Herpesvirus-Induced Diseases: Oral Manifestations and Current Treatment Options

The dentist is often the first health professional to be contacted by patients who develop acute orofacial symptoms of viral conditions such as shingles (varicella zoster) or herpetic gingivostomatitis. The diagnosis, treatment, and management of virally induced oral diseases is a challenge inasmuch as their presentation is atypical and may be complicated by immunosuppression. However, an increasing body of knowledge regarding the manifestations of viral infections in immunocompromised patients and the advances achieved in antiviral drug therapy during the past several years should make the task less daunting for the dentist. In this paper, the natural history, typical and atypical oral manifestations, diagnosis, current treatment options, and advances in the prevention of common herpesvirus-induced diseases are reviewed, with particular attention to primary and recurrent varicella zoster virus and herpes simplex type 1 infections.

Varicella zoster virus (VZV), Herpes simplex virus types 1 and 2 (HSV-1, HSV-2), Epstein Barr virus and cytomegalovirus are all capable of causing oral mucosal disease through damage to epithelial cells. These viruses, as do all eight of the human herpesviruses discovered to date, share common features in virion and genomic structure and in their ability to establish lifelong latent infections; but they differ in their patterns of infectivity and pathogenicity. The human herpesviruses can be classified broadly according to tropism and pathogenicity as neurotropic and lymphotropic: VZV and HSV-1 and -2 are considered neurotropic, and Epstein Barr virus and cytomegalovirus are primarily lymphotropic. The morbidity associated with herpesviruses is considerably enhanced and potentially life-threatening in neonates and severely immunosuppressed patients. The immunosuppression may be due to infection with human immunodeficiency virus, cancer treatment with cytotoxic agents, or immunosuppressive therapy for the prevention of transplant rejection. The prevalence of oralmucosal ulcerative diseases of various etiology in HIV-infected individuals is high, especially in advanced cases.^1-3 The past few years have brought about dramatic changes in the morbidity and mortality of HIV-infected patients. In general, the profile of HIV-associated oral diseases in newer cohorts of AIDS-affected populations in the Western world is changing, with some conditions such as hairy leukoplakia and necrotizing ulcerative periodontitis decreasing in prevalence.⁴ Nevertheless, there appears to be little difference between the prevalence of HSV-1-associated lesions in a cohort of patients treated by new, highly active anti-HIV treatment protocols (by combined protease inhibitors and nucleoside analogues), as compared with that found in an earlier cohort, as documented in a large population from North Carolina.⁴ It is likely that the number of patients presenting with viral orofacial mucosal diseases will increase as the HIV-infected population lives longer.

The aim of this review is to provide an update of the natural history, typical and atypical oral manifestations, diagnosis, and current treatment options for herpesvirus-induced diseases, with special emphasis on VZV and HSV-1 disease severity in the immunocompromised patient.

Primary and Recurrent VZV Infections

Herpes zoster, also known as shingles or zona zoster, is caused by the ubiquitous human varicella zoster virus, a DNA virus and member of the herpesvirus suborder termed alpha herpesviridae, to which HSV-1 and -2 also belong. VZV causes varicella (chickenpox), the childhood epidemic disease still affecting populations worldwide. The majority of individuals with primary VZV infection fully recover and have lifelong immunity against re-infection, but the virus remains in the host in a dormant state in the sensory ganglia (dorsal root ganglia of the spinal cord or extramedullary cranial nerve ganglia, especially the trigeminal ganglion), and possibly in other neuronal and nonneuronal sites such as lymphoid cells.⁵ In the normal, healthy host, the dormant virus is kept under surveillance by effective immune mechanisms. In about one-fifth of individuals, zona zoster develops when the reactivation of the virus is associated with considerable viral replication in the ganglia. It is to be noted that even modest decreases in immunosurveillance due to oral prednisone dosages of less than 2 mg/kg of body weight and inhaled beclomethasone may precipitate a severe clinical course of zoster.⁶ Even in individuals with no apparent underlying condition, emotional stress, physical trauma, or surgical intervention may trigger reactivation of dormant VZV infection.

VZV is highly infectious. Respiratory spread is probably an important route of transmission. Patients are most contagious just before the onset of the rash. Even indirect contact -- e.g., through airflow between a patient’s hospital room and a nurses’ station,^6,7 between hospitalized patients, or between previously unexposed health care personnel and patients -- may carry the risk of nosocomial transmission from patients with shingles to previously unexposed health care personnel.⁶

The symptoms of the primary VZV infection (varicella or chickenpox) are cutaneous hemorrhagic maculopapular rash (which later may become secondarily infected by bacteria and leave a small scar or "pox"), fever, malaise, sore throat, and minor oral vesicular lesions that rupture easily and resemble oral aphthous ulcers.^8,9 The mucocutaneous manifestations of zona zoster are characterized by grape-like clusters of vesicular eruptions that exhibit a restricted unilateral geographic distribution in an area corresponding to a single sensory neuron and complication by pain. The term "herpes" (from the Greek herpes, meaning snake) was suggested originally for the snakelike shape of the dermatomal lesions, while "shingles" (from the Latin cingulum meaning belt) refers to the painful girdle.¹⁰ Skin lesions most often affect the trunk. Unilateral orofacial manifestations along the trigeminal nerve (ophthalmic, maxillary, and mandibular branches) include skin eruptions with small vesicles coalescing then crusting quickly and mucosal vesicles that rupture easily to form crateriform ulcers^8,9 (Figure 1). In the immunocompetent or mildly immunosuppressed patient, the ulcers normally heal within a month. In some instances, pre-herpetic neuralgia develops prior to the eruption. Persistent "stinging" pain is consistently associated with the mucocutaneous eruptions. Chronic postherpetic neuralgia is attributable to inflammatory responses to injury (demyelinization, necrosis) in sensory neurons, but aberrant central nervous system responses perpetuating the perception of pain may also play a role.⁵ Chronic pain is often a problem in the management of varicella zoster. Less than 2 percent of immunocompetent patients develop severe complications such as superinfection of the mucocutaneous lesions, blindness due to acute retinal necrosis, and motor neuropath.⁶ Primary VZV infection in the adult is rare, but the lesions may be more severe and persist longer, and they carry the risk of interstitial pneumonia. The symptoms and complications of varicella may be particularly severe in pregnant women. In the first trimester of pregnancy, VZV may induce fetal malformations with atrophy and scarring of the affected limb (fetal varicella syndrome). In HIV-infected children, even a modest decrease of CD4 lymphocyte counts may precipitate recurrent varicella. Individuals infected with HIV are at increased risk of developing multiple zoster attacks. Severe disease with extensive hemorrhagic pustules coalescing to cover the entire dermatome and prolonged healing with extensive crusting, scarring, and pigmentation may develop in patients with significant decreases in CD4 counts. Among the severe complication of VZV infection reported in advanced AIDS are progressive retinal necrosis, meningoencephalitis, and fatal disseminated visceral disease. Verrucous skin lesions that are resistant to anti-VZV drug treatment have been reported in HIV patients who have been on long-term antiviral therapies.⁶

A case of alveolar bone necrosis due to maxillary herpes zoster has recently been reported.¹¹ Dental complications may also include loss of pulp vitality, root resorption, and tooth exfoliation. Conditions associated with pain -- including trigeminal neuralgia, maxillary sinusitis, and atypical facial pain -- should be considered in the differential diagnosis of zoster, especially in cases presenting without a rash (zoster sine herpete).^11-13 However, these can be eliminated through careful clinical examination and detailed history. The association with stinging or burning pain and the unilateral distribution are features that allow the oral lesions of zoster to be easily distinguished from those of similar appearance in herpes simplex and aphthous stomatitis.

As the onset and symptoms of VZV infections are characteristic, laboratory confirmation of the diagnosis is not usually necessary. Because the virus does not grow well in culture, less than 60 percent of the cultures are positive.⁵ Detection of the virus in skin or mucosal scrapings by VZV-specific, tagged antibodies is more sensitive and specific (Figure 2). Amplification of viral DNA sequences with specific DNA primers (polymerase chain reaction) from the samples may be necessary for the diagnosis of neurological disorders in severely immunosuppressed patients lacking VZV seropositivity or when the cultures are negative.

The timing of effective antiviral therapy for the treatment of varicella and zona zoster is dependent on a limited time span of active viral replication: within 72 hours after the onset of the rash in the normal host, but more extended in the severely immunocompromised because replication and virus shedding are sustained in such individuals. Based on advances in the understanding of the molecular mechanisms of viral infection and replication, a series of new antiviral drugs has been developed and tested recently in clinical trials.^14-20 The antiviral compounds found effective for the treatment of VZV infections are acyclovir (Zovirax), valaciclovir (Valtrex), famciclovir (Famvir), and foscarnet. The first three are guanosine (nucleoside) analogues that inhibit viral DNA synthesis by competing with deoxy-guanosine triphosphate as substrate for the viral DNA polymerase. Acyclovir, the prototype of these drugs, has been pursued in several clinical trials and experimental model systems since the early 1980s. The mechanism of action of the drug is based on the selective activation (monophosphorylation) by the product of a viral gene (thymidine kinase), then further activation (di- and tri-phosphorylation) by cellular proteins (kinases); the active acyclovir acts as both competitor and chain terminator for the viral DNA polymerase. Nucleoside analogues cannot prevent virally induced cell damage or death, but they reduce the number of virion produced in the cells and thus prevent or inhibit the intercellular spread of infection. Valaciclovir is a chemical derivative of acyclovir that has more recently been developed and tested. While less than 50 percent of orally administered acyclovir is bioavailable, oral valaciclovir is absorbed readily and converted enzymatically into acyclovir in the liver. Famciclovir is the orally bioavailable analogue of penciclovir. Penciclovir-triphosphate has a longer half-life in infected cells. Foscarnet, another viral-DNA-polymerase inhibitor is recommended for intravenous use as an alternative treatment in acyclovir/famciclovir resistance. The treatment regimens for the therapy of varicella and zoster in patient groups classified by age, cause, and level of immunosuppression -- as recommended at a clinical staff conference held at the National Institutes of Health -- have recently been reviewed in detail.⁶ The recommendations are summarized in Table 1. The management of most common HIV-related opportunistic infections (including those caused by herpesviruses) have more recently been reviewed.²¹ Drugs reported to interact with famciclovir include cimetidine (Tagamet, used commonly for peptic ulcers) digoxin (Lanoxin, cardiotropic drug), and theophylline products (in a variety of medications, e.g., for bronchospastic conditions). Intravenous administration of acyclovir or foscarnet requires hospitalization, as does oral antiviral therapy in patients with pneumonitis, disseminated disease, or drug-resistant lesions and in more severely compromised patients. In neonates, children, and women early in their pregnancies, valaciclovir and famciclovir are not recommended because of the lack of trials concerning the toxicity of the drugs. Famciclovir should be used with caution in patients with renal function impairment.

Early intervention is recommended for the treatment of pain in the acute zoster phase before the onset of chronic postherpetic neuralgia. Clinical trials attest to the efficacity of high-dose acyclovir and its derivatives in alleviating acute pain and preventing chronic neuralgia. However, there are no surefire cures for the acute pain of shingles, and the management of chronic pain remains difficult. Low doses of tricyclic antidepressants such as amitryptyline (Elavil) and the addition of the anticonvulsant gabapentin (Neurontin) to standard pain-management regimens have been effective.¹⁹ Regional blocks of nerve roots or ganglia may provide relief in some patients. Topical anesthetics such as 2 percent lidocaine viscous applied with cotton swabs²² or in anesthetic rinses are helpful for lesions limited to the oral mucosa. Applications of over-the-counter preparations containing capsaicin (extract of chili pepper, Zostrix, Capzasin-P) may be beneficial in individual cases as desensitizing regimens, but the active ingredient causes extreme irritation and burning of the mucosa. Prescription narcotics are recommended for severe cases. The use of systemic corticosteroid treatment to prevent postherpetic neuralgia (presumably by suppressing inflammation in dorsal root ganglia) has been discussed critically for some time.²³ However, at least one placebo-controlled clinical trial indicates that acyclovir/prednisone combination therapies provide considerable benefits in the management of postherpetic pain in patients in which high-dose corticosteroids are not contraindicated.^14,24

In the United States, vaccination against VZV infection is indicated for immunocompetent people older than 12 months without history of varicella. In children older than 12 years and adults, the administration of two doses of the vaccine, four to eight weeks apart, is recommended because they respond less well to a single dose.^6,25-27 For the universal immunization of children, several countries have adopted the use of vaccine preparations containing live attenuated varicella virus derived from the Oka-strain (originally isolated in Japan from a child with varicella). The Oka vaccine currently marketed in the United States is estimated to be about 70 percent to 90 percent effective, and children who acquire chickenpox in spite of vaccination experience significantly milder symptoms.⁶ In immunocompetent individuals, the vaccine is safe. In most recipients, it causes subclinical infection; in less than 20 percent of cases, the vaccines may cause a fever or varicella-like rash. There is risk of infectious viral transmission from vaccines that cause a rash (even before the onset of the rash) to previously unexposed individuals; although the risk is low, it is advisable for people at high risk for complications from varicella (pregnant women and the immunocompromised) to avoid close contact with recently vaccinated people. Zoster due to the reactivation of the Oka strain in vaccine recipients is not considered to be a significant problem as the incidence of zoster in vaccinated children does not appear to exceed zoster rates found in naturally infected children (as reviewed by Krause and Straus²⁷). The Oka strain vaccine is contraindicated in immunocompromised individuals, because of the significant risk of severe vaccine-induced varicella; in pregnant women, because of the risk of fetal varicella syndrome in early pregnancy and the risk of severe clinical infection in late pregnancy; and in people with history of hypersensitivity to vaccine components. In these groups, postexposure prophylaxis with anti-VZV immunoglobulin, and in some cases with oral acyclovir, is recommended.⁶

Primary and Recurrent HSV-1 Infections

The cause of primary herpetic gingivostomatitis is infection with HSV-1, but oral disease with identical clinical manifestations may also be caused by the genital type HSV-2 when the latter is transmitted by genito-oral or oral-oral contact. Recent molecular epidemiologic studies have substantiated the notion that most HSV-1 genotypes are often shared by genital and nongenital lesions.²⁸ It is also apparent that initial genital HSV-1 may be acquired through oral contact, as evidenced by cross-sectional analyses of data collected in urban sexually transmitted disease clinics from patients who had positive genital HSV cultures.²⁹ The development of immunity to HSV is not well-understood, but cross-immunity between these two HSV types is known to develop so that previous exposure to one type results in milder manifestations of infection with the other.³⁰

Primary infection with HSV-1, or primary herpetic gingivostomatitis, seen most often in children, is characterized by fever, malaise, lymphadenopathy, and multiple crops of vesicular eruptions located on the attached gingiva and movable mucosa of the oral cavity; the oropharyngeal mucosa and the conjunctiva may be involved.^8,9 The vesicles rupture easily and leave small ulcers covered by a pseudomembrane and surrounded by erythema (Figure 3). The infected patient, as well as susceptible people in contact with the patient, may show the typical sign of herpetic whitlow (viral, primary or recurrent, vesicular or pustular dermatitis of the finger) (Figure 4). In immunocompetent patients, the primary infection runs its course within one to two weeks without scarring. In children with herpetic gingivostomatitis, eating and drinking difficulties, fever, and drooling may often lead to dehydration.³¹

The prevalence of recurrent or recrudescent disease in the general population has been estimated as 20 percent to 40 percent worldwide and 35 percent to 38 percent in the United States.³² HSV-1 is ubiquitous and highly contagious. Approximately 60 percent to 80 percent of American adults are latently infected, i.e., asymptomatic HSV-1 seropositive.²⁷ De novo infections similar in course to primary infections may develop in seropositive individuals on contact with active lesions of other patients or even through self-inoculation. The highest risk of transmission is during the limited time span of viral shedding during active infection (one to four days, but prolonged in immunocompromised patients). The possibility of contagion due to viral shedding into saliva or genital secretions during asymptomatic infection should be taken into account, albeit the risk is considerably lower than in contact with active lesions. Reports of viable HSV contaminating door handles and passing through latex gloves damaged by solvents³² emphasize the need for proper infection control in the dental office.

Significant knowledge has accumulated over the past few years regarding the cellular/molecular mechanisms of latency and reactivation of HSV infection.^5,33 For example, latency-associated genes of several herpesviruses have been discovered, and it is known that latent HSV genomes express latency-associated transcripts, which are antisense to cellular regulatory proteins. To date, however, there are no known encoded proteins associated with HSV-1 latency-associated transcripts, and how the latency-associated transcripts function in HSV-1 latency remains obscur.⁵ The models proposed to explain HSV-1 pathogenesis on reactivation from dormancy, and the putative role of mucosal immunity in reactivation have been reviewed thoroughly by Oakley and colleagues.³⁴ It appears that in HSV reactivation, only a few neurons become involved, whereas in VZV infection, replication from numerous neurons is required for reactivation.⁵ This would account for the relatively small and focal lesions in typical recrudescent HSV-1-associated herpes, as compared to those of zoster. However, the symptoms of recrudescent or recurrent HSV infection may range from subclinical to debilitating, depending on the level of impairment of the host’s immune surveillance mechanisms.

The list of known triggers of HSV reactivation includes stress, surgical trauma, dental extraction, menses and other hormonal changes, infectious febrile conditions and hyperthermia, ultraviolet radiation, and drugs such as corticosteroids and prostaglandin E2.^34,35 Two cases of oral mucosal HSV infection associated with the radiotherapy of the head and neck have recently been described.³⁴ In these cases, a combination of triggering factors, including stress in one case and HIV- and drug-induced immunosuppression as well as concurrent cytomegalovirus infection in the other, were recognized. In the general population, the typical manifestation of recurrent HIV-1 infection is herpes labialis ("cold sores"): unilateral vesicular eruptions surrounded by erythema, followed by crusting and healing. The eruptions are sometimes preceded by a prodromal tingling sensation (Figure 5). Oral mucosal lesions are rare, nonfebrile, and usually restricted to small clusters of microvesicles that rupture to leave punctate ulcers, typically on the palatal gingiva (occasionally elsewhere on the gingivae) unilaterally (Figure 6). The lesions are self-limited, resolving within one to four days^8,9 . Extensive or persistent lesions of both primary and secondary infections should raise the suspicion of immunosuppression. In HIV-infected patients, there is a risk of disseminated lesions with severe morbidity, including herpes encephalitis. Such risk has declined with current antiviral therapies; but, in advanced AIDS, it remains a serious problem, especially in developing countries.

The differentiation of uncomplicated oral mucosal HSV infection from recurrent aphthous ulcers is based on the presence of elevated temperature in primary herpetic gingivostomatitis and the unilateral appearance of the microvesicles in the palatal mucosa in typical recurrent intraoral HSV infections. The widely held distinction between recurrent aphthous ulcers and recurrent HSV on the basis of distribution (always on the nonkeratinized mucosa in the former, and mainly on the keratinized surfaces of the palate, gingiva, alveolar mucosa or alveolar ridge in the latter) still largely holds true, as indicated by the findings of a recent study of 52 immunocompetent patients with positive HSV cultures.³⁶ However, a minority (roughly 10 percent in this series) of HSV-positive ulcerations occurred on the nonkeratinized mucosa, a feature often reported in immunocompromised individuals. The differential diagnosis of mucosal HSV-1 infection also includes the oral mucosal vesicles of hand-foot-and-mouth disease. The latter, seen mostly in children, can be diagnosed and distinguished easily from HSV-1-induced herpetic stomatitis by positive Coxsackie virus culture (from the lesions or stool) and the presence of concomitant vesicular eruptions on the skin of extremities. Similarly, positive viral Coxsackie virus culture and the limited distribution of the vesicles on the oropharynx are diagnostic of herpangiana.

For the definitive diagnosis of HSV, viral culture from swabs of active lesions has been

considered the gold standard, but the usefulness of this method is limited by the relatively short time span of viral shedding and by the relatively low number of viral particles present in the samples. Immunocytochemistry with anti-HSV antibodies and in-situ hybridization with HSV-nucleic acid probes applied to biopsy sections of early lesions are sensitive alternatives to viral culture (Figure 7). Polymerase chain reaction-based methods, albeit less cost-effective, are highly sensitive, specific, and applicable to samples in the absence of symptomatic shedding. However, the sample collection and the interpretation of positive polymerase chain reaction results of the swabs should take into consideration the possibility of normal shedding of viral DNA in saliva, peripheral blood, and exfoliated epithelial cells distant from the active ulcers. This is less of a problem in immunocytochemistry and in situ hybridization applied to biopsy samples. Biopsy samples have the added advantage that sections from them can be subjected to multiple testing for coinfection with other pathogens and that the histopathological features of viral cyptopathic changes such as intraepithelial vesicles with eosinophilic inclusion bodies and clear cell ballooning (common characteristic of infections with herpesviruses) can be corroborated with the molecular findings.

Primary and recurrent oral HSV infections in immunocompetent patients are self-limited, generally requiring only symptomatic treatment. For first episodes of painful mucosal HSV infection, acyclovir 5 percent ointment (Zovirax) applied hourly at the onset of symptoms is known to reduce the extent of viral shedding and pain, but it provides little benefit in recurrent herpes labialis. For recurrent herpes labialis, penciclovir 1 percent (Denavir) cream applied every two hours (while awake) for four days, starting at the onset of symptoms, is recommended. This regimen has been found to significantly decrease the mean duration of lesions and pain and to be well-tolerated.¹⁷ However, more studies are needed to establish the efficacy of this topical nucleoside analogue in primary infections and immunocompromised patients. Systemic medication is required in patients experiencing six or more painful episodes per year. Studies show that at least in genital herpes, valaciclovir 500 mg only twice daily provides the pharmacological benefit of 200 mg of acyclovir administered more frequently (five times daily).¹⁷ Famciclovir is effective in reducing shedding time and the severity symptoms of genital herpes in HIV-infected patients.³⁷ Multicentric, controlled clinical trials have indicated that famciclovir (at 500 mg four times daily) also promotes healing in experimental UV-radiation-induced labial herpes in volunteer subjects.³⁸ However, in immunocompetent patients, the benefits of oral medications with nucleoside analogues should be weighed against potential side effects, as well as costs. For acyclovir, the following have been reported in the first year or so of use in 1 percent to 5 percent of patients: nausea, diarrhea, headaches, and rash. Paresthesia/esthesia, also in a minority of patients, is reported with more prolonged use. The frequency and severity of these symptoms rarely necessitate discontinuation of the treatment with acyclovir, but famciclovir is expensive and knowledge of its toxicity is still lacking. The treatment of severe, complicated, and disseminated HSV infections requires hospitalization. Valaciclovir 500 mg twice daily was found effective for HSV-suppression in a randomized, controlled study of HIV-infected subjects with CD4 lymphocyte counts higher than 100. For the treatment of recurrent genital herpes, valaciclovir is relatively well-tolerated at this dosage³⁹ However, as found in cases of advanced AIDS, valaciclovir prophylactic therapy with high doses (8 g/day) increases the risk of thrombotic microangiopathy, which is potentially fatal.³⁹ Foscarnet has been shown to be effective in resistant herpetic infections in adults and in very severe cases in children.^23,39,40

Several new strategies have been explored in the experimental development of genetically

engineered HSV-DNA vaccines.^27,41-46 The aim is to obtain vaccines that are highly

immunogenic but nonpathogenic. Efforts have been directed primarily at preventing the

acquisition and recurrence of genital herpes, which would be particularly important

in preventing neonatal infection, for example. Earlier attempts with vaccines containing killed viruses failed to produce adequate immunity. New strategies are aimed at creating a live "mutant" virus with a limited replication capacity in vivo, or recombinant DNA plasmid vaccines; genes that have been associated with virulence are deleted from the latter, but they contain DNA sequences encoding for viral proteins that are capable of eliciting natural immunity when injected directly into the tissues. Such strategies are currently being tested with considerable promise in animal models of genital herpes. Further, plasmid DNA carrying sequences encoding for the glycoprotein D of HSV-1 are being tested for immunogenicity in experimental animal models;⁴⁶ however, much is still to be learned about the molecular mechanisms of immunogenicity of both HSV-1 and -2.

HSV and Erythema Multiforme

Erythema multiforme is an acute, polymorphous mucocutaneous disorder of complex etiology, often associated with drugs, mycoplasma, and HSV infection. It is now accepted that erythema multiforme minor, erythema multiforme major, Stevens-Johnson syndrome, fixed drug reactions, and toxic epidermal necrolysis are parts of a single spectrum of disease. The typical skin lesions are characterized by papules that develop into "target" lesions (a zone of central necrosis with peripheral erythema). The lesions may be limited to the skin, or they may be accompanied by mucosal lesions. In the oral cavity, they are characterized by bullae and vesicles that rupture to form raw, erythematous ulcerations or ragged erosions.^8,9 The pathogenesis of HSV-associated erythema multiforme has not been elucidated, but it has been postulated to be attributable to viral protein products that act as superantigens in the tissues, eliciting specific cell mediated immunity with the production of cytokines that mediate cellular signaling cascades ultimately leading to epithelial cell death.^47,48 The treatment of HSV-associated erythema multiforme is often difficult, and the various regimens suggested for its management have not been proven by rigorous clinical trials. The therapeutic dilemma is whether priority should be given to corticosteroid treatment of the immunopathologic condition of erythema multiforme or to the antiviral treatment of HSV. According to at least one recent study,⁴⁷ the treatment should be considered carefully in each individual case taking into consideration the severity of the lesions and individual response to antiviral drug therapy, but corticosteroids should be considered as a mode of treatment in all HSV-induced erythema multiforme, especially in cases of failure of antiviral therapy.

Other Herpesviruses

In immunocompetent individuals, cytomegalovirus infections are rare, but they are a cause of severe morbidity (e.g., retinitis, esophagitis, pneumonitis) and mortality in severely immunocompromised patients. Even in moderately immunocompromised adults and children, cytomegalovirus-associated mucosal lesions may mimic those of other viral or nonviral ulcerative lesions, including those of recurrent aphthous ulcers, persistent and recurring herpetic stomatitis, and necrotizing stomatitis^34,40,49,50 (Figure 8). A definitive diagnosis can only be made through the specific identification of the virus in culture, or the detection of cytomegalovirus DNA or antigens in biopsy specimens. Characteristic ballooning of cytomegalovirus-infected cells (cytomegaly) and typical inclusion-bodies are pathognomonic histomorphological features.⁴⁹ Until recently, Ganciclovir (administered intravenously in severe cases) has been the drug of choice in AIDS-associated cytomegalovirus infections; however, it does have significant side effects due to the toxicity of the drug.¹⁸ A number of clinical trials are ongoing to establish the efficacy of alternative therapies. Valaciclovir has been tested in preventing cytomegalovirus infection in advanced HIV-disease patients and bone marrow and renal transplant recipients.^17,51 Recent data have confirmed the expectation that valaciclovir is effective not only in the prophylaxis of cytomegalovirus-associated morbidity, but also in reducing the frequency of acute graft rejections in transplant patients.³⁹

Epstein Barr virus is the major cause of infectious mononucleosis, a significant etiologic cofactor in the development of Burkitt’s lymphoma and nasopharyngeal carcinoma, and has been associated with various other lymphoproliferative disorders, mainly those of the B-cell series. Organ transplant recipients are particularly vulnerable to Epstein Barr virus-induced lymphomas.⁵² While the oropharyngeal epithelium is the site of Epstein Barr virus entry and replication, and viral shedding can be detected in saliva, the virus establishes persistent infection of lymphoid cells. In the oral cavity, ulcerations due to Epstein Barr virus infection are rare.^1,49,53 Epstein Barr virus is more commonly associated with oral hairy leukoplakia, which was first defined as a clinical entity in HIV-infected individuals;⁵⁴ and it is found more commonly in patients who are immunocompromised. This white hyperkeratotic lesion develops primarily on the lateral border of the tongue (Figure 9). Oral hairy leukoplakia and similar Epstein Barr virus-associated lesions have also been reported in immunocompetent patients, but the significance of this condition as a harbinger of emergence from latency in HIV infection should be kept in mind.^9,55

Human herpesvirus type 8 has been implicated in the pathogenesis of several diseases, most of them neoplastic. Examples of human herpesvirus type 8-associated diseases are Kaposi’s sarcoma, a vascular neoplasm found often in AIDS patients (The virus is also known as Kaposi’s sarcoma-associated virus.); multiple myeloma; and a subset of lymphomas.^56-58 In the oral cavity, advanced Kaposi’s sarcoma may present as ulcerative lesions, but these are distinguishable from HSV-associated ulcers as the former are "tumefactive," or tumor-like lesions (Figure 10). They are typically vascular (hemorrhagic), initially presenting as macules or nodules; in Kaposi’s sarcoma, the ulceration is secondary to the tumor.^1,9,53,59

In immunosuppressed patients, oral ulcerations with an atypical presentation have also been attributed to coinfection of HSV-1 with other herpesviruses, namely Epstein Barr virus, cytomegalovirus, and other opportunistic pathogens.^12,49,60 Generally, such lesions are described as single large or multiple ulcerations on any keratinized or nonkeratinized mucosal surface (palate, interdental papilla, buccal mucosa, lateral surface, or tip of tongue).

Other Pathogens in Recurrent Oral Aphthous Ulcers

The advent of highly sensitive and specific methods for the detection of viral and bacterial products in minute amounts of tissue specimens has allowed for the investigation of the role of microorganisms in the pathogenesis of mucosal ulcerative diseases with multifactorial etiology. In several case series, HSV-1, cytomegalovirus, and other human herpesviruses have been found in association with recurrent oral aphthous ulcers.^61-64 A direct causal role for these pathogens has not been established, nevertheless it is plausible that products of the microorganisms have an indirect, cofactorial role at least in a proportion of classical recurrent aphthous ulcer cases. Several hypotheses have been advanced for future testing. For example, products of HSV genes may act as superantigens in activating humoral and local cell-mediated immune responses that in turn may induce or contribute to epithelial cell damage. However, the polymerase chain reaction-based detection of viral nucleic acids in tissue scrapings or vesicular fluid is not sufficient for diagnosis unless it correlates well with clinical and histomorphological features of biopsy samples.

As a general rule, persistent herpetiform lesions, especially those found to harbor VZV, HSV, cytomegalovirus or Epstein Barr virus should raise the suspicion of immunosuppression. In these cases, hematologic testing for indicators of immune functions (T4:T8 lymphocyte ratios and CD4 lymphocyte counts) is recommended.

Author

Catalena Birek is an associate professor at the Faculty of Dentistry, University of Manitoba, Canada.

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To request a printed copy of this article, please contact/Catalena Birek, DDS, PhD, University of Manitoba, Department of Oral Pathology, 780 Bannatyne Ave., Winnepeg, Manitoba R3E OW2, CANADA.

Table I. Summary of Antiviral Treatment Options in Varicella and Varicella Zoster (adopted from Cohen et al.⁶)

Legends

Figure 1. Herpes zoster of the third division of the trigeminal nerve. Vesicles are distributed over the skin and stop abruptly at the midline.

Figure 2. Tissue section from lesional tissue treated with an antibody to VZV tagged with a brown dye. The positivity is striking within epithelial cells confirming the identify of the virus.

Figure 3. Primary herpetic gingivostomatitis affects movable mucosa of the lips and lesions of the gingiva.

Figure 4. Herpetic Whitlow

Figure 5. Herpes labialis

Figure 6. Recurrent palatal herpes

Figure 7. DNA in situ hybridization with red chromogen localizing HSV1 in oral epithelial cells from a herpetic lesion.

Figure 8. CMV ulceration in an HIV-seropositive patient. This also harbored HSV.

Figure 9. Oral hairy leukoplakia (Epstein Barr virus).

Figure 10. Herpesvirus 8 is associated with Kaposi’s sarcoma in an HIV-positive patient.