Herpes simplex in children

Simple herpes is clinically manifested by damage to many organs and tissues, accompanied by the appearance of grouped vesicular rashes on the skin and mucous membranes. It has a tendency to a long latent course with periodic relapses.

Epidemiology

The infection is widespread. Infection occurs during the first three years of life. Children in the first six months of life do not suffer from simple herpes due to the presence of specific IgG antibodies received transplacentally from the mother. In the absence of immunity in the mother, children in the first months of life in case of infection suffer especially severely - generalized forms occur. Almost 70-90% of 3-year-old children have a fairly high titer of virus-neutralizing antibodies against the herpes simplex virus (HSV). From the age of 5-7, the number of children with a high level of antibodies to HSV2 increases.

The source of infection is sick people and virus carriers. Transmission occurs through contact, sexual and airborne droplets. Infection occurs through kissing through saliva, as well as through toys, household items infected with the saliva of a sick person or virus carrier.

Transplacental transmission is possible, but infection of the child most often occurs during passage through the birth canal.

Usually there are sporadic cases of disease, but in organized groups and especially among weakened children, in hospitals small epidemic outbreaks are possible, more often in winter.

[ 1 ], [ 2 ], [ 3 ], [ 4 ], [ 5 ], [ 6 ], [ 7 ], [ 8 ], [ 9 ]

Causes herpes simplex

The herpes simplex virus is a DNA-containing virus with a diameter of 120 to 150 nm, it reproduces well in the tissues of the chicken embryo. In infected cells, it forms intranuclear inclusions and giant cells, has a pronounced cytopathic effect, manifested in rounding and the formation of multinuclear giant cells. A distinction is made between HSV1 and HSV2. The first group is associated with the most common forms of the disease - lesions of the skin of the face and mucous membranes of the oral cavity. Viruses of the second group more often cause lesions of the genitals, as well as meningoencephalitis. Infection with one type of herpes simplex virus does not prevent the occurrence of an infection caused by a herpes simplex virus of another type.

Pathogenesis

The entry points for infection are injured mucous membranes and skin. The herpes simplex virus is characterized by dermato-neurotropism. In the body, it multiplies at the entry points, causing herpetic eruptions at the sites of damage. From the sites of primary localization, the virus rarely penetrates into the regional lymph nodes and even more rarely into the blood, causing viremia. In the future, the development of herpes simplex will depend on the virulence of the pathogen, and mainly on the state of the immunocompetent systems of the macroorganism, preceding sensitization. In localized forms, the process ends with local manifestations. In generalized forms, the virus is carried by the bloodstream to the internal organs (liver, lungs, spleen, etc.), causing their damage. In this case, virus-neutralizing and complement-binding antibodies quickly accumulate in the blood. Since the herpes simplex virus is a weak interferon inducer, inactivation of viral DNA inside the cells does not occur. The virus remains in the body throughout life, periodically causing relapses of the disease. The presence of virus-neutralizing antibodies in the blood does not prevent relapses.

Symptoms herpes simplex

HSV infections in neonatal and childhood populations range from uncomplicated mucocutaneous diseases to severe, life-threatening infections involving the central nervous system (CNS).

HSV causes lifelong infection, although the spectrum of disease caused by HSV varies widely depending on host factors such as age, immunodeficiency, virus type, and site of infection.[ 10 ]

Mucosal lesions

The most common clinical manifestation of herpes simplex is acute stomatitis or gingivostomatitis. It is observed in children of any age, but most often at the age of 2-3 years. After an incubation period (from 1 to 8 days), the disease begins acutely, with a rise in body temperature to 39-40 ° C, the appearance of chills, anxiety, general malaise, refusal to eat due to severe pain in the mouth. Increased salivation and bad breath are noted. In young children, body weight decreases, intestinal disorders and slight dehydration are possible. The mucous membrane of the oral cavity is clearly hyperemic, edematous. On the mucous membrane of the cheeks, gums, tongue, inner surface of the lips, on the soft and hard palate, palatine arches and tonsils - herpetic eruptions in the form of bubbles, elements 2-10 mm in diameter, first with transparent, and then yellowish contents. They quickly open up, forming erosions with remnants of exfoliated epithelium. Regional lymph nodes are always enlarged and become painful when palpated. The disease lasts 1-2 weeks. Body temperature normalizes in 3-5 days. In some cases, the disease takes a recurrent course.

Skin lesion

Most often occurs around the mouth (herpes labialis), nose (herpes nasalis), auricles (herpes oticum). At the site of virus introduction, grouped blisters with a diameter of 0.1-0.3 cm appear against the background of erythema and swelling. Sometimes, 1-2 days before the rash, prodromal phenomena are noted - burning, tingling, itching, slight pain or a feeling of stretching. A few hours later, blisters appear filled with a clear liquid, which then becomes cloudy, and sometimes can become hemorrhagic due to an admixture of blood. After opening the blister, a superficial erosion remains, and then a brownish-yellowish crust. Soon the crusts fall off, and for some time a slight reddening of the skin or light pigmentation remains in their place. The blisters are usually located in groups on a moderately infiltrated base and are surrounded by a hyperemic zone. On average, the entire process lasts 10-14 days. In some patients, the blisters merge into a multi-chamber flat blister, after which an erosion of irregular shape is formed.

A distinction is made between localized and widespread (disseminated) skin lesions caused by the herpes simplex virus.

A peculiar form of generalized herpes is herpetic eczema. It occurs in children with eczema, neurodermatitis and other dermatoses, with erosive lesions (entry gates of infection). The literature also presents other names for the disease: vacciniform pustulosis, Kaposi's variola-like rash, herpetiform eczema, etc.

The incubation period is short - 3-5 days. The disease begins acutely, sometimes after a short prodrome, with a rise in body temperature to 39-40 ° C and rapidly progressing symptoms of toxicosis (lethargy, anxiety, drowsiness, prostration), convulsions with short-term loss of consciousness are possible, vomiting is common. A profuse vesicular rash appears from the 1st day of illness, but more often - on the 2nd-3rd day. The rash is located on large areas of the skin, especially in places affected by eczema, neurodermatitis, etc. Painful regional lymphadenitis is noted. The rash can last 2-3 weeks.

The blisters are initially filled with transparent contents, but on the 2nd-3rd day the liquid becomes cloudy, the blisters flatten, an umbilical depression appears, the elements of the rash resemble vaccine pustules. The blisters often merge, burst, and become covered with a solid crust. After the crusts fall off, a pink spot remains, in especially severe cases cicatricial changes are possible.

Eye lesions (ophthalmic herpes)

Isolated eye lesions are possible, but combined lesions of the eye, skin, and oral mucosa are often observed. Follicular, catarrhal, or vesicular-ulcerative conjunctivitis develops with concomitant enlargement of regional lymph nodes. Combined lesions of the conjunctiva and eyelids are more common.

Ophthalmic herpes begins acutely, with the appearance of conjunctivitis, ulcers or herpetic vesicles on the skin of the eyelid near the ciliary margin (blepharoconjunctivitis). When the process is localized in the area of the inner third of the eyelids, canaliculitis may develop with subsequent obstruction of the lacrimal points and canals and the appearance of lacrimation. Involvement of the cornea in the process is accompanied by herpetic rashes in the epithelial layer, after opening the vesicles, an eroded surface or superficial ulcer remains, which is accompanied by lacrimation, photophobia, blepharospasm, injection of scleral vessels and neuralgic pain.

Genital herpes (herpes genitalis)

It most often occurs in adolescents and young men when infected sexually. In younger children, genital lesions usually occur secondarily, following other manifestations of herpes simplex. In these cases, the infection is transmitted through infected hands, towels, and underwear. Primary lesions of the external genitalia are also possible. Infection occurs through contact from parents with herpes simplex. The disease is most often caused by HSV2.

Clinically, genital herpes manifests itself as vesicular and erosive-ulcerative rashes on erythematous-edematous skin and mucous membrane of the genitals. In girls, the rash is localized on the labia majora and minora, in the perineum, on the inner surface of the thighs, less often on the mucous membrane of the vagina, clitoris, anus; in boys - on the inner leaflet of the foreskin, on the skin of the scrotum. The rash can also be on the mucous membrane of the urethra and even spread to the bladder. The disease is accompanied by fever, severe pain, itching, burning, tingling, and aching in the affected areas. At the site of herpetic vesicles, as a result of friction, erosions quickly form, which are then covered with a dirty gray crust, sometimes with hemorrhagic impregnation.

Nervous system damage

Infection of the brain and its membranes is usually caused by viremia. CNS damage can occur as encephalitis, meningitis, meningoencephalitis, meningoencephaloradiculitis. Encephalitis and meningitis are the most common forms of herpes neuroinfection. They are usually observed in young children and newborns.

In terms of clinical manifestations, herpetic encephalitis does not differ from other viral encephalitides. CNS damage is possible against the background of herpetic lesions of other localizations (lips, mouth, eyes), but in young children, primary generalized infection occurs more often. The disease begins acutely or even suddenly, with an increase in body temperature to high values, severe headache, chills, repeated vomiting. Children are depressed, inhibited, drowsy, sometimes excited. At the height of intoxication, convulsions, loss of consciousness, paralysis, impaired reflexes and sensitivity are possible. The disease is severe, in some cases there may be long-term residual phenomena in the form of loss of memory, taste, smell due to extensive necrosis in the temporal and visual areas of the cerebral cortex.

The disease may occur as aseptic meningitis with pronounced meningeal symptoms. Lymphocytic cytosis and increased protein concentration are found in the cerebrospinal fluid.

Visceral forms manifest as acute parenchymal hepatitis, pneumonia, damage to the kidneys and other organs.

Congenital herpes simplex

Intrauterine infection of the fetus may occur as a result of viremia in the mother during pregnancy. Ascending infection from the mother's genitals is allowed. However, in any case, infection of the fetus is possible only if the placenta is damaged. Infection of the fetus with the herpes simplex virus can lead to intrauterine death or death immediately after birth. In these cases, the disease is especially severe, like herpetic sepsis, with damage to the skin, mucous membranes, eyes, liver, brain, lungs, and adrenal cortex. If the fetus is infected in the early stages of gestation, developmental defects may develop.

During recovery, residual effects in the form of microcephaly, microphthalmia and chorioretinitis cannot be ruled out.

[ 11 ], [ 12 ], [ 13 ]

Forms

Depending on the localization of the pathological process, a distinction is made between:

• damage to the mucous membranes (gingivitis, stomatitis, tonsillitis, etc.);
• eye damage (conjunctivitis, blepharoconjunctivitis, keratitis, keratoiridocyclitis, chorioretinitis, uveitis, retinal perivasculitis, optic neuritis);
• skin lesions (herpes of the lips, nose, eyelids, face, hands and other areas of the skin);
• herpetic eczema;
• genital herpes (lesions of the penis, vulva, vagina, cervical canal, perineum, urethra, endometrium);
• CNS damage (encephalitis, meningoencephalitis, neuritis, etc.);
• visceral forms (hepatitis, pneumonia, etc.).

The diagnosis should also indicate the prevalence of lesions (localized, widespread or generalized herpes simplex). The course of the disease can be acute, abortive and recurrent. In any case, after the elimination of clinical manifestations, despite the formation of specific antibodies, the herpes virus remains in the body in a latent state for life and, under unfavorable conditions, can reappear in the same place as initially, or affect other organs and systems.

Examples of diagnosis formulation: "Localized herpes simplex, facial skin lesions, acute course"; "Disseminated herpes simplex, lesions of the mucous membranes of the mouth, nose, genitals, recurrent course"; "Generalized herpes simplex. Liver and lung lesions, acute course."

[ 14 ], [ 15 ], [ 16 ], [ 17 ], [ 18 ]

Diagnostics herpes simplex

Simple herpes is diagnosed by typical grouped vesicular rashes on the skin or mucous membranes, often recurring. For laboratory confirmation of the diagnosis, detection of the virus in the contents of the vesicles, skin ulcers, blood, cerebrospinal fluid by the PCR method is of decisive importance. Serological methods are less informative, with the exception of the determination of specific IgM. For the diagnosis of recurrent herpes, detection of high IgG titers or an increase in titer in the dynamics of the disease is of certain importance.

[ 19 ], [ 20 ], [ 21 ], [ 22 ], [ 23 ], [ 24 ]

Differential diagnosis

Simple herpes is differentiated from herpes zoster, enterovirus infection accompanied by herpetic eruptions on the mucous membranes of the oral cavity, adenovirus keratoconjunctivitis, and vaccine eczema.

Treatment herpes simplex

With the development of acyclovir and other related acyclic nucleoside analogues such as valacyclovir and famciclovir, treatment of herpes simplex in children has become more effective and also less toxic.

Treatment of pediatric herpes simplex virus infections [ 25 ]

Orolabial	First episode	Acyclovir 75 mg/kg/day orally ÷ 5 times/day (max. 1 g/day) × 7 days or 5 mg/kg/dose intravenously 3 times/day × 5-7 days
		Valaciclovir* 1 g orally x 7 days or 2 g orally x 1 day (if ≥12 years)
		Famciclovir 500 mg orally x 7 days (≥18 years)
	Recurrent	Acyclovir 400 mg orally 5 times a day for 5 days
		Valaciclovir* 2 g orally x 1 day (≥12 years)
		Famciclovir* 1.5 g orally x 1 day (≥18 years)
Anogenital	First episode	Acyclovir 40–80 mg/kg/day PO ÷ 3–4 times/day × 5–10 days (max 1 g/day) or 1–1.2 g/day PO ÷ 3–5 times/day (if ≥12 years) × 5–10 days or 5 mg/kg/dose IV 3 times/day × 5–7 days
		Valaciclovir* 1 g orally 7–10 days (≥18 years)
		Famciclovir* 250 mg orally 7–10 days (≥18 years)
	Recurrent	Acyclovir 200 mg orally 5 times/day x 5 days (≥12 years) or 400 mg orally x 5 days
		Valaciclovir 500 mg orally x 3-5 days; 1 g orally daily x 5 days; 1 g orally x 1 day (≥18 years)
		Famciclovir 125 mg orally x 5 days, 500 mg orally x 5 days, or 1 g orally x 1 day (≥18 years)
Neonatal	SEM (herpes encephalitis)	Acyclovir 60 mg/kg/day IV ÷ 3 times/day × 14 days
	CNS	Acyclovir 60 mg/kg/day IV ÷ 3 times/day × 21 days
	Common	Acyclovir 60 mg/kg/day IV ÷ 3 times/day × 21 days
HSE	≤12 years	Acyclovir 45–60 mg/kg/day IV ÷ 3 times/day × 14–21 days
	> 12 years	Acyclovir 30 mg/kg/day IV ÷ 3 times/day × 14-21 days
Ophthalmic herpes	Epithelial	Trifluorothymidine, vidarabine, idoxuridine, or topical acyclovir; no topical steroids
	Stromal	Trifluorothymidine, vidarabine, idoxuridine, or topical acyclovir; topical steroids indicated, also consider systemic acyclovir
Patients with weakened immunity (localized, visceral or disseminated)	<12 years	Acyclovir 30 mg/kg/day IV ÷ 3 times/day 7–14 days
	≥12 years	Acyclovir 15 mg/kg/day IV ÷ 3 times/day 7–14 days
	≥2 years	Acyclovir 1 g/day orally ÷ 3–5 times/day × 7–14 days
	Foscarnet*	80–120 mg/kg/day ÷ 2–3 times/day
	Cidofovir*	Induction: 5 mg/kg/dose IV once a week x 2 weeks Maintenance: 5 mg/kg/dose IV once every 2 weeks

^* There is insufficient data to determine pediatric dosage.

Acyclovir is a deoxyguanosine analogue that must undergo a series of three phosphorylation steps before it can exert its antiviral effect by competitively inhibiting viral DNA polymerase and terminating DNA chain extension. Within the infected cell, the first phosphorylation of acyclovir occurs via virally encoded thymidine kinase (TK), while the second and third phosphorylation steps are carried out by cellular kinases. Valaciclovir is an L-oral prodrug, the valyl ester of acyclovir, with improved bioavailability. Famciclovir is a prodrug of the diacetyl ester of penciclovir, an acyclic guanosine analogue. Like acyclovir, penciclovir acts via a TK-dependent phosphorylation pathway to form the active form of the agent, penciclovir triphosphate; the latter then acts as a competitive inhibitor of DNA polymerase. Unlike acyclovir, penciclovir is not incorporated into the elongating DNA chain and therefore has no activity in terminating DNA chain elongation.

Given that acyclovir, valacyclovir, and famciclovir are the mainstays of HSV treatment, the emergence of acyclovir-resistant HSV strains is of concern. In immunocompetent individuals infected with HSV, acyclovir resistance has not yet become a clinically significant problem, with reported resistance rates of <1%.[ 26 ] Resistance rates in immunocompromised patients are somewhat higher on average (5–6%), which should be taken into account when managing these patients.[ 27 ] Mutations resulting in TK alterations or deficiencies are the most common mechanism of acyclovir resistance in HSV, although alterations in the viral DNA polymerase can also lead to resistance. Foscarnet, a pyrophosphate analogue that directly inhibits viral DNA polymerase without the need for prior phosphorylation, and cidofovir, a nucleotide analogue that inhibits DNA polymerase after a TK-independent phosphorylation process, are the two most common antiviral alternatives used to treat acyclovir-resistant HSV infections.

Idoxuridine and vidarabine remain available as topical preparations for the treatment of ocular herpes, as do other antivirals such as trifluorothymidine and acyclovir. In ocular infections, it is important to distinguish between epithelial keratitis and stromal keratitis; epithelial keratitis is treated with topical antivirals alone, whereas immune-mediated stromal disease also requires topical steroids and possibly systemic antiviral therapy. Topical penciclovir and acyclovir have shown modest efficacy in the context of recurrent orolabial infections in adults.[ 28 ]

For primary mucocutaneous HSV infections, including orolabial and anogenital disease, oral acyclovir, valacyclovir, and famciclovir have been shown to hasten symptom resolution and shorten the duration of viral shedding.[ 29 ],[ 30 ] Therapy should be initiated early (within 72 hours of symptom onset) for optimal benefit. Initiating oral therapy at the first sign of relapse of mucocutaneous disease may provide some symptom relief, but the benefit is less significant than for primary HSV infections. Thus, chronic suppressive therapy should be considered in patients with frequent mucocutaneous relapses.

In case of localized lesions of the skin and mucous membranes, it is recommended to apply acyclovir ointment, 5% cycloferon liniment and other antiviral drugs locally. Interferon in the form of ointment, lotions, rinses, and instillations is effective. The affected areas of the skin and mucous membranes are treated with a 1-2% alcohol solution of brilliant green, 1-3% alcohol solution of methylene blue. A good sanitizing effect in case of herpetic stomatitis is provided by a 3% hydrogen peroxide solution (the oral cavity and gums are treated). Locally, painkillers (anesthesin, lidocaine) are used to eliminate pain and make it possible to feed the child.

In case of recurrent herpes simplex, a course of treatment is carried out with Viferon, vitamins B1 _, B2 _, B12 _, pyrogenal (up to 20 injections per course), liquid extract of eleutherococcus, ginseng tincture, etc. A good therapeutic effect is provided by specific antiherpetic immunoglobulin and a vaccine for the prevention of herpes infections. The use of Imudon in accordance with the age dose is effective for herpetic stomatitis. It is possible to use interferon inducers (cycloferon, ridostin, neovir, arbidol, children's anaferon, etc.). Antibacterial therapy is carried out only in case of secondary bacterial infection. Glucocorticoids are contraindicated, but in severe forms of herpes encephalitis and meningoencephalitis, they are recommended to be included in the complex therapy.

Suppressive therapy

In the context of recurrent mucocutaneous HSV infections, the decision to treat individual outbreaks (episodic therapy) or to use suppressive therapy is based primarily on the frequency of relapses and the resulting frailty of each patient. When given chronically, oral acyclovir, valacyclovir, and famciclovir reduce the frequency of relapses, the severity of individual episodes, and the rate of viral shedding in adults with recurrent mucocutaneous HSV infections.[ 31 ] Because of their bioavailability and tolerability, valacyclovir and famciclovir are particularly attractive options for chronic suppressive therapy in individuals with frequent relapses, but these drugs are significantly more expensive than acyclovir, and famciclovir is not currently available in a pediatric formulation.

Suppression of childhood HSV infections [ 32 ]

Orolabial	Acyclovir 40–80 mg/kg/day PO ÷ 3 times/day or 400 mg PO 3 times/day for adolescents; continue until 12 months, then reassess need
	Valaciclovir 500 mg daily or 1 g once daily (≥18 years)
	Famciclovir* 250 mg orally. (≥18yo)
Anogenital	Acyclovir 40–80 mg/kg/day PO ÷ 3 times/day or 400 mg PO 3 times/day for adolescents; continue until 12 months, then reassess need
	Valaciclovir 500 mg daily or 1 g once daily (≥18 years)
	Famciclovir* 250 mg orally (≥18 yo)
After neonatal infection	Acyclovir 80 mg/kg/day PO ÷ 4 times/day 7 days at first relapse; then 300 mg/m2 / dose PO × 6 months, then reassess need. Monitor CBC during suppressive therapy

*Insufficient data to determine pediatric dosing

Suppressive therapy after completion of a course of intravenous acyclovir in patients with neonatal HSV infection may also be beneficial. Some experts recommend initiating suppressive therapy with oral acyclovir for neonates with HSV infection after the first mucocutaneous relapse.[ 33 ] A previous phase I/II study evaluating oral suppressive therapy with acyclovir in neonates with HSV and SEM demonstrated a reduction in cutaneous relapses, but nearly half of the infants receiving acyclovir developed neutropenia.[ 34 ] Two recent randomized controlled trials evaluating oral suppressive therapy in patients with SEM and CNS have been completed and are in the final stages of data analysis. Results are expected soon.

Prevention

Of great importance is the hardening of children and the formation of general hygiene skills. Factors that contribute to the exacerbation of the disease are eliminated (physical activity, ultraviolet rays, other stressful effects). Since children are most often infected through saliva when kissing parents with clinically expressed herpes, sanitary and educational work is of great importance. It is especially important to protect children suffering from eczema and weeping forms of atopic dermatitis. Newborns who have been in contact with patients with herpes must be isolated. A mother with manifestations of herpes on the skin and mucous membranes must wear a surgical mask when communicating with the child, she must not press or kiss the newborn until the crusts have completely fallen off and the erosions have healed. Breastfeeding can be allowed if there are no skin lesions on the chest.

To prevent intrauterine infection of the fetus, all pregnant women should be tested for the herpes simplex virus. If clinical signs of infection are present, it is recommended to administer immunoglobulin at a rate of 0.2 ml/kg. If signs (clinical or laboratory) of genital herpes are detected immediately before delivery, it is better to resort to a cesarean section. This, although it does not completely exclude the possibility of fetal damage, significantly reduces its likelihood, especially if the amniotic membranes were not damaged more than 4-6 hours before delivery.

Children born to women with signs of genital herpes or suspected of it are subject to careful examination. If herpes is detected in children, they are prescribed treatment with acyclovir. Children without clinical and laboratory signs of herpes are monitored for 1-2 months, since the initial symptoms may not appear immediately after birth.

[ 35 ], [ 36 ], [ 37 ], [ 38 ], [ 39 ]

Forecast

Overall, the vast majority of HSV-1 infections are asymptomatic, and when symptomatic, present with mild, recurrent mucocutaneous lesions. The prognosis of HSV-1 infection varies depending on the presentation and location of HSV-1 infection. Most cases of HSV-1 infection have a chronic latent period and reactivation. Herpes simplex virus encephalitis is associated with high mortality; approximately 70% of untreated cases are ultimately fatal. The prognosis of ophthalmic herpes can also be poor if the patient develops globe rupture or corneal scarring, as these processes can ultimately lead to blindness.[ 40 ]

There is no cure for herpes simplex virus type 2 infection, but early recognition of symptoms and prompt initiation of drug therapy may result in early suppression of viral replication. Abstinence during known viral shedding may reduce the risk of transmission to a seronegative partner. [ 41 ] Unfortunately, HSV-2 persists in a seropositive person for life.