Herpes Simplex Virus Infection: Symptoms, Transmission, and Complications

Summary

Herpes simplex infection is a viral disease caused by the Herpes simplex virus, commonly known as the cold sore virus. It is characterized by vesicular lesions of the skin and mucous membranes, skin rashes, and, more rarely, damage to the nervous system and parenchymal organs. In children, the infection is usually diagnosed based on clinical findings; however, in severe cases, laboratory or instrumental diagnostic methods are required. Patients with mild Herpes simplex infection typically require only symptomatic treatment. Antiviral therapy with nucleoside analogues (such as acyclovir) is used for more severe forms of Herpes simplex virus infection. The frequency of complications depends on the patient’s age and the severity of the disease, ranging from acute dehydration and secondary bacterial or fungal infections to acute encephalitis. Nevertheless, the prognosis of Herpes simplex infection is generally favorable. Currently, no vaccines are available for Herpes simplex virus infection; therefore, only non-specific preventive measures can be applied.

Introduction

Herpes simplex virus infection, also known as the common cold sore, is a viral infection caused by the Herpes simplex virus, which most commonly induces vesicular lesions of the skin and mucous membranes, skin rashes, and, more rarely, damage to the nervous system and parenchymal organs [1].

Etiology and Epidemiology

The causative agents of cold sores are Herpes simplex virus type 1 (HSV-1) and Herpes simplex virus type 2 (HSV-2), DNA viruses belonging to the Herpesviridae family [2]. HSV-1 more commonly causes infections of the skin and mucous membranes, whereas HSV-2 primarily causes genital infections. However, both HSV-1 and HSV-2 can cause infections in different anatomical locations: HSV-1 can cause genital infections, while HSV-2 can cause cold sores affecting the skin and mucous membranes [1, 3]. HSV infection is widespread worldwide. It is estimated that more than 3.7 billion individuals under 50 years of age (approximately 67% of the global population) are infected with HSV-1, and about 471 million individuals aged 15 to 49 years are infected with HSV-2 [4]. Individuals infected with HSV-1 are also at risk of acquiring HSV-2 infection. The prevalence of HSV-1 and HSV-2 infections varies according to socioeconomic status, race, and other risk factors. In the United States, 20–30% of 5-year-old children have antibodies against HSV-1, with seroconversion occurring in 70–80% of adolescents later in life. The prevalence of HSV-2 infection increases with age: among individuals aged 15–29 years, 20–30% are infected in the United States, whereas among people aged 60 years, prevalence ranges from 35–60% [2]. Once infected with Herpes simplex virus, an individual remains infected for life, as the virus enters a latent phase and periodically reactivates. Many infected individuals do not notice the primary HSV infection because it may be asymptomatic. As a result, most infected people become lifelong carriers of the virus and can transmit it to others both during latency and during active infection [1, 5]. HSV infection is transmitted through respiratory droplets, direct contact with infected mucous membranes, skin lesions, saliva, sexual contact, or blood transfusion [1, 2]. The virus can also be transmitted vertically from a pregnant woman to her fetus or newborn during childbirth through infected birth canals [1]. The frequency of HSV recurrences varies between individuals. Active infection may occur several times per year or only once, or even less frequently [5]. Recurrence is influenced by psychosocial stress, excessive physical exertion, lack of rest, concurrent illnesses, immune system function, and other factors.

Pathophysiology

During primary infection, HSV attaches to target cells, fuses with the cell membrane, sheds its envelope, and allows the viral capsid to enter the host cell. Viral DNA then enters the nucleus and utilizes the host cell machinery for viral replication. Newly produced virions ultimately cause cell death [2]. Within the first 24 hours after infection, virions travel along axons to sensory ganglia, including the trigeminal ganglion and the sacral dorsal root ganglia. In these ganglia, the virus either continues to replicate or enters a latent stage and persists throughout life. The immune system cannot eliminate latent HSV infection, resulting in periodic low-level viral reactivation and the potential for transmission, although this risk can be reduced through daily suppressive therapy with acyclovir. During recurrent infection, virions produced in the ganglia travel back along nerve pathways to the innervated areas of the skin and mucous membranes. There, they infect epithelial cells, causing either symptomatic lesions or asymptomatic viral shedding into the environment [2]. Clinical manifestations of recurrent HSV infection are generally milder than those of primary infection because immune mechanisms partially inhibit viral replication and tissue damage. It is believed that a stronger nonspecific immune response is required to control primary infection. Unfortunately, the immune response cannot prevent viral latency, although it may reduce the frequency of disease recurrence [2].

Clinical Manifestations

The clinical manifestations of Herpes simplex infection vary depending on the type of virus causing the infection (HSV-1 and HSV-2 typically cause lesions in different anatomical locations) and the age of the infected patient. The incubation period ranges from 1 to 26 days [1].

Neonatal Herpes Simplex Infection

HSV infection in newborns may manifest as skin and mucosal lesions, although encephalitic and disseminated forms of infection may also occur. The cutaneous form usually develops during the second week of life and is characterized by vesicular lesions affecting the skin, oral mucosa, and conjunctivae. Dissemination of the infection is possible. Neonatal herpes encephalitis typically begins between the second and third weeks of life. It is characterized by fever and central nervous system symptoms such as irritability or lethargy, seizures, focal neurological signs, and atypical skin and mucosal lesions. Disseminated neonatal herpes usually presents between the first and second weeks of life with symptoms resembling sepsis, including fever or hypothermia, lethargy, jaundice, pneumonia, and hepatitis. Skin rash is not a common feature of this form.

Herpes Simplex Infection in Infants and Young Children

In this age group, the most common clinical manifestations of HSV infection are herpetic gingivostomatitis and eczema herpeticum [1].

Herpetic Gingivostomatitis

This is one of the most common manifestations of HSV infection in children and usually occurs in patients younger than 6 years of age. HSV-1 is responsible for approximately 90% of cases of primary herpetic gingivostomatitis. Most children experience asymptomatic primary HSV infection. In symptomatic cases, the diagnosis is usually made based on clinical findings [6]. During the first 1–2 days of herpetic gingivostomatitis, children may become irritable, develop fever, refuse food and fluids, and exhibit swelling or increased sensitivity of the oral mucosa and gingiva. Two to four days after the onset of illness, vesicular lesions develop on the oral mucosa and tongue. These lesions vary in size and often progress into painful ulcers (aphthae), leading to difficulties with eating and drinking. In addition to the symptoms described above, herpetic gingivostomatitis is characterized by excessive salivation and enlarged cervical lymph nodes. The lesions may spread to the lips and surrounding skin. The disease typically lasts 2–3 weeks [1]. Herpetic gingivostomatitis is highly contagious. The most common complication is acute dehydration, accompanied by disturbances in fluid, electrolyte, and acid-base balance due to reduced oral intake. In a study involving 61 patients aged 1–6 years with herpetic gingivostomatitis, 89% were unable to consume an adequate daily amount of fluids independently [6]. A similar rash in the oropharynx may occur in Coxsackie virus-induced herpangina. When differentiating between these conditions, it is important to note that Coxsackie virus lesions typically localize to the posterior oropharynx, whereas HSV lesions more commonly affect the anterior oropharynx [7].

Eczema Herpeticum

This manifestation of HSV infection occurs more commonly in young children with atopic dermatitis. The inflamed, dry, and cracked skin associated with atopic dermatitis becomes infected with Herpes simplex virus. Following HSV infection, the affected eczematous areas become significantly more inflamed, exudative, and covered with characteristic herpetic vesicles [8]. The vesicular eruption is accompanied by systemic symptoms similar to those seen in herpetic gingivostomatitis and may result in acute dehydration and disturbances in electrolyte and acid-base balance. Eczema herpeticum frequently leads to complications, particularly secondary bacterial skin infections that require antibacterial treatment [1].

Herpes Simplex Infection in Older Children and Adults

HSV infection in older children and adults most commonly presents in the following forms [1]:

• Herpes labialis;
• Pharyngitis;
• Genital herpes;
• Meningoencephalitis.

Herpes Labialis

Herpes labialis is characterized initially by tingling, itching, burning, and increased sensitivity of the lips and surrounding skin. After 1–3 days, the characteristic vesicular HSV rash develops, often replacing the prodromal symptoms. The condition usually lasts 5–12 days [1].

HSV Pharyngitis

HSV pharyngitis is clinically similar to herpetic gingivostomatitis. However, in pharyngitis, vesicles and ulcers are more likely to develop on the soft palate, posterior pharyngeal wall, and tonsils. A grayish exudative coating may also be present. Fever and cervical lymphadenopathy are common features of this form [1].

Genital Herpes

Genital herpes is an HSV infection affecting the genital region. During primary infection, fever, dysuria, itching, pain, and enlargement of the inguinal lymph nodes are common. Vesicles and ulcers develop on the genital skin and mucous membranes. Recurrent episodes are generally milder than the primary infection [1]. Women are more susceptible to HSV infection because the mucosal surfaces of the female external genitalia are more vulnerable to viral entry than the keratinized skin of the male genital organs [2].

Herpetic Meningoencephalitis

This form of HSV infection is characterized by a prodromal phase during which both systemic and neurological symptoms appear, including fever, irritability, weakness, headache, vomiting, hyperesthesia, and, in some cases, hallucinations. After approximately one week, signs of central nervous system involvement become evident, manifesting as impaired consciousness, focal neurological deficits, hemiparesis, seizures, dysphagia, and visual field defects. Skin rash is uncommon in this form of the disease [1].

Herpetic Keratoconjunctivitis

HSV-induced keratoconjunctivitis can occur in patients of any age. It is usually a unilateral eye disease characterized by systemic symptoms such as fever, myalgia, and general weakness. Clinical examination may reveal conjunctival hyperemia, excessive tearing, itching, ocular discharge, and increased sensitivity. Eyelid edema, photophobia, and impaired visual acuity may also occur. It is important to note that herpetic keratoconjunctivitis is the leading cause of blindness associated with corneal disease in developed countries [1].

Diagnosis

In cases of classic HSV infection, the diagnosis is usually based on clinical findings. In more severe cases, the diagnosis can be confirmed by:

• Isolation of the virus from affected tissues, vesicular fluid, or cerebrospinal fluid;
• Detection of elevated HSV-specific IgM and IgG antibodies in serum and cerebrospinal fluid using enzyme-linked immunosorbent assay (ELISA);
• Detection of HSV nucleic acid in cerebrospinal fluid using polymerase chain reaction (PCR) testing [1].

Differential Diagnosis [1]

• Varicella (chickenpox);
• Herpes zoster;
• Enteroviral exanthems;
• Allergic and drug-induced skin eruptions;
• Cutaneous streptococcal and staphylococcal infections;
• Fungal stomatitis;
• Streptococcal pharyngitis;
• Epstein-Barr virus infection;
• Adenoviral infection;
• Meningoencephalitis of other etiologies (bacterial, viral, or protozoal).

Read more in Pediatrics Magazine, Issue No. 3, 2018. Evelina Liukpetrytė Vilnius City Clinical Hospital, Children's Clinic