Herpesvirus-Related Lesions of the Oral Mucosa

The human herpesvirus (HHV) family is a group of enveloped DNA viruses containing 8 members known to produce oral mucosal lesions. Following initial exposure, which may result in symptomatic primary infection, the viruses establish latency within specific cells/tissues. After reactivation, herpesviruses can cause localized symptomatic or asymptomatic recurrent (secondary) infections or diseases. HHV may have a significant role in the cause of oral mucosal infectious diseases in immunocompromised patients. This article discusses the role of those herpesviruses that can induce oral mucosal lesions, with focus on the clinical features and treatment/management.

Key points

  • Herpesvirus-related lesions should be considered in the differential diagnosis of oral ulcerations.

  • The appearance of clusters of coalescing ulcers due to rupture of vesicles following prodromal symptoms is the classic presentation of herpes simplex virus infection.

  • Although herpes infection is a self-limiting process, systemic antiviral medication administered within the first 72 hours of symptom onset reduces the severity and duration of clinical disease.

  • Midline termination of vesicles/ulcers is highly suggestive of herpes zoster.

  • Immunocompromised patients are at higher risk for herpesvirus infections and may benefit from antiviral prophylaxis.


At least 100 species of herpesviruses have been described in the nature but only 8 of those can infect humans, known as human herpesviruses (HHVs). Herpesviruses are double-stranded DNA-containing viruses in which the genome is surrounded by a capsid, tegument, and envelop. All are characterized by the establishment of latency in sensory nerves.

There are 3 subfamilies of herpesviruses: The α-herpesviruses are those with a short (hours) replicative cycle and that are able to destroy host cells promptly and replicate in a wide variety of host tissues. This subfamily consists of herpes simplex virus (HSV) types 1 and 2 and varicella-zoster virus (VZV). The second subfamily is β-herpesviruses. Cytomegalovirus (CMV), and human herpes viruses 6 and 7 belong to this family. These viruses are characterized by a long (days) replicative cycle and restricted host range. ϒ-herpesviruses are the third class and include Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV-8). These have the most limited host range and can cause infections in certain targeted cells.

HHVs and their associated lesions/diseases are summarized in Table 1 .

Table 1
Herpesvirus-related conditions
Data from Refs.
Herpes Virus Type Oral Lesion Other Manifestation
Herpes simplex virus (HSV)-1
  • Primary herpetic gingivostomatitis

  • Recurrent herpes labialis

  • Recurrent/recrudescent herpes stomatitis

  • Herpetic whitlow

  • Herpes gladiatorum

  • Herpes encephalitis

  • Ocular herpes

  • Eczema herpeticum

  • Herpes esophagitis

Herpes simplex virus (HSV)-2
May cause oral lesions identical to those of HSV-1
  • Lesions on skin and mucosal sites below the waist (genital)

  • Herpetic whitlow

  • Neonatal infection

  • Possible oral ulcers caused by primary infection as chickenpox

  • Possible unilateral lesions due to the shingles (recrudescent infection) along the distribution of the branches of trigeminal nerve

  • Skin lesions in primary infection (chickenpox)

  • Shingles due to activation of the latent virus

  • Acute neuritis

  • Postherpetic neuralgia

  • Severe complications in immunocompromised patients

  • IM

  • OHL (tongue)

  • EBV-related chronic oral ulcers in immunocompromised or immunosenescent patients

  • Nasopharyngeal carcinoma

  • Burkitt lymphoma

  • Hodgkin lymphoma

  • Angio-immunoblastic T-cell lymphoma

  • T/NK cell lymphoma

  • Nasal T/NK cell lymphoma

  • Plasmablastic lymphoma

  • EBV-associated chronic ulcers

  • (EBV-associated, B-cell lymphoproliferative disorder)

Deep oral ulcers
  • IM-like syndrome

  • Congenital cytomegalic inclusion disease

  • Severe complications in immunocompromised patients

HHV-6 and HHV-7 No reported oral lesions Roseola (exanthema subitum, sixth disease) with rejection of transplanted kidneys
  • AIDS-related lymphomas of organ cavities

  • Castleman disease

Herpes simplex virus infection


The group of herpes simplex viruses (HSV) includes HSV-1 and HSV-2. Although both types of viruses have similar structure and share 50% to 70% of their genetic profiles, they are distinguished based on antigenic properties. Both HSV-1 and HSV-2 infections can affect mucocutaneous surfaces, the central nervous system (CNS), and visceral organs. Both viruses can cause similar primary or recurrent/recrudescent infections in the oral or genital regions. HSV-1 primarily affects mucosal sites including oral mucosa and skin above the waist, whereas HSV-2 predominantly affects mucosal sites including urogenital and skin below the waist. The highest incidence of HSV-1 infection occurs after 6 months of age due to the loss of maternal anti-HSV antibodies and peak incidence is between 2 and 3 years of age. HSV-1 seroprevalence is 70% to 90% in populations of low socioeconomic status versus 40% to 60% in those with a higher socioeconomic status. HSV-2 infection typically presents after the onset of sexual activity and seroprevalence increases with age. Geographic, racial, socioeconomic, and ethnic characteristics among the general population may affect the seropositivity for HSV-2. , Recent data suggests declining seroprevalence of both HSV-1 and HSV-2 in the United States (US) and elsewhere.


Oral HSV-1 infection is a common worldwide disease. The main route of transmission is through saliva or direct contact with an active lesion. Breaks in the epithelial barrier caused by mechanical or chemical injury can result in infection of a susceptible host. In up to 90% of cases, primary HSV infection is subclinical or causes a mild pharyngitis mimicking other upper respiratory viral or bacterial infections. , On entry of the virus into the oral mucosa or skin, and an incubation period of 4 to 6 days, HSV initially replicates in the epithelial cells and causes intraepithelial vesicle formation through the process of acantholysis. Then the virus migrates through sensory nerve axons to a dorsal root ganglion such as the trigeminal sensory ganglion where it remains latent indefinitely.

Primary Herpetic Stomatitis

Primary HSV infection may be symptomatic in subset of the patients, mostly observed in children and young adults and manifest as gingivostomatitis, which is preceded by prodromal symptoms including fever, sore throat, malaise, headache, gastrointestinal symptoms, and cervical lymphadenopathy. Within 1 to 2 days after the onset of the prodrome, the patient initially develops gingivitis and erythematous gingiva, followed by the formation of numerous vesicles within 2 to 3 days. The vesicles quickly rupture, giving rise to painful ulcers covered by yellowish white pseudomembrane. Both keratinized and nonkeratinized mucosa can be affected. Viral shedding occurs in the saliva during active disease. Gingiva, tongue, labial mucosa, palate, and the pharynx are the most common sites of involvement. The ulcers heal spontaneously in 7 to 10 days ( Figs. 1 and 2 ). , , ,

Fig. 1
Primary herpes simplex infection in a 23-year-old man. ( A ) Extensive crusted/hemorrhagic ulceration of the lower lip mucosa and generalized gingivitis of the mandibular gingiva. ( B ) Generalized maxillary gingivitis and ulcers on the right upper lip mucosa. ( C ) Multiple ulcers on the upper lip and generalized erosion with coalescing ulcers of the palatal gingiva/palate. ( D ) Right palatal gingivitis and multiple, coalescing ulcers caused by ruptured vesicles.

Fig. 2
Primary herpes simplex infection in a 19-year-old woman. ( A ) Crusted ulcerations on the left lower lip vermilion. ( B ) Ulcers on right upper and lower lip and generalized mandibular gingivitis with erosion/ulceration. ( C ) Generalized maxillary gingivitis and erosion with lower lip ulcers. ( D ) Multiple ulcers along the lateral borders of the tongue and lower lip.

Clinically, primary herpetic gingivostomatitis may mimic other viral vesiculoulcerative processes such as hand-foot-and-mouth disease or herpangina, which are primarily seen in children, or certain autoimmune/immune-mediated vesiculoulcerative disorders. Patient age and the presence of prodromal symptoms can help to exclude autoimmune vesiculoulcerative processes.

Secondary Herpetic Stomatitis

Reactivation of HSV-1 causes secondary (recurrent/recrudescent) lesions. During reactivation of the virus, retrograde axonal spread of the virus back to the skin or oral mucosa takes place along peripheral sensory nerves. Replication of the virus within the epithelium leads to vesicle development. Triggering factors for reactivation include exposure to cold, heat, sunlight, tissue trauma (such as trauma induced by dental procedures or local anesthetic injection), fever, stress, medications, or immunosuppression. , , , , , Along with other upper-respiratory infections, recent data have shown coronavirus disease-2019 may have a role in the reactivation of HSV.

The most common form of recurrent HSV-1 infection is herpes labialis (colloquially referred to as a cold sore or fever blister), which is characterized by clusters of vesicles appearing on the mucocutaneous junction of the lip, perioral, or perinasal skin that rupture to a crusted or hemorrhagic surface. Before the development of the vesicles, patients usually experience a prodromal burning/tingling sensation with an erythematous background ( Fig. 3 A). , , , ,

Fig. 3
Recurrent herpes simplex. ( A ) Herpes labialis in a 24-year-old man. Clusters of multiple coalescing ruptured and unruptured vesicles in the right commissural area and perioral skin. ( B ) Multiple coalescing ulcers on the hard palate in a 51-year-old woman. ( C ) Clusters of multiple coalescing ulcers in the right palatal gingiva/palate showing serpentine borders in a 22-year-old man. ( D ) Cluster of few, discrete ulcers in the mandibular gingiva/alveolar ridge mucosa in a 58-year-old man.
( Courtesy of [ A ] Caroline Bissonnette, DDS, MS, Quebec, CA; [ C ] Masoud Hatami, DDS, MS, Kermanshah, IR.)

Intraoral recurrent HSV infection initially manifest as discrete solitary vesicles or multiple clustered vesicles. Typically, following rupture of the vesicles, coalescing ulcers form larger areas of ulceration with serpentine borders ( Fig. 3 B, C). Lesions in recurrent HSV infection usually last 7 to 10 days.

Distinguishing features of primary and secondary HSV infections are shown in Table 2 .

Table 2
Distinguishing features of primary and recurrent HSV infection
Features Primary HSV Recurrent HSV
Location Both attached and unattached tissue Attached, bone-bound tissue
Distribution Widespread, diffuse Localized, clustered
Number of lesions Numerous Fewer
Pain Acute Rarely
Treatment Systemic antivirals Intraoral: treatment usually unnecessary
Extraoral: systemic antivirals

Herpes Simplex Virus and Immunocompromised Patients

Recurrent HSV-1 infection in immunocompromised patients may seem atypical as enlarging deep ulcers and can affect both keratinized and nonkeratinized mucosal sites, whereas in immunocompetent individuals, only the keratinized mucosa is involved. , , The prevalence of recurrent oral HSV has been reported as 18% to 95% in organ transplant recipients. Although the use of immunosuppressive medications has been shown to have an association with an increased risk of reactivation of HSV, using antiviral prophylactic regimens demonstrates efficacy in the prevention and reduction of recurrent HSV episodes in immunocompromised patients. However, close monitoring is recommended to prevent adverse treatment effects. Interestingly, the use of mTOR (mammalian target of rapamycin) inhibitors may results in decreased HSV reactivation.

Differential Diagnosis

Recurrent lesions may be misdiagnosed as recurrent aphthous ulcers, traumatic ulcers, or chemotherapy-associated ulcers.

Diagnosis and Laboratory Confirmation

Diagnosis of HSV infection is primarily made by clinical presentation; however, adjunctive diagnostic tests may be required for atypical presentations. These may include viral culture, cytologic evaluation, histopathologic studies, direct fluorescent assay, serologic tests, and PCR.

HSV culture or polymerase chain reaction (PCR) studies are recommended for atypical or persistent oral ulcers in immunocompromised patients, regardless of whether there are preceding prodromal symptoms or herpes labialis present. Biopsy may be indicated to rule out other infectious causes such as CMV or deep fungal infection. Coinfection of HSV and CMV has been reported in immunosuppressed patients. ,


Recurrent herpetic infection may be associated with complications such as erythema multiforme, herpetic pneumonia, and herpetic esophagitis. In immunocompromised patients, it is possible for reactivation of HSV in a retrograde fashion from the ganglion to the CNS, leading to meningoencephalitis. There is also potential for dissemination and induction of a generalized infection. ,

Treatment and Prognosis

Most HSV infections are self-limiting, requiring only symptomatic and supportive treatment. Antiviral treatment can reduce the severity of symptoms and accelerate the healing process. Antiviral medications may be effective if taken within 24 to 48 hours of lesion onset. Treatment regimens are shown in Table 3 .

Nov 25, 2023 | Posted by in Oral and Maxillofacial Surgery | Comments Off on Herpesvirus-Related Lesions of the Oral Mucosa

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