OVERVIEW: What every practitioner needs to know

Are you sure your patient has Herpes Simplex type-1 Infection beyond the neonatal period? What are the typical findings for this disease?

Typical findings of herpes simplex virus-1 (HSV-1) infection in children depend on the site of infection.

1. Primary orolabial infection (gingivostomatitis): children present with oral lesions described as small vesicles on the tip of the tongue, gums, and around the lips. These lesions often are accompanied by fever, irritability and tender lymphadenopathy in the sub-mandibular region. The throat usually is spared, but a small number of children with primary HSV-1 infection will have some lesions in the esophagus. Dehydration resulting from refusal to drink and/or eat is the most common reason for admission to the hospital. Recurrences after primary infection can occur, but are generally less symptomatic than the primary infection.

2. Skin infections: in toddlers and small children, infection of the finger tip or nail bed is known as herpetic whitlow. This infection can be secondary to autoinoculation of the virus or inoculation by a different person who bites or sucks on the finger. The lesions are generally vesicular or pustular, and can be confused with bacterial infection due to erythema and swelling that usually accompany the infection. Another type of cutaneous herpes in active athletes involved in wrestling or other contact sports is called herpes gladiatorum. A similar process in children with atopic dermatitis is called eczema herpeticum.

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3. Keratoconjunctivitis: ocular involvement with HSV-1 beyond the neonatal period presents as ocular pain, excessive tearing, photophobia, blurred vision and chemosis. Corneal lesions can rapidly appear, which under a Wood’s lamp appear as the classic branching dendritic lesions. The clinician should be aware of this diagnosis and prevent further damage to the deep eye structures by starting therapy promptly and by avoiding the use of topical steroids in the absence of antiviral medication. Recurrences can threaten normal vision.

4. Central nervous system (CNS) disease: encephalitis caused by HSV-1 is a rapidly progressive illness characterized by altered mental status, fever, and focal neurologic findings. Treatment should be started upon suspicion of this illness.

Key Symptoms

1. Muco-cutaneous lesions (gingivostomatitis): vesicular, pustular, and ulcerative are the most common types

2. Fever

What other disease/condition shares some of these symptoms?

Infection with coxsackie virus causes a syndrome called herpangina, which is similar to orolabial herpes simplex. Herpangina involves vesicles in the posterior aspect of the mouth, including the throat and soft palate. In addition, a mild case of orolabial herpes can resemble secondary bacterial infection, so that the physician can make an erroneous diagnosis of impetigo. Viral meningoencephalitis of many different pathogens can have features similar to the CNS form of HSV-1 disease.

What caused this disease to develop at this time?

Herpes simplex virus type 1 (HSV-1) infection is caused by a large double-stranded DNA virus from the herpesvirus family. In immunocompetent children, various clinical syndromes can be associated with primary HSV-1 infection, including orolabial, conjunctival, skin, and central nervous system infections. Other sites of infection have been described but are encountered very infrequently in immunocompetent children outside the neonatal period. The majority of children acquire their HSV-1 infection from family members, siblings, or playmates, who transmit the virus in their saliva during primary infection or reactivation. Saliva containing virus may contaminate toys that are passed from one child to another. Young children may also drink out of a cup that is shared with another child who may be secreting virus in saliva. Autoinoculation is the most common route of infection of the involved finger in herpetic whitlow. By adulthood, around 70% of people are HSV-1 seropositive.

HSV-1 infections are generally asymptomatic, and when symptoms are present, children usually have a mild muco-cutaneous febrile illness that resolves without complications or sequelae. Less commonly, orolabial infection can be accompanied by tender lymphadenopathy, irritability and refusal to drink or eat, a situation which often requires hospitalization for hydration and treatment. Other clinical syndromes, including encephalitis and keratoconjunctivitis, require a high index of suspicion by the treating physician in order to provide prompt diagnosis and initiation of antiviral therapy. After children recover from their primary HSV-1 infection, the virus enters a latent state in the ganglia that innervate the initial site of infection, e.g., the trigeminal ganglia. Thereafter, HSV-1 occasionally reactivates in the ganglia, travels anterograde in the neurons, and causes recurrent clinical infection. Reactivations tend to occur more frequently in the months after the primary infection, but in some children, reactivations continue for years thereafter.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Isolation of the virus via culture has been the most reliable method to confirm the diagnosis of active HSV infection. Cultures can be obtained from skin lesions or mucosal surfaces. Cultures usually are positive within the first 3 to 5 days after inoculation. Amplification of HSV DNA by PCR is now widely available commercially, and is gradually replacing virus culture as the preferred diagnostic method. For the diagnosis of encephalitis, a lumbar puncture should be performed and a PCR test should be obtained on the CSF. Some diagnostic laboratories continue to perform a rapid HSV immunofluorescence assay on skin cells removed from a vesicle. The latter test is less sensitive than culture or PCR but is highly specific.

In the past, HSV serology often was not helpful for diagnosis of acute disease because the serology test could not differentiate between antibody to HSV-1 and HSV-2. However, a commercial test kit called HerpeSelect® 1 and 2 can accurately differentiate antibodies to HSV-1 and HSV-2. The test is FDA-approved. Therefore, a physician can now determine if a sick child has ever had either HSV-1 or HSV-2 infection. The only caveat is that the test may not detect the specific HSV antibody until 6-8 weeks after the onset of the primary infection.

Would imaging studies be helpful? If so, which ones?

Magnetic resonance imaging can be very helpful to evaluate the extent and severity of the viral infection in cases of encephalitis. With HSV-1 infection of the brain, localization to the temporal lobes is commonly seen by MRI. Computed tomography is less sensitive than MRI.

If you are able to confirm that the patient has HSV-1 infection, what treatment should be initiated?

Treatment with oral acyclovir has been shown to decrease the duration of illness and duration of viral shedding. Only modest benefit was seen in earlier studies that used what is now considered to be a low dose of acyclovir. Treatment of symptomatic primary orolabial infection is encouraged with acyclovir at a higher oral dose of 80 mg/kg/day, up to a maximum of 3200 mg (four 800 mg tablets divided over 1 day). Treatment can be continued for 5-10 days, until the skin lesions have cleared. Studies in adults over several decades have shown that HSV resistance to acyclovir rarely occurs in immunocompetent people, even after treatment of multiple recurrences.

Children who are dehydrated during their primary herpes infection of the mouth should be admitted for 2-3 days of treatment with intravenous acyclovir (30 mg/kg/day, divided every 8 hours). After discharge, the children should be treated with oral acyclovir until the herpetic lesions have cleared and the child can drink without discomfort. Topical treatment has only marginal or no benefit in the treatment of orolabial or cutaneous diseases caused by HSV-1.

Keratoconjunctivitis is treated with topical trifluridine or vidarabine. To prevent recurrences in these cases, oral acyclovir as suppressive therapy may be indicated. Generally, suppressive therapy is 30 mg/kg/day of oral acyclovir (maximum: 2400 mg/day) of oral acyclovir. Ganciclovir 0.15% ophthalmic gel is a newer agent approved for treatment of children >2 years.

Herpes gladiatorum can cause havoc when the disease spreads to several members of a high school or college athletic team. To avoid this problem, many team physicians now assess all participants to determine if any athlete has recurrent orolabial herpes. The athletes with a positive history are placed on prophylaxis with oral acyclovir during the entire season of their particular sport (e.g., wrestling) to prevent the spread of herpes gladiatorum to other team members. Acyclovir is now a generic drug, so the tablets are not expensive. The usual suppressive dosage is 30 mg/kg/day (maximum: 2400 mg/day). Acyclovir tablets are available as 200 mg, 400 mg, and 800 mg sizes.

CNS disease caused by HSV-1 in children >3 months requires therapy with intravenous acyclovir at a dosage of 30-45 mg/kg/day, divided every 8 hours for a total of 21 days. Serum creatinine levels must be carefully monitored.

Valacyclovir is a second generation acyclovir derivative. Valacyclovir is much better absorbed than acyclovir. Valacyclovir was previously an extremely expensive drug, but the drug is now generic and therefore much less expensive. Although the drug is FDA-approved for adolescents 18 years and older, some physicians are now prescribing valacyclovir for both treatment and prophylaxis of recurrent HSV-1 infections in adolescents younger than 18 years, including herpes gladiatorum. Valacyclovir is produced as 500 mg and 1000 mg tablets.

Treatment of infants and toddlers with primary HSV-1 orolabial infection (gingivostomatitis) is often delayed until the young children have disease of such severity that they must be admitted for intravenous acyclovir. To avoid this dilemma, it is important to remember that herpes generally requires 2-3 days of oral acyclovir treatment before a response is seen. Therefore, the only approach by which to avoid admission for intravenous treatment is to initiate oral acyclovir treatment earlier in young children with moderately severe orolabial herpes. Acyclovir suspension is formulated at 200 mg in 5 mL.

What are the adverse effects associated with each treatment option?


What are the possible outcomes of herpes simplex infection?

Acyclovir therapy, especially intravenous acyclovir, has been associated with bone marrow suppression and impaired renal function, usually during the third week of therapy. These complications are unlikely during shorter courses of oral acyclovir therapy.

What causes this disease and how frequent is it?

The syndromes described above are caused by HSV-1 in the majority of cases. About 70% of children will acquire HSV-1 infection by the time they reach adulthood. Children with more siblings and children who attend child care are more likely to contract HSV-1 infection.

How do these pathogens/genes/exposures cause the disease?


Other clinical manifestations that might help with diagnosis and management

Herpes simplex infection is a rare cause of acute retinal necrosis in children. The diagnosis is usually made by an ophthalmologist after examination of the retina.

What complications might you expect from the disease or treatment of the disease?


Are additional laboratory studies available; even some that are not widely available?


How can HSV-1 infection be prevented?

Reducing transmission is an important aspect of prevention. Children with gingivostomatitis should be excluded from child care to prevent transmission to susceptible infants. Athletes should be evaluated for the presence of lesions suggestive of oral HSV, and counseled about the infectivity of recurrent oral herpes.

What is the evidence?

Gilbert, S, Corey, L, Cunningham, A. “An update on short-course intermittent and prevention therapies for herpes labialis”. Herpes. vol. 14. 2007. pp. 3A-18A. (Review article on the current strategies for how to treat and prevent recurrences of herpes labialis.)

Whitley, RJ. “Therapy of herpes virus infections in children”. Adv Exp Med Biol. vol. 609. 2008. pp. 216-32. (Review article on the current standard of care for the treatment of herpes viruses including HSV in neonates and HSV encephalitis.)

Anderson, BJ. “Managing herpes gladiatorum outbreaks in competitive wrestling: the 2007 Minnesota experience”. Curr Sports Med Rep. vol. 7. 2008. pp. 323-7. (Treatment and prevention recommendations against HSV skin infection in competitive wrestling. This review emphasizes the importance of prevention of HSV transmission in high-risk settings. The targeted population is adolescents.)

Corey, L, Wald, A. “Maternal and neonatal herpes simplex virus infections”. N Engl J Med. vol. 361. 2009. pp. 1376-85. (Review article exploring the current evidence in the prevention of mother-newborn transmission of HSV.)

Ongoing controversies regarding etiology, diagnosis, treatment