Herpes Simplex Oral Infection in Children. Acute herpetic gingivostomatitis (AHGS): Clinical Characteristics, Diagnostics, Treatment

Herpesviruses have the remarkable ability to affect nearly every organ and system in the human body. Once they establish themselves, they persist long-term, leading to non-sterile immunity and, in some cases, immunodeficiency. While virus-neutralizing antibodies may hinder the spread of infection, they are ineffective in preventing recurrences. Primary infection with herpes simplex virus usually occurs during early childhood, often asymptomatically. The virus typically enters through mucosal surfaces of the lips, oral cavity, conjunctiva, or genitals, with overt clinical manifestations in only 10–15% of cases.

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Herpes infections can manifest as acute diseases with short incubation periods and distinct symptoms or remain asymptomatic. The subsequent interaction between the virus and the human body is characterized by its prolonged persistence, which takes on three primary forms:

1. Latent infection: The viral replication cycle is incomplete, and the virus resides within host cells as subviral structures.
2. Chronic infection: Symptoms persist for extended periods.
3. Progressive slow infection: Severe clinical symptoms develop, often with fatal outcomes.

The hallmark biological traits of human herpesviruses are their abilities to persist and remain latent within the host. Persistence involves continuous and cyclical viral replication in infected cells, contributing to disease progression. Latency, in contrast, is clinically “silent” and detected only through low titers of specific IgG antibodies (seropositivity). During this phase, the virus is undetectable in peripheral blood, even with highly sensitive PCR methods.

To date, about 200 members of the Herpesviridae family have been identified, with 8 serotypes known to be pathogenic to humans. Based on the nature of cellular damage, replication speed, and latency sites, herpesviruses are classified into three subfamilies:

1. Alpha-herpesviruses (Herpes Simplex Virus types 1 and 2, Varicella-Zoster Virus): Characterized by rapid replication (4–8 hours), cytolytic activity, and asymptomatic persistence in neuronal cells.
2. Beta-herpesviruses (Cytomegalovirus, Herpesvirus types 6 and 7): Slowly replicating viruses causing cytomegalic transformation in cells. Latency primarily occurs in monocytes, endothelial cells, alveolar macrophages, T-lymphocytes, and bone marrow stromal cells.
3. Gamma-herpesviruses (Epstein-Barr Virus, Herpesvirus type 8). Transforming viruses that persist lifelong in B-lymphocytes or remain latent, contributing to malignant cell transformation.

Infections with Herpes Simplex Virus (HSV-1 and HSV-2) commonly present as vesicular eruptions on the skin and mucous membranes, with potential nervous system involvement. These infections often exhibit a chronic course with periodic recurrences.

HSV is a DNA-containing virus composed of a nucleoid, capsid, and an outer lipoprotein envelope embedded with glycoproteins that facilitate viral attachment and entry into host cells. The virus targets ectodermal and endodermal tissues, affecting the skin, mucous membranes, nervous system, liver, blood vessels, and various blood cells (T-lymphocytes, erythrocytes, leukocytes, platelets).

Humans are the sole reservoir of HSV, with the virus typically transmitted through contact, droplets, sexual activity, or perinatally. Infection often occurs within the first 3–5 years of life, with most adults carrying antibodies by adulthood. The virus enters through mucous membranes or skin, replicates locally, and spreads to regional lymph nodes. Subsequent viremia facilitates viral dissemination to internal organs and, in some cases, the central nervous system. HSV establishes latency in neural ganglia, allowing for potential reactivation during immunosuppression or stress.

Recurrent HSV infections occur despite the presence of neutralizing antibodies. Reactivation is often triggered by factors such as stress, hormonal changes, or environmental conditions, leading to viral release and renewed disease activity.

After initial exposure, HSV replicates at the site of entry, leading to vesicular lesions. Primary infection triggers viremia, with the virus spreading via hematogenous, lymphatic, or neural pathways. The progression depends on the host's immune system, infection route, and viral strain and type. Hematogenous dissemination can cause generalized herpes, especially in immunocompromised individuals or those undergoing immunosuppressive therapy.

In severe cases, HSV spreads to visceral organs such as the lungs, liver, spleen, and kidneys, triggering secondary viremia and acute infection lasting 7–14 days. Specific antibodies develop within 4–7 days, peak at 2–3 weeks, and often persist for life. Humoral immunity prevents reinfection, while cellular immunity aids recovery. Despite the immune response, HSV establishes latency in sensory ganglia, ready to reactivate under stress, ultraviolet light exposure, fever, or emotional disturbances.

• Primary Infection: Frequently subclinical, especially in children aged 6 months to 3 years. Symptomatic cases include acute herpetic stomatitis, respiratory diseases, or skin and eye lesions. Genital herpes often emerges with sexual debut.
• Recurrent Infections: Reactivation leads to localized or generalized lesions, often milder than primary episodes. Common forms include oral and genital herpes, with recurrences varying from once a year to monthly episodes.

Epidemiological data indicate that over 90% of adults older than 40 have antibodies against HSV-1, with HSV-2 antibodies correlating with sexual activity. Primary infections, often acquired in early childhood or adolescence, present a broad spectrum of clinical manifestations, from mild local lesions to systemic complications.

In some cases, HSV extends beyond localized lesions:

• Meningitis and Encephalitis: Neurological involvement, often life-threatening.
• Visceral Involvement: Rare complications include hepatitis, pneumonia, and nephritis.
• Disseminated Infections: Multiorgan involvement with severe systemic symptoms, including fever, intoxication, and hemorrhagic manifestations.

The persistence of herpesviruses, their ability to evade immune responses, and their diverse clinical implications continue to challenge medical science. Advances in antiviral therapies and vaccines offer hope for reducing the burden of herpes infections, but their eradication remains elusive.

Classification

Infections caused by Herpes Simplex Virus

Herpes Simplex Virus (HSV-1 and HSV-2) typically cause:

• Mucocutaneous infection (most common)
• Ocular infection
• Central nervous system infection
• Neonatal herpes

ICD-10 Classification

Viral infections characterized by skin and mucous membrane lesions
(B00-B09)

B00 Herpesviral [herpes simplex] infections:

B00.1 Herpesviral vesicular dermatitis:

• Herpes simplex:
  • facialis
  • labialis
• Vesicular dermatitis of (due to human (alpha) herpesvirus 2):
  • ear
  • lip

B00.2 Herpesviral gingivostomatitis and pharyngotonsillitis:

• Herpesviral pharyngitis

ICD-11 Classification

• 1F00  Herpes simplex infections
  • 1F00.0 Herpes simplex infection of skin or mucous membrane
    • 1F00.00 Herpes simplex infection of skin
    • 1F00.01  Herpes simplex labialis
    • 1F00.02 Herpes simplex gingivostomatitis
    • 1F00.03 Disseminated cutaneous herpes simplex infection complicating other skin diseases
  • 1F00.0Y Other specified herpes simplex infection of skin or mucous membrane

Clinical Presentation of Acute Herpetic Gingivostomatitis (AHGS) in Children

Acute herpetic gingivostomatitis (AHGS) manifests as an acute infectious process, varying in severity as mild, moderate, or severe forms. The severity is determined by the virulence of the specific strain of HSV, the extent of systemic symptoms, the spread of oral mucosal lesions and the host’s immune response.

Evolution of Lesions in the Oral Cavity

The progression of lesions follows a specific pattern:

1. Spot – Initial discoloration.
2. Vesicle – Fluid-filled, fibrinous vesicles appear.
3. Erosion – Uneven, scalloped borders emerge as vesicles rupture; erosions often group and merge into larger areas.
4. Healing Erosion – Covered with a fibrinous film surrounded by hyperemia.
5. Resolution – Returns to a spot as healing completes.

Early Diagnostic Markers

Key indicators for early clinical diagnosis include submandibular lymphadenitis, catarrhal gingivitis, and respiratory symptoms. Clinically, HSV-1 infections typically begin with early symptoms such as fever, appetite loss, fatigue, and muscle aches. A few days later, areas of redness accompanied by clusters of vesicles develop. These are commonly found on the hard palate, attached gingiva, and the dorsal surface of the tongue, as well as on non-keratinized mucosal areas, including the buccal and labial mucosa, the ventral side of the tongue, and the soft palate. The vesicles rupture, leaving behind ulcers that range from 1 to 5 mm in size, often merging into larger lesions with irregular, scalloped edges and pronounced surrounding redness. The gingiva may appear intensely inflamed and bright red, with the resulting pain making eating particularly difficult.

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Mild Form

• Prodromal Period: Asymptomatic. No signs of intoxication.
• Catarrhal Period: Slight fever (37.2–37.5 °C), minimal respiratory symptoms, mild catarrhal gingivitis (primarily along the lower front teeth). Submandibular lymphadenitis lasts for about 2 days.
• Eruption Period: Fever rises to 37.5 °C, mild discomfort while eating. Up to five grouped lesions appear, typically resolving in one episode. Submandibular lymphadenitis persists for about 2 days.
• Resolution: Lesions epithelialize. Gingivitis may resolve with timely treatment. Duration: 4-6 days.
• Recovery: Normal temperature, no gingivitis, lymphadenitis resolves within 7 days.

Moderate Form

• Prodromal Period: Fever (37.2–37.5 °C), mild weakness, irritability, reduced appetite.
• Catarrhal Period: Fever rises to 38–39 °C. Symptoms include headache, nausea, pallor, and prominent respiratory symptoms. Acute gingivitis and stomatitis are evident, often accompanied by perioral skin eruptions. Duration: 2-3 days.
• Eruption Period: Gingivitis worsens as 3–25 lesions develop, often recurring 2–3 times. Fever spikes coincide with new eruptions, creating "false polymorphism" (lesions at different stages of development). Lymphadenitis persists. Duration: 2-3 days.
• Resolution: Lesions epithelialize, appetite and sleep improve. Delayed healing or secondary necrosis may occur with inadequate treatment. Duration: 5-7 days.
• Recovery: Gingivitis resolves, though lymphadenitis may linger for a week.

Severe Form

• Prodromal Period: High fever (38–39 °C), severe lethargy, headache, muscle and joint pain, skin hypersensitivity, and possible cardiovascular symptoms (bradycardia, hypotension). Often preceded by another illness.
• Catarrhal Period: Fever spikes to 39.5–40 °C. Severe intoxication, conjunctivitis, dry and cracked lips, ulcerative gingivitis, and submandibular or cervical lymphadenitis. Duration: 3-4 days.
• Eruption Period: Up to 100 lesions emerge in multiple cycles, merging into large necrotic zones. Gingivitis becomes ulcerative and necrotic with a foul odor and blood-streaked salivation. Skin lesions may appear on eyelids, fingers, or buttocks. Duration: 3-5 days.
• Resolution: Gradual recovery of appetite and sleep, though gingivitis persists. Healing is slower, with lymphadenitis lasting longer. Duration: about 8-9 days.
• Recovery: Residual gingivitis and lymphadenitis linger for 7–10 days.

Chronic Implications and Reactivation

The herpes virus persists in the body for life. Children recovering from AHGS often become carriers or develop recurrent forms, such as herpes labialis. Recurrence occurs in 1 out of every 7–8 cases, often within the first year after AHGS.

Triggers for Reactivation

Herpes simplex virus can spontaneously reactivate but is commonly induced by:

• External Factors: Cold exposure, heat, UV radiation, fever, respiratory infections.
• Internal Factors: Stress, hormonal changes, pregnancy and menstruation, gastrointestinal upset, immune suppression, and certain medications.
• Local Trauma: Micro-injuries to the oral mucosa from habits (lip or cheek biting), dental procedures, or cosmetic treatments. These factors disrupt the host-virus balance, favoring viral replication.

Treatment

Currently, there are no methods to completely eliminate HSV from the human body. Therefore, treatment is mainly supportive and aims to achieve the following objectives:

1. Analgesia and hydration.
2. HSV suppression.
3. Developing a robust and long-lasting immune response.

Main Approaches to Treating Herpes Simplex Virus

Primary strategies for managing herpes simplex infections:

1. Pain relief and adequate fluid intake.
2. Antiviral chemotherapy, primarily using acyclic nucleosides, such as acyclovir, valacyclovir, and famciclovir – effective if started at the onset of prodromal period prior to lesions erupting (within 72 hours of symptom onset).

Antiviral Agents for Treating and Preventing Herpetic Infections

• Acyclic nucleosides: Acyclovir, Valacyclovir, Famciclovir, Vidarabine, Trifluorothymidine, Ribavirin, Cytarabine, Iodoxuridine, Penciclovir, Foscarnet.
• Specific inhibitors: Bonafton, Florenal, Tebrofen, Deoxyribonuclease, Flacoside, Helepin, Alpizarin, Panavir, Oxolin.

Antiviral Drugs with Proven Efficacy

Randomized clinical trials have demonstrated the effectiveness of nucleoside analogs such as acyclovir, valacyclovir, and famciclovir. In the body, valacyclovir is converted to acyclovir, while famciclovir is converted to penciclovir. These medications are primarily used for treating herpes infections in adults.

Acyclovir, a pioneer among DNA synthesis inhibitors, is considered the "gold standard" in anti-herpetic therapy. It becomes active only in virus-infected cells due to the viral enzyme thymidine kinase, which converts it into acyclovir triphosphate. This compound inhibits viral DNA polymerase and halts viral DNA synthesis, making it highly specific and minimally toxic.

General Treatment of Acute Herpetic Gingivostomatitis

1. Antiviral medications: Acyclovir, Valacyclovir, Famciclovir. 
2. Detoxification: Adequate hydration and multivitamin supplements.
3. Antipyretics: For fevers above 38°C.
4. Specialized nutrition: Non-irritating foods like vegetable broths, pureed fruits and vegetables, dairy products, and soft, nutrient-rich meals.

Local Treatment of Acute and Recurrent Herpetic Stomatitis

1. Pain relief: Lidocaine, trimecaine, or specialized gels (e.g., Lidoxor).
2. Antiseptic rinses: Herbal infusions (chamomile, sage), or mild antiseptics (hydrogen peroxide, chlorhexidine).
3. Epithelium-restoring agents: Vitamin A oil.
4. Physical therapy: Laser treatments as needed.

Antiviral therapies remain the most scientifically validated approach, effectively reducing the frequency and severity of herpes recurrences.

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