% of children with disseminated herpes simplex virus disease develop evidence of neurologic impairment 2 years after infection.^{[19, 44]}

The results of one study noted that infants who survived neonatal herpes simplex virus infection with CNS involvement who received suppressive therapy with oral acyclovir (300 mg/m²/dose PO tid for 6 mo) had significantly higher mean Bayley mental-development scores at 12 months than did infants who did not.^[44] Another multicenter, retrospective, cohort study suggest that delayed initiation of acyclovir therapy was associated with significantly greater odds of death in neonates with herpes simplex virus infection.^[45]

Genital herpes simplex virus infection may not be life threatening but is an important cause of physical and psychological morbidity.

Morbidity/mortality

Most cases of infection with either HSV-1 or HSV-2 do not result in serious morbidity. Morbidity and mortality associated with herpes simplex virus are discussed in Complications. Mortality associated with herpes simplex virus is primarily associated with perinatal infection, encephalitis, and infection in individuals who are immunocompromised.

At the time of vaginal delivery, the risk of herpes simplex virus transmission from a mother with true primary herpes simplex virus infection to her infant is approximately 50%. Women with primary infections at delivery are 10-30 times more likely than women with a recurrent infection to transmit the virus to their babies.^[19] Infants born to mothers with newly acquired infections who do not have primary infections in the presence of preexisting immunity caused by another viral infection (ie, first-episode nonprimary) have a transmission risk of 25-30%.^[46]

The neonatal herpes simplex virus infection rate is considered to be less than 2% when the mother has active infection caused by the shedding of herpes simplex virus acquired before pregnancy or during the first half of pregnancy (recurrent infection). Approximately two thirds of women who acquire genital herpes during pregnancy have no symptoms.^{[31, 47]} Of mothers who deliver an infant with herpes simplex virus infection, 60-80% have no evidence of genital herpes simplex virus infection at the time of delivery, have no history of previous genital herpes infection, and have sexual partners without a reported history of genital HSV infection^[48]. Of babies born to mothers with a primary infection near the time of delivery, 30-50% acquire the infection.

Neonatal herpes simplex virus infection is estimated to occur in approximately 1 per 3000 deliveries in the United States. In 2006, a lower incidence of 9.6 cases per 100,000 births was ascertained.^[49] Studies have determined that herpes simplex virus infections in neonates and infants are associated with substantial morbidity, mortality, and resource use.^[50] A study by Melvin et al found that mortality was 40.9% for infants with disseminated neonatal herpes simplex virus disease.^[51]

Complications

Complications of cutaneous herpes simplex virus infections in children and adolescents include eczema herpeticum in children with underlying atopic skin disease, herpetic whitlow of the fingers, and herpes gladiatorum in wrestlers (see History, Physical). Secondary bacterial infections can also occur.

Herpes simplex virus infection of the visceral organs results from viremia with dissemination to many organs. Although this disease is most common in the immunocompromised population, it can also occur in immunologically healthy individuals. Most cases reflect disseminated skin disease, though multiple organs may be involved and hepatitis may be prominent. Disseminated infection can also result in esophagitis, pneumonitis, encephalitis, and adrenal necrosis. Leukopenia, thrombocytopenia, and disseminated intravascular coagulation are not uncommon.

Newborns with herpes simplex virus skin disease may have recurrences for months to years, particularly with HSV-2 disease, even if antiviral therapy was appropriately administered. The role of suppressive oral antiviral therapy with acyclovir in prevention of these cutaneous herpes simplex virus recurrences is an area of active investigation.^[52]

Patient Education

Because increasing rates of STIs are occurring in adolescents, offer patients regular and appropriate education in sexual health as well as in the diagnosis and treatment of their diseases. The presence of an STI should prompt assessment and potential treatment for other infections (eg, chlamydia, HIV infection, syphilis, hepatitis B, hepatitis C).

Antiviral therapy may decrease the duration of clinical manifestations of herpes simplex virus disease but does not cure the infection.

Initiate antiviral therapy as soon as possible after signs and symptoms of disease are noted.

Daily suppressive management with oral antiviral agents reduces the frequency of herpes simplex virus recurrences and viral shedding. Consider antiviral suppressive therapy in adolescents with frequent genital recurrences (6 or more per year).

Condom use decreases the risk of the sexual transmission of HSV-2^[53].

Clinical Presentation

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Media Gallery

Primary herpes simplex virus (HSV) gingivostomatitis in an infant is shown. This same patient also had concomitant herpes whitlow as shown in the following image.
Herpes whitlow in an infant.
Cutaneous herpes simplex virus (HSV) lesions in a child in whom sexual abuse is suspected.
Vesicular scalp lesions caused by herpes simplex virus (HSV) in a 7-day-old infant.
Herpes gladiatorum in an adolescent wrestler.
MRI shows abnormal signal intensity in the left temporal lobe of an 18-year-old man with herpes simplex virus (HSV) encephalitis.

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Author

J Michael Klatte, MD Assistant Professor of Pediatrics, University of Massachusetts Medical School; Adjunct Assistant Professor of Pediatrics, Tufts University School of Medicine; Medical Director, Pediatric Antimicrobial Stewardship, Baystate Medical Center

J Michael Klatte, MD is a member of the following medical societies: American Academy of Pediatrics, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Society for Healthcare Epidemiology of America

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Mark R Schleiss, MD Minnesota American Legion and Auxiliary Heart Research Foundation Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota Medical School

Mark R Schleiss, MD is a member of the following medical societies: American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Russell W Steele, MD Clinical Professor, Tulane University School of Medicine; Staff Physician, Ochsner Clinic Foundation

Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, Southern Medical Association

Disclosure: Nothing to disclose.

Additional Contributors

Leonard R Krilov, MD Chief of Pediatric Infectious Diseases and International Adoption, Vice Chair, Department of Pediatrics, Winthrop University Hospital; Professor of Pediatrics, Stony Brook University School of Medicine

Leonard R Krilov, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Swetha G Pinninti, MD Assistant Professor of Pediatric Infectious Diseases, Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Swetha G Pinninti, MD is a member of the following medical societies: American Academy of Pediatrics, Infectious Diseases Society of America, Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Drugs & Diseases gratefully acknowledge the contributions of previous author Sherman Alter, MD, to the original writing and development of this article.