Pediatric Herpes Simplex Virus Infection Clinical Presentation

Herpes simplex virus (HSV) causes myriad clinical presentations. The course depends on the age of the patient, the immune status of the host, the site of infection, the individual's previous immunity to autologous or heterologous viruses, and the antigenic type of the virus. Herpes simplex virus type 1 (HSV-1) classically causes infection above the waist and the infections are localized to the mouth and oropharynx, whereas herpes simplex virus type 2 (HSV-2) usually causes genital infections and can also cause CNS or disseminated disease in neonates. ^[47]

Compared with latent infection, primary infection with either virus is frequently associated with systemic signs, increased severity of symptoms, and increased rates of complications. Upon reactivation, both viruses establish latent infections in sensory neurons and can cause recurrent disease at or near the entry site into the body.

Orolabial infection

Primary infection

Most infections are caused by HSV-1 and are localized to the mouth and oropharynx. Only 10-30% of orolabial infections are symptomatic.

The most common clinical presentation of first-episode, primary herpes simplex virus infection in children (usually aged 6 mo to 5 y) is acute herpetic gingivostomatitis, as is shown in the image below.

Clinical features 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

The lesions can be quite painful and symptoms may persist for 10-14 days. Primary herpes simplex virus infection of the oropharynx may be associated with viral shedding for as long as 23 days.

Primary HSV-1 infection of the oropharynx in adolescents and adults usually manifests as pharyngotonsillitis rather than gingivostomatitis. Patients usually present with fever, malaise, odynophagia, and headache with vesiculoulcerative lesions on the tonsils.

Primary HSV-2 infection can have a presentation similar to this after orogenital contact and it may occur concurrently with genital herpes simplex virus infection.

Reactivation

Reactivation of herpes simplex virus from the trigeminal ganglion may follow oral trauma or dental procedures but is usually asymptomatic.

A mild prodrome of localized pain, tingling, burning, or itching is followed by eruption of vesicular lesions. The prodrome may occur 6-53 hours before the first vesicular lesions appear.

The most common site of recurrent orolabial lesions is the vermilion border. On occasion, vesicles may be noted on other areas of the face or in the nares, often at sites contaminated by infected saliva during the initial infection. The pattern of recurrent disease varies greatly from one person to another. However, specific triggers may be fairly predictable for individual patients and the lesions tend to recur at the same site as the original lesions.

HSV-1 orolabial infections recur at a rate of approximately 0.1 episode per month or 1.2 per year.

Genital infections

Primary infection occurs in the absence of preexisting antibodies to herpes simplex virus, either HSV-1 or HSV-2. First episode nonprimary infections occur in the absence of any previous signs or symptoms of genital herpes but in the presence of preexisting heterologous antibodies. Formerly, HSV-2 accounted for 80-90% of herpes genitalis, however, HSV-1 has been associated with an increasing prevalence of genital outbreaks. ^[48]  

Primary infection

Primary, symptomatic, first-episode genital infections are characterized by severe constitutional symptoms, including fever, malaise, and myalgias. ^[2] Itching and pain usually are the initial symptoms, followed in 24-48 hours by more troublesome signs and symptoms.

Lesions evolve from vesicles to pustules to wet ulcers and heal by crusting. New lesions develop over 7-8 days, and are primarily distributed over the labia majora, labia minora, mons pubis, vaginal mucosa, cervix, and on the shaft of the penis. Painful inguinal lymphadenopathy, dysuria, and vaginal discharge are frequent complaints. Complications in both sexes can include paresthesias of the legs and perineum. Urinary retention, more common in women than in men, may be reported. Approximately 85% of women report vaginal discharge, with 25% of men reporting urethral discharge ^[18] . Mean duration of viral shedding is 12 days.

Preexisting antibodies to HSV-1 have an ameliorating effect on the severity of disease caused by HSV-2. Previous orofacial infection with HSV-1 generally protects a person against genital infection with HSV-1 but not HSV-2.

Most primary genital herpes simplex virus infections are asymptomatic, and 70-80% of seropositive individuals have no history of symptomatic genital herpes. Periodic subclinical recurrences with viral shedding make these individuals sources of infection, however. ^[49]

Nonprimary first episode infections have lower frequencies of systemic symptoms, fewer lesions and more rapid healing of those lesions than in patients with primary infections, presumably due to preexisting heterologous antibodies.

Reactivation

Recurrences are more common with HSV-2 infections than with HSV-1 infections (5 vs 1 per y). Individuals with HSV-2 infection generally have high rates of recurrence in the first and second years followed by a substantial decrease in subsequent years (median, 2 per y). About 25% of individuals have at least one recurrence in 5 years. Recurrences often follow stressful events, illness, trauma, and menstruation.

Most reactivations are asymptomatic (1% of individuals with previous HSV-2 infection have asymptomatic viral shedding on any given day). ^[50]

When symptomatic reactivation occurs, genital lesions are typically few. Tender lymphadenopathy, dysuria, vaginal discharge, and systemic symptoms are less common.

Intrauterine and perinatal infections

Congenital herpes simplex virus infection is a very rare entity and has been infrequently reported in the literature. ^{[51, 52]} Manifestations can include skin lesions and scars, chorioretinitis, and microcephaly.

Most neonatal herpes simplex virus infections occur at the time of delivery through the genital tract of a woman asymptomatically shedding virus. History of previous infection and presence of maternal antibody are protective, as approximately half of neonates exposed to maternal primary herpes simplex virus infection contract the virus as opposed to less than 5% of those exposed to recurrent herpes simplex virus disease. ^{[19, 3, 4]}

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

• Skin, eye, and mucous membrane (SEM) disease: Infection with herpes simplex virus limited to SEM historically accounts for about 20% of all neonatal herpes simplex virus infections. Infants with SEM infections generally present at age 10-12 days. Skin lesions tend to appear at the site of trauma. Many newborns with herpes simplex virus–related SEM disease do not present with symptoms of systemic illness. Outcome of SEM disease is excellent with prompt antiviral therapy; however, without treatment 75% of the cases progress to disseminated disease.

• Disseminated infection: Disseminated infection now accounts for approximately 25% of herpes simplex virus infections in newborns. The early recognition and prompt treatment of herpes simplex virus–related SEM disease has resulted in lower rates of progression to disseminated disease than in years past. Neonatal HSV infection acquired peripartum and manifesting as disseminated disease will usually present between days 2-12 of life, given a minimum incubation period for HSV infection of 2 days. ^{[4, 41, 53]} Disseminated disease manifests as severe infection, often with hepatic, pulmonary, and neurologic dysfunction or failure. In the absence of prompt recognition and early institution of antiviral treatment, disseminated disease has a high mortality rate.

• CNS infection: Nearly one-third of infants with neonatal herpes simplex virus infection have meningoencephalitis as the sole manifestation of disease. Patients usually present with symptoms and signs of illness at 2-3 weeks of age. Initial manifestations include lethargy, irritability, and focal seizures. Without treatment, most children with CNS disease die and survivors sustain severe neurologic impairment.

Herpes simplex virus CNS infection

Herpes simplex virus is the most common cause of sporadic encephalitis in the United States. ^{[54, 55, 56]}  and HSV-1 is the second most commonly identified cause of encephalitis in children (behind only enterovirus encephalitis). ^[57] One third of all cases of herpes simplex virus encephalitis are believed to occur in the pediatric population.

Herpes simplex virus encephalitis may be a manifestation of primary or recurrent infection with the virus. The infection may have an insidious or an abrupt onset. Patients present with headache, altered consciousness, and focal neurological abnormalities (often consistent with temporal lobe involvement).

Aseptic meningitis caused by herpes simplex virus can occur after primary genital HSV-2 infection. Patients with herpes simplex virus meningitis present with headache, fever, stiff neck, and photophobia. Symptoms usually begin 3-12 days after the onset of genital lesions. They reach maximum severity by 2-4 days into the illness, and gradually diminish over 2-3 days.

Dysfunction of the autonomic nervous system and transverse myelitis has been associated with genital herpes simplex virus infection. Symptoms may include hyperesthesia or anesthesia of the lower back, perineum, or sacral region. Urinary retention and constipation are other associated symptoms.

Infection in immunocompromised hosts

Severe herpes simplex virus infection in immunocompromised children is similar to that in adults. ^{[58, 59]} Infection is a frequent source of morbidity but is rarely fatal. The severity of disease is proportional to the deficiency of cellular immune responses.

It is characterized by the presence of oral and genital lesions that progress slowly to involve contiguous mucosal surfaces and cause esophageal, tracheal or pulmonary involvement, leading to disseminated infection.

Other herpes simplex virus infections

Herpes simplex virus infection of the tip of the finger is referred to as herpetic whitlow. ^[60] It presents much as other infections of the fingertip. Associated fever and enlarged regional adenopathy are common. An example is shown in the image below.

Herpes gladiatorum is a manifestation of herpes disease seen in wrestlers. ^[61] It results in painful herpes simplex virus lesions, frequently with numerous cutaneous vesicles. An example is shown in the image below.

Keratoconjunctivitis manifests with acute onset of pain, watery discharge, itching, blurred vision, lid swelling, and conjunctival injection. ^[62] Acute retinal necrosis can result in blindness.

Mollaret meningitis, (a recurrent aseptic meningitis) is rarely associated with herpes simplex virus. ^[63] Low-grade fever, headache, and myalgias may occur with these episodes. Approximately 50% of patients have transitory neurologic symptoms of meningeal irritation. The disease usually spontaneously remits over days.

Herpes simplex virus is one of the most common precipitating factors for erythema multiforme (EM). ^[64] Approximately 15% of patients with EM provide a history of recurrent herpes simplex virus infections before the characteristic skin lesions erupt.

Eczema herpeticum refers to herpes simplex virus infection superimposed on atopic dermatitis. The incidence of eczema herpeticum in children with atopic dermatitis is between 3-6%. ^[65]  Risk factors for hospitalization of children with eczema herpeticum include young age (3-4 years) and non-white, non-Hispanic races/ethnicities. ^[66]   

Neonatal infections

Skin lesions in SEM disease appear as macules which progress rapidly to vesicles on an erythematous base in areas of trauma, most commonly the site of insertion of a fetal scalp electrode (but also the oropharynx, circumcision site, or the presenting part). ^[19] Vesicular scalp lesions are shown in the image below.

Herpes simplex virus CNS disease usually presents between the ages of 2-3 weeks with lethargy and focal seizures. ^[6] Skin lesions are present in about 50% of patients. Cerebrospinal fluid (CSF) examination reveals pleocytosis and modestly elevated protein. The electroencephalogram is diffusely abnormal.

Disseminated herpes simplex virus disease in neonates usually mimics severe bacterial infection, and can present within the first few days of life. Skin lesions are often absent at the onset of illness but 70% of the patients demonstrate skin lesions at some point during the illness. Disease manifestations may include vascular instability, jaundice, hepatomegaly, and pneumonitis. ^[58]

 

Orolabial herpes simplex virus infections  ^[67]

Primary herpetic gingivostomatitis results in vesicles and ulcers involving the hard and soft palate, gingiva, tongue, and lips. These lesions are initially vesicular, but rupture fairly rapidly, leaving 1-3 mm, shallow, gray-white ulcers on erythematous bases. Fever and cervical and/or submandibular adenopathy are common.

Patients with herpes simplex virus pharyngotonsillitis typically present with ulcers and exudates on the posterior pharynx and tonsillar area. Lesions may also be noted on the tongue, buccal mucosa, or gingiva. Fever may last 2-7 days. Cervical adenopathy is common.

Recurrent orolabial herpetic infection is preceded by a prodrome of pain, burning, tingling, and itching. The prodrome is followed by the emergence of painful vesicles 24-48 hours later. The vesicles evolve into pustules and heal by crusting. Lesions most frequently appear on the vermillion border of the lip.

Genital infections

The rash of primary genital herpes initially appears as macular and papular lesions, followed by a distribution of vesicles, blisters and pustules, with eventual rupture and formation of ulcers. Fever and localized inguinal adenopathy are frequently noted. Lesions are typically observed on labia majora, labia minora, and mons pubis in females and on the shaft of the penis in males. ^{[68, 26]}

The painful and tender lesions are associated with dysuria and may involve the buttocks, perineum, and vagina. Urinary retention is observed in 10-15% of female patients.

As many as 25% of women with genital herpes simplex virus have findings suggestive of meningitis.

Symptomatic recurrent herpes simplex virus infection can cause ulcerating vesicular lesions to appear (which are typically few in number and localized), or may manifest as merely irritation of the vulva in women. ^[18]

Herpes simplex virus CNS disease

Disease occurs in those aged 5-30 years and older than 50 years.

Patients typically have malaise, irritability, and nonspecific symptoms lasting 1-7 days followed by acute onset of fever and focal neurologic signs. ^[54]

CSF analysis reveals pleocytosis with lymphocytic predominance. In the past, increased RBCs in the CSF were considered suggestive of CNS infection; however, with earlier recognition and diagnosis that laboratory finding is rare today. ^[11]

Electroencephalography may demonstrate paroxysmal lateralizing epileptiform discharges (PLEDs) but more commonly shows focal spike and slow-wave abnormalities.

Edema with hemorrhagic necrosis is observed on MRI of the brain.

Herpes simplex virus in the immunocompromised patient

Patients with primary immunodeficiencies, AIDS, malignancy, malnutrition, burns, and transplant recipients (eg, bone marrow, organs) receiving immunosuppressive therapy can have unusually severe herpes simplex virus infections.

Severe orolabial infections may begin as typical herpes simplex virus lesions in or around the mouth. Over several days, the papules and vesicles can progress to bullae, frequently with hemorrhagic fluid. These bullae then may evolve into large, chronic, bloody lesions that coalesce and erode into the subcutaneous tissue or deeper tissues.

Orolabial herpes simplex virus infection may involve contiguous mucosal surfaces to cause herpes simplex virus esophagitis, tracheitis, pneumonitis, or disseminated infection. Patients with esophagitis typically present with fever, retrosternal pain, and odynophagia, and patients with pneumonitis present in respiratory failure.

Other herpes simplex virus infections

Herpes simplex virus infection of the eye presents as blepharitis, follicular conjunctivitis, or keratoconjunctivitis. Signs include corneal or conjunctival injection, watery discharge, lid swelling, and preauricular adenopathy.

Patients with Mollaret meningitis present with fever, nuchal rigidity, and transitory neurologic findings that accompany meningeal irritation.

Patients with eczema herpeticum are more frequently affected over the head, neck, and trunk than elsewhere on the body. Although the lesions begin to appear over eczematous areas of skin, they can spread to involve normal areas of skin approximately 7-10 days into the course of the illness. Lesional spread to the eye can cause keratoconjunctivitis. Fevers are present in approximately half of children with eczema herpeticum. ^[65] Secondary bacterial infections with staphylococci and streptococci are present in up to 90% of children with eczema herpeticum. ^[69]