Etiology and Pathogenesis

The Herpesviridae family of viruses contains eight different viruses that are pathogenic in humans with one affecting simians (Table 3‐1). This chapter discusses only herpes simplex virus (HSV)‐1 and varicella‐zoster virus (VZV) which cause multiple ulcers, and cytomegalovirus (CMV) and Epstein‐Barr virus (EBV) infections, which usually cause single ulcers. Herpes viruses have a common structure: an internal core containing the viral genome, an icosahedral nucleocapsid, the tegument, and an outer lipid envelope containing viral glycoproteins on its surface that are derived from host cellular membranes.¹ Nonetheless, each of the herpesviruses is distinct.

HSV‐1, an α‐herpesvirus, is a ubiquitous virus, and 54% of adults aged 14–49 between 2005–2014 in the United States are seropositive for it.² In general, infections above the waist are caused by HSV‐1 and those below the waist by HSV‐2, although with changing sexual practices, it is not uncommon to culture HSV‐2 from oral lesions and vice versa.³ The primary infection, which occurs on initial contact with the virus, is acquired by inoculation of the mucosa, skin, and eye with infected secretions. The virus then travels along the sensory nerve axons and establishes chronic, latent infection in the sensory ganglion (such as the trigeminal ganglion).⁴ Extraneuronal latency (i.e., HSV remaining latent in cells other than neurons such as the epithelium) may play a role in recurrent lesions of the lips.⁵ Recurrent HSV results when HSV reactivates at latent sites and travels centripetally to the mucosa or the skin, where it is directly cytopathic to epithelial cells, causing recrudescent HSV infection in the form of localized vesicles or ulcers.⁶

The most common sites of infection are the oral and genital mucosa and the eye. HSV infection of the cornea (keratitis) is a major cause of blindness in the world. HSV‐1 or ‐2 may cause herpes whitlow, an infection of the fingers when virus is inoculated into the fingers through a break in the skin (Figure 3‐1). This was a common occupational hazard (including within the dental profession) before the widespread use of gloves.^7,8 Other HSV‐1 infections include herpes gladiatorum (infections of the skin spread through the sport of wrestling),⁹ herpes encephalitis, HSV esophagitis, HSV pneumonia and neonatal and disseminated infection.⁶

HSV is an important etiologic agent in erythema multiforme, which is discussed below.^10,11 HSV has been recovered in the endoneurial fluid of 77% of patients with Bell palsy.¹² However, VZV has also been strongly implicated in the development of Bell palsy.¹³ Treatment with antiviral therapy (especially with corticosteroids) within the first 48 hours resulted in better outcomes further supporting the concept of herpesvirus involvement in the pathogenesis of Bell palsy.¹⁴ However, a recent study showed that approximately 60% of cases of Bell palsy were associated with HHV6, and only 13% with HSV.¹⁵

Clinical Manifestations

Primary Gingivostomatitis

The majority of primary HSV‐1 infections are subclinical and generally occur in children and teenagers.^6,13 There is a 1‐ to 3‐day viral prodrome of fever, loss of appetite, malaise, and myalgia that may also be accompanied by headache and nausea. Oral pain leads to poor oral intake, and patients may require hospitalization for hydration. The disease is self‐limiting in otherwise normal patients and resolves within 10 to 14 days, typical for a viral illness.

Oral Findings

Within a few days of the prodrome, erythema and clusters of vesicles and/or ulcers appear on the keratinized mucosa of the hard palatal mucosa, attached gingiva and dorsum of the tongue, and the nonkeratinized mucosa of the buccal and labial mucosa, ventral tongue, and soft palate (Figures 3‐2 and 3‐3). Vesicles break down to form ulcers that are usually 1 to 5 mm and coalesce to form larger ulcers with scalloped borders and marked surrounding erythema. The gingiva is often erythematous, and the mouth is extremely painful, causing difficulty with eating. Pharyngitis causes swallowing difficulties. Primary HSV infection in adults follows a similar pattern.¹⁶

Recrudescent Oral HSV Infection

Reactivation of HSV may lead to asymptomatic shedding of HSV, in the saliva and other secretions, an important risk factor for transmission; it may also cause ulcers to form. Asymptomatic shedding of HSV is not associated with systemic signs and symptoms and occurs in 8 to 10% of patients following dental treatment.¹⁷ The term recrudescent HSV should be used to refer to the actual ulcerations caused by reactivated virus. Fever, ultraviolet radiation, trauma, stress, and menstruation are important triggers for reactivation of HSV.

Recrudescent HSV on the lips is called recurrent herpes labialis (RHL) and occurs in 20 to 40% of the young adult population.^18,19 These are associated with a prodrome of itching, tingling, or burning approximately 50% of the time, followed in succession by the appearance of papules, vesicles, ulcers, crusting, and then resolution of lesions (Figure 3‐4).²⁰ Pain generally is present only within the first 2 days. There is a suggestion that patients who do not experience a prodrome develop lesions from extraneural latent HSV within the epithelium and these lesions are less responsive to topical therapy.²¹

Recrudescent intraoral HSV (RIH) in the immunocompetent host occurs chiefly on the keratinized mucosa of the hard palatal mucosa, attached gingiva, and dorsum of the tongue.²² They present as 1 to 5 mm single or clustered painful ulcers with a bright erythematous border (Figure 3‐5). One common presentation is the complaint of pain in the gingiva 1 to 2 days after a scaling and prophylaxis or other dental treatment. Lesions appear as 1 to 5 mm painful vesicles but more often ulcers on the marginal gingiva.

HSV in Immunocompromised Patients

In immunocompromised patients (such as those undergoing chemotherapy, who have undergone organ transplantation, or who have acquired immune deficiency syndrome [AIDS]), RIH infection may occur at any site intraorally and may form atypical‐appearing ulcers that may be several centimeters in size and may last several weeks or months if undiagnosed and untreated (Figures 3‐6 and 3‐7).^23,24 In one study, 50% of patients with leukemia and 15% of patients who had undergone renal transplantation developed RIH infections.²⁵ Single RIH ulcers are indistinguishable from recurrent aphthous ulcers if they occur on a nonkeratinized site.²⁶ These ulcers are painful and similar to HSV lesions seen in immunocompetent patients except that they may be larger and often occur on nonkeratinized sites. They appear slightly depressed with raised borders. The presence of 1 to 2 mm vesicles or satellite ulcers at the edges of the main ulcer is a helpful sign.

If undiagnosed and left untreated, RIH infection may disseminate to other sites and cause morbidity in the immunocompromised population.²⁷ This is a particular problem in patients undergoing hematopoietic stem cell transplantation, where reactivation of HSV occurs in approximately 70% of patients, prompting prophylaxis in patients who are seropositive.^28,29

Management

Primary HSV Infection

Management is directed toward pain control, supportive care, and definitive treatment (Table 3‐2). In the past, healthy patients with primary herpetic gingivostomatitis were treated only with hydration and supportive measures. However, since the acyclovir family of drugs is inexpensive, safe, and readily available, it is appropriate to treat even primary infections definitively because it reduces viral shedding and infectivity.

Pain Management

2% viscous lidocaine (swish 5 mL for 3–5 min. and spit out 4–5 times/d)

Liquid diphenhydramine (swish 5 mL for 3–5 min and spit out 5 4–5 times/d)

Combination of viscous lidocaine, diphenhydramine, and a covering agent (such as KaopectateTM or MaaloxTM) in 1:1:1 ratio (swish 5 mL for 3–5 min and spit out)

0.1% diclonine hydrochloride

Benzydamine

Systemic analgesia

Supportive care

Hydration

Ice chips or popsicles

Soft bland diet

Antipyretics such as ibuprofen as needed (avoid aspirin products)*

^*The use of aspirin products in children who have a viral illness (especially varicella infection, influenza, or coxsackievirus infection) has been associated with Reye syndrome, a potentially fatal condition characterized by fatty degeneration of the liver and encephalopathy.

Acyclovir inhibits viral replication and is activated by virally produced thymidine kinase. As such, it has little activity against nonvirally infected cells.³¹ The use of acyclovir at 15 mg/kg five times a day in children reduces the duration of fever, reduces HSV shedding, halts the progress of lesions, improves oral intake, and reduces the incidence of hospital admissions.³² Valacyclovir, the prodrug of acyclovir, has three to five times the bioavailability of acyclovir and, together with famciclovir, are now widely used.

Biology and Pathogenesis

Primary infection with VZV, an α‐herpesvirus, leads to varicella (chicken pox). As with all herpesviruses, the virus then becomes latent, usually in the dorsal root ganglia or ganglia of the cranial nerves.⁴⁹ Reactivation produces herpes zoster infection (HZI), commonly called shingles. The incidence of HZI increases with age and the degree of immunosuppression. There are 1.5 to 3 cases of HZI per 1000 subjects; this increases to 10 per 1000 in those over age 75 years.⁵⁰ Therefore, it is not uncommon to see HZI in the elderly, in patients undergoing cancer chemotherapy, in patients on chronic immunosuppressive drug therapy (such as those who have received organ transplants), and in patients with AIDS.⁵¹ As with HSV, this virus is cytopathic to the epithelial cells of the skin and mucosa, causing blisters and ulcers. Transmission is usually by the respiratory route, with an incubation period of 2 to 3 weeks.⁵²

Postherpetic neuralgia, a morbid sequela of HZI, is a neuropathy resulting from peripheral and central nervous system injury and altered central nervous system processing.⁵³

Clinical Findings

Primary VZV or varicella infection generally occurs in the first two decades of life. The disease begins with a low‐grade fever, malaise, and the development of an intensely pruritic, maculopapular rash, followed by vesicles that have been described as “dewdrop‐like.” These vesicles turn cloudy and pustular, burst, and scab, with the crusts falling off after 1 to 2 weeks. Lesions begin on the trunk and face and spread centrifugally. Central nervous system involvement may result in cerebellar ataxia and encephalitis.

Immunocompromised hosts usually experience more severe disease with more blisters, a bilateral distribution, a protracted course, and, not infrequently, with disseminated disease leading to encephalitis, hepatitis, and pneumonia. There is a significantly higher mortality rate.⁵⁴ Secondary bacterial infection by gram‐positive cocci may have severe septic consequences.

Recrudescence of VZV leads to herpes zoster infection (HZI) or shingles which tends to occur in adult and starts with a prodrome of deep, aching, or burning pain, itching, and dysesthesia. There is usually little to no fever or lymphadenopathy. This is followed within 2 to 4 days by the appearance of crops of vesicles in a dermatomal or “zosteriform” pattern. This pattern describes the unilateral, linear, and clustered distribution of the vesicles, ulcers, and scabs in a dermatome supplied by one nerve. Thoracic/lumbar dermatomes are the most frequently involved, followed by the craniofacial area. Lesions heal within 2 to 4 weeks, often with scarring and hypopigmentation. Occasionally, HZI may occur without the appearance of dermatomal lesions (zoster sine eruptione or zoster sine herpete), which makes the diagnosis of this condition challenging; these patients often present with facial palsy. In fact, VZV has been detected in 3% of patients with Bell palsy.^13,15 A On rare occasions and especially in immunocompromised patients, HZI may involve not just the dorsal root ganglion but also the anterior horn cells, leading to myelitis; other rare complications include retinitis and encephalitis.⁴⁹

One of the most important complications of HZI is postherpetic neuralgia, defined as pain that lingers for 120 days^53,55 after the onset of the acute rash (see Chapter 12). Postherpetic neuralgia affects up to 20% of patients over age 65 and up to 30–50% of patients over age 80; affected individuals have debilitating pain, usually of a sharp, stabbing, burning, or gnawing nature lasting more than 1 month.^51,56 Some unfortunate patients experience pain for years. Predisposing factors include older age (most important), prodromal pain, and more severe clinical disease during the acute rash phase.^57,58

Oral Manifestations

Primary VZV infection presents as minor acute ulcerations in the mouth that often pale in clinical significance when compared with the skin lesions.

In recurrent VZV infection, the ophthalmic division of the trigeminal (V) nerve is the cranial nerve most often affected (herpes zoster ophthalmicus); corneal involvement may lead to blindness.⁵¹ Involvement of this nerve leads to lesions on the upper eyelid, forehead, and scalp with V₁; midface and upper lip with V₂; and lower face and lower lips with V₃ (Figure 3‐9). With involvement of V₂, patients experience a prodrome of pain, burning, and tenderness, usually on the palate on one side. This is followed several days later by the appearance of painful, clustered 1 to 5 mm ulcers (rarely vesicles, which break down quickly) on the hard palatal mucosa or even buccal gingiva, in a distinctive unilateral distribution (Figure 3‐10). Ulcers often coalesce to form larger ulcers with a scalloped border similar to those of HSV. These ulcers heal within 10 to 14 days, and postherpetic neuralgia in the oral cavity is uncommon. Involvement of V₃ results in blisters and ulcers on the mandibular gingiva and tongue.

An uncommon complication of HZI involving the geniculate ganglion is Ramsay Hunt syndrome. Patients develop Bell palsy, vesicles of the external ear, and loss of taste sensation in the anterior two‐thirds of the tongue.⁵² HZI has been reported to cause resorption and exfoliation of teeth and osteonecrosis of the jawbones, especially in patients with HIV disease.^59–62

Differential Diagnosis

The pain that is often experienced in the prodrome before the onset of vesicles and ulcers may lead to an incorrect diagnosis of pulpitis, leading to unnecessary dental treatment such as endodontic therapy.

HSV infection appears in a similar fashion and if mild and localized to one side may be mistaken for HZI; laboratory tests differentiate between the two. Other blistering/ulcerative conditions such as pemphigus or pemphigoid are chronic and/or progressive diseases that do not present unilaterally.

In severe cases of localized necrosis of the soft tissues and bone, acute necrotizing ulcerative periodontitis should be considered, particularly in the HIV population. Coinfection with CMV may occur in immunocompromised patients.⁶³ Medication‐ (such as bisphosphonate) and radiation‐induced osteonecrosis of the jaws will have a history of exposure to bisphosphonate and radiation, respectively, and often is precipitated by dentoalveolar trauma in the absence of clustered ulcers.

In this age of bioterrorism, clinicians should be familiar with the signs of infection with vaccinia (smallpox virus), which presents with characteristic skin blisters and pustules.

Laboratory Findings

As with HSV infection, identification is by viral isolation using cell culture – a traditional method – although VZV is more fastidious and difficult to culture, use of fluorescein‐labeled antibody to detect antigen, and use of molecular techniques such as real‐time PCR using commercially available kits.^64,65 A simple smear stained with a standard laboratory stain would reveal the presence of multinucleated epithelial cells similar to HSV.

After primary infection, the patient seroconverts and IgG against VZV is detectable in the serum. HZI causes a transient rise in IgM and an increase in levels of IgG, but these are not reliable for diagnostic purposes.⁶⁶

Biopsy is usually not required and is not the diagnostic test of choice since the clinical presentation is usually characteristic. If one should be performed, tissue should always include the intact epithelium adjacent to the ulcer since that is where the cytopathic effect in epithelium is best seen. VZV and HZI are cytopathic to the epithelial cells and result in the formation of multinucleated epithelial cells with viral inclusions, similar to and indistinguishable from HSV infection.

Management

As with HSV infection, management of oral lesions of varicella and HZI is directed toward pain control (particularly the prevention of postherpetic neuralgia), supportive care and hydration (see Table 3‐2), and definitive treatment to minimize the risk for dissemination, particularly in immunocompromised patients. Aspirin use, especially in patients with VZV infection or oral viral infections may result in the development of Reye syndrome, which is potentially fatal, and ibuprofen is the preferred analgesic.⁶⁷

Treatment of primary VZV infection and VZI includes the use of acyclovir (800 mg five times a day), valacyclovir (1000 mg three times a day or 1500 mg twice a day), famciclovir (500 mg three times a day), and brivudine (125 mg once a day) for 7 days and these should be started within 72 hours of disease onset.^68,69 This reduces infectivity, the severity of lesions, and hospitalizations for complications. However, acyclovir has poor bioavailability. These drugs also reduce the incidence of pain and postherpetic neuralgia. Combination therapy with 3‐weeks of tapering corticosteroid therapy up‐front reduces pain, and quickens return to normal activities.⁶⁸

The first line of treatment for postherpetic neuralgia is gabapentin,⁷⁰ 5% lidocaine patch,⁷¹ and 0.025–0.8% topical capsaicin, and the second line of treatment is with tricyclic antidepressants and corticosteroids.^55,68 The use of corticosteroids and antiviral therapy together in an attempt to reduce postherpetic neuralgia has not proved effective, although early treatment with famciclovir or valacyclovir may prevent it.^68,72 Case reports suggest that botulinum toxin may provide pain relief.⁷³

A vaccine against VZV which contains live, attenuated virus reduces the incidence of varicella outbreaks, but because it establishes latency may be associated with increased zoster incidence.⁷⁴ Vaccination of older adults using Zostavax^TM (live, attenuated virus), or Shingrix^TM (recombinant VZV antigen) reduces incidence of HZI significantly and the latter, post‐herpetic neuralgia.^75,76 The use of recombinant virus in a vaccine is more appropriate for use in immunocompromised hosts.

Etiology and Pathogenesis

CMV is a β‐herpesvirus, and 50 to 100% of the population world‐wide and 50% of the U.S. population has been exposed.^77,78 Risk for exposure increases with age, low socio‐economic status, and crowded living conditions. Primary infection may be asymptomatic or cause an infectious mononucleosis‐like disease. As with other members of Herpesviridae, CMV establishes latency within the connective tissue cells, such as the endothelium of blood vessels, mononuclear cells, and white blood cells in the connective tissue. Transmission is by direct transfer of infected white blood cells through intimate contact, vertical transmission, blood products, and transplanted organs.⁷⁹

Clinical Findings

Primary CMV infection presents similarly to other viral infections with fever, malaise, and leucopenia and organ‐specific findings such as gastroenteritis (most common), pneumonitis, retinitis and hepatitis, and even thromboembolism. Six to 7% of patients with infectious mononucleosis‐like symptoms (fever, pharyngitis, and lymphadenopathy) have CMV or HSV infection rather than EBV infection.^80,81

Manifestations of recrudescent infection and disease are most evident in the immunocompromised population, such as patients who have received organ transplants or those who have AIDS where CMV‐related retinitis and gastroenteritis are common. A study on mucocutaneous CMV infection (mostly perianal) in patients with human deficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) revealed that CMV infection of mucocutaneous sites was usually part of a polymicrobial infection with HSV or VZV.⁸² The authors suggest that CMV in such cases is not the pathogenic agent for these ulcers since the presence of those two α‐herpesviruses alone could account for the ulceration and tissue damage. These authors also noted that CMV was often found in nonlesional skin.

In organ transplant recipients, CMV in the donor organ leads to a high incidence of CMV infection in the recipient.⁸³ It causes gastrointestinal and pulmonary disease in the first 100 days after allogenic hematopoietic stem cell transplantation.⁸⁴ There is growing evidence that CMV infection is associated with Guillain‐Barré syndrome especially after renal transplantation, as well as polyradiculopathy and encephalitis in patients with AIDS.^83–85

Oral Manifestations

CMV infection in the mouth in the immunocompromised patient tends to present as a single large ulcer and less often as multiple ulcers (Figure 3‐11). They are usually painful and may have been present for weeks or months. Any site may be involved. Up to one‐third of such ulcers are coinfected with other viruses of the herpes family, especially HSV and CMV. ^86,87

There have been occasional reports of mandibular osteomyelitis and tooth exfoliation associated with CMV and VZV infection.^63,88 Both viruses are associated with vasculopathy and thrombosis, which may be the underlying etiopathogenesis.^89,90

Differential Diagnosis

As indicated earlier, CMV is often seen in association with HSV or VZV infections and, in such situations, may be a bystander rather than pathogenic. Therefore, evaluation for these other two viruses is essential for single or multiple ulcers in the immunocompromised population. In patients with HIV/AIDS, infections with mycobacteria, fungi, and other organisms must be ruled out.

Single ulcers present for weeks or months should be evaluated for squamous cell carcinoma or other malignancies. Since patients who develop such ulcers caused by opportunistic pathogens are often immunocompromised, one should have a high index of suspicion for a malignancy.

Benign or malignant salivary gland tumors or soft tissue tumors may also become secondarily ulcerated from trauma. Single ulcers on the tongue may also represent traumatic ulcerative granuloma (see below).

Laboratory Tests

CMV infections of the oral cavity presenting as ulcers tend to be deep with viral particles residing in endothelial cells and tissue monocytes. As such, a culture of an ulcer infected by CMV is unlikely to be positive unless there is shedding of CMV from the ulcer surface. Furthermore, CMV may be difficult to grow in shell vial culture so current diagnosis of CMV infection is through real‐time PCR viral nuclei acid identification from blood or plasma, and detection of pp65 antigen within leukocytes using a monoclonal antibody.⁹¹ Antibody titers against CMV are unreliable for the diagnosis of active infection.

Biopsy for microscopic examination and/or to obtain tissue for culture is sensitive and specific for identification of CMV in oral ulcers.^88,91 CMV infection produces large intranuclear inclusions within endothelial cells and monocytes in the connective tissue, with an associated nonspecific chronic inflammation. The use of immunohistochemical techniques helps identify CMV if there are only a few infected cells. A biopsy has the advantage of also ruling out any of the other differential diagnoses discussed, such as other viruses or deep fungal infection. It is important to make sure that the biopsy includes normal epithelium because if the ulcer is coinfected with HSV or VZV, these would be identified on the biopsy in the intact epithelium adjacent to the ulcer.

Management

As with all ulcerative lesions, pain is managed with topical anesthetics and systemic analgesics as needed, with appropriate dietary modifications and good hydration (see Table 3‐2). CMV infection is treated with ganciclovir 5 mg/kg IV twice daily, valganciclovir (a valine ester and oral prodrug of ganciclovir with approximately 10‐fold bioavailability of ganciclovir) 900 mg twice daily, foscarnet, or cidofovir. Newer drugs that include letermovir and vaccines are in development.^92,93

Clinical Findings

HFM disease usually afflicts children younger than 10 years in summer. Patients have a low‐grade fever, emesis, and sore mouth; 75 to 100% of patients have a skin rash, especially on the hands and feet (dorsa, palms, and soles) and 30% on the buttocks.⁹⁴ The rash is first red and macular and then becomes vesicular. The incubation period is from 3–7 days and oropharyngeal shedding may last for 4 weeks while gastrointestinal shedding may last 8 weeks to many months.

Oral Manifestations

Patients are febrile and complain of a sore mouth and throat. Lesions begin as erythematous macules that become vesicles and quickly break down to ulcers. Lesions are usually located on the tongue, hard and soft palate, and buccal mucosa but can present on any oral mucosal surface.⁹⁴

Clinical Findings

As with hand‐foot‐mouth disease, children under 10 are usually afflicted and outbreaks usually occur in epidemics in summer. Patients develop high fever, headache, and myalgia that usually last only 1 to 3 days.

Oral Manifestations

The first oral symptoms of herpangina are sore throat and pain on swallowing. There may be erythema of the oropharynx, soft palate, and tonsillar pillars. Small vesicles form, but these rapidly break down to 2 to 4 mm ulcers and these persist for 5 to 10 days (Figure 3‐12).

Lymphonodular pharyngitis is associated with CVA10 and patients report a sore throat, and develop diffuse small nodules (likely lymphoid hyperplasia) in the oropharynx.¹⁰⁵

Differential Diagnosis

Lesions of both HFM disease and herpangina may resemble primary herpetic gingivostomatitis. However, lesions on the palms and soles are typical for HFM disease, and ulcers located only in the posterior oral cavity are typical for herpangina. Bright red and painful gingiva also characterize primary HSV infection, and this is uncommon in CV infections. Chickenpox presents with generalized vesicular skin lesions, but ulcers are not prominent in the oral cavity; patients also appear more ill. Infectious mononucleosis (primary EBV infection) may also present with sore throat and purulent exudates, but serology distinguishes this from CV infections.

Streptococcal infections of the throat generally do not produce vesicles or ulcers seen in HFM disease or herpangina but rather a purulent exudate, although the two may appear similar; cultures distinguish between the two.

Aphthous ulcers are generally not associated with fever or malaise except for the periodic fever syndrome.

Laboratory Tests

Diagnosis is usually made on clinical findings, and culture and biopsies are rarely necessary for diagnosis unless the presentation is atypical or the more virulent subtypes are suspected. CV infections may be diagnosed by culture (usually from the throat or stools), but real‐time PCR is now employed for typing.¹⁰⁶

Management

CV infections are self‐limiting (unless complications arise or the patient is immunocompromised), and management is directed toward control of fever and mouth pain, supportive care, and limiting contact with others to prevent spread of the infection. Effective antiviral agents for CV are not available but vaccines are under development.¹⁰⁷

Etiology and Pathogenesis

The more important and constant of the microbes involved include Treponema species, Prevotella intermedia, Fusobacterium nucleatum, Peptostreptococcus species, Porphyromonas gingivalis, Selenomonas species, Aggregatibacter actinomycetemcomitans and Campylobacter.^112,113 In HIV patients, candida and herpesvirus are also commonly present.¹¹⁴ Since some of these fusospirochetal organisms are common in the periodontal tissues, many believe that it is the permissive environment of an immunocompromised host that allows these microbes to proliferate. The tissue destruction is most probably a result of the production of endotoxins and/or immunologic activation and subsequent destruction of the gingiva and adjacent tissues. In addition, patients show reduced neutrophil chemotaxis and phagocytosis, resulting in poor control of infection. Some have identified herpesviruses within the crevicular fluid,¹¹² but such viruses shed readily in oral secretions, particularly in areas where there is tissue destruction and therefore maybe nonpathogenic bystanders.

If there is underlying systemic illness, NUG and NUP can spread rapidly from the gingiva to the periodontium and into the soft tissues, giving rise to cancrum oris, noma, or orofacial gangrene.¹¹¹ This is particularly devastating in children who are malnourished and live in poverty and is seen not infrequently in Africa. Fusobacterium necrophorum is likely to play an important role in the progression of NUP to cancrum oris because this organism produces a dermonecrotic toxin, hemolysin, leukotoxin, and proteolytic enzymes, all leading to extensive tissue destruction.¹¹² It may also stimulate the growth of P. intermedia.

Clinical Findings

NUG and NUP may or may not be associated with fever and malaise, although submandibular lymphadenopathy is usually present. This may be more prominent in patients with an underlying immunodeficiency.

However, noma generally is accompanied by fluctuating fever, marked anemia, high white cell count, general debilitation, and a recent history of some other systemic illness, such as measles.¹¹¹

Oral Manifestations

NUG has a rapid and acute onset. The first symptoms include excessive salivation, a metallic taste, and sensitivity of the gingiva. This rapidly develops into extremely painful and ery‐thematous gingiva with scattered punched‐out ulcerations, usually on the interdental papillae, although any part of the marginal gingiva may be affected (Figure 3‐13). There is accompanying malodor, and there may be gingival bleeding. Because of the pain associated with the gingivitis, there is usually abundant build‐up of dental plaque around the teeth because it may be too painful to perform effective oral hygiene.

Patients who are immunocompromised and neutropenic are prone to developing such lesions (Figure 3‐14). In patients with AIDS, the prevalence of NUP is strongly predictive of a CD4 count below 200 cell/mm³.¹¹⁵ In this population; these areas may lead to osteonecrosis or necrosis of the soft tissues (Figure 3‐15).¹¹⁶

In patients in whom there is severe immunodeficiency or malnutrition, NUG and NUP may progress to noma (Figure 3‐16). The overlying skin becomes discolored, and perforation onto the skin ensues. The orofacial lesions are cone‐shaped, with the base of the cone within the oral cavity and the tip at the skin aspect. There is sloughing of the oral mucosa followed by sequestration of the exposed, necrotic bone and teeth. Without treatment, the mortality rate is 70 to 90%.¹¹²

Differential Diagnosis

The acute onset of erythematous and ulcerated gingiva of NUG may suggest a diagnosis of primary herpetic gingivostomatitis and this is readily ruled out with a culture and by PCR. Desquamative gingivitides (caused by lichen planus, mucous membrane pemphigoid, pemphigus vulgaris, and hypersensitivity reactions) may present primarily on the gingiva, with no skin findings. However, these conditions are not of acute onset but rather chronic and/or progressive over months and years and are characterized by inflammation rather than necrosis.

Neutropenic ulcers in patients on cancer chemotherapy may appear similar, leading to extensive ulceration and necrosis of the marginal gingiva and other mucosal surfaces.

Single large necrotic ulcers of noma suggest deep fungal infections or infections with the herpes family of viruses, especially in immunocompromised patients. Squamous cell carcinoma is also a consideration in this group of patients.

Laboratory Testing

Secretions from the gingival sulcus grow mixed flora but in particular will be positive by culture or PCR for Treponema species, Prevotella intermedia, Fusobacterium nucleatum, and other bacteria as indicated above. Necrotizing gingival lesions may also be caused by microbes other than fusospirochetes, such as Pseudomonas aeruginosa.¹¹⁷

A biopsy usually is not helpful in making a diagnosis, although biopsies may be performed to rule out some other condition that may have a similar clinical presentation. The lesions demonstrate ulceration, extensive necrosis, leukocytoclasia, and a mixed inflammatory infiltrate. More than half of the cases in patients who were HIV positive were immunoreactive for HIV p24 within focal histiocytes, whereas EBV RNA was identified in 1 (6%) of 17 cases.¹¹⁸

Management

This is directed toward supportive care and pain control (see Table 3‐2), definitive treatment, and identification of underlying predisposing factors. In patients who are malnourished, nutritional rehabilitation is essential to halt the progress of gingival lesions to noma.

Definitive treatment of NUG and NUP consists of gentle débridement to remove as much of the debris and plaque as possible; this is best accomplished under topical anesthesia during the first few visits. The use of chlorhexidine digluconate mouth rinse led to resolution in >90% of cases.¹¹⁹ Patients with more extensive disease and/or systemic symptoms may require antibiotics active against gram‐negative anaerobes, such as β‐lactams.¹¹⁶ Interestingly, metronidazole, which has little activity against spirochetes, also is effective, suggesting that resolution can occur without treatment of the entire microbial complex.¹²⁰

Once the acutely painful episodes have resolved, scaling and root planing to completely remove all residual plaque and calculus are indicated. Periodontal surgery may be necessary to correct gingival and periodontal defects. It may be appropriate to test the patient for HIV or other immunosuppressive conditions, such as blood dyscrasia.

Cases of noma need aggressive treatment with nutritional supplementation, antibiotics, and tissue débridement. Nevertheless, survivors exhibit significant disfigurement and functional impairment from tissue loss and scarring.¹¹³

Etiology and Pathogenesis

EM is a hypersensitivity reaction, and the most common inciting factor is infection, particularly with HSV. Drug reactions to NSAIDS, anticonvulsants, or other drugs play a smaller role.¹²¹ Cases of oral EM precipitated by benzoic acid, a food preservative, have been reported.^123,124

Some studies show that recurrent EM is associated with HSV infection both by history of HSV infection 1 to 3 weeks before onset of EM, seropositivity for HSV antibodies, and identification of HSV antigens.¹²⁵ Using PCR techniques, HSV gene products have been identified in 71 to 81% of cases of recurrent EM.^10,11 It is postulated that HSV antigens incite a T cell‐mediated delayed‐type hypersensitivity reaction that generates interferon‐γ, with the amplified immune system recruiting more T cells to the area. Cytotoxic T cells, natural killer cells, and/or cytokines destroy the epithelial cells. It has been suggested that CD34+ cells, Langerhans cell precursors, carry fragments of HSV DNA to the skin where it incites EM.¹²⁶

A condition reported as mycoplasma‐induced rash and mucositis (MIRM) appears similar to EM and also SJS in that patients, almost always pediatric, present with extensive oral and mucosal lesions but usually less prominent skin lesions.¹²⁷ However, infection with Chlamydia pneumonia may cause similar lesions.¹²⁸ Some have classified such lesions under Mycoplasma‐associated SJS but current classification considers it a distinct entity because of the much milder skin presentation.

Clinical Findings

EM generally affects those between ages 20 and 40 years, with 20% occurring in children.¹²¹ Patients with recurrent EM have an average of 6 episodes a year (range 2–24), with a mean duration of 9.5 years; remission occurred in 20% of cases.¹²⁵ Episodes usually last several weeks.^121,122 There may be a prodrome of fever, malaise, headache, sore throat, rhinorrhea, and cough. These symptoms suggest a viral (especially respiratory tract) infection, and this is not surprising since infectious agents are known to trigger EM.

Skin lesions appear rapidly over a few days and begin as red macules that become papular, starting primarily in the hands and moving centripetally toward the trunk in a symmetric distribution. The most common sites of involvement are the upper extremities, face, and neck. The skin lesions may take several forms—hence the term multiforme. The classic skin lesion consists of a central blister or necrosis with concentric rings of variable color around it called typical “target” or “iris” lesion that is pathognomonic of EM; variants are called “atypical target” lesions (Figure 3‐16). The skin may feel itchy and burnt. Postinflammatory hyperpigmentation is common in dark‐skinned individuals and may be worsened by sun exposure.

Oral Findings

The oral findings in EM range from mild erythema and erosion to large painful ulcerations (Figures 3‐17 and 3‐18).¹²³ When severe, ulcers may be large and confluent, causing difficulty in eating, drinking, and swallowing, and patients with severe EM may drool blood‐tinged saliva. Extensive lip involvement with inflammation, ulceration, and crusting is common (Figure 3‐19).

Oral lesions are present in 23 to 70% of patients with recurrent EM.^125–130 The most commonly affected sites are the lips (36%), buccal mucosa (31%), tongue (22%), and labial mucosa (19%).¹²⁸ Genital and ocular sites are affected in 25 and 17% of cases, respectively.¹²⁵

The concept of pure oral EM is controversial and not universally accepted since some dermatologists believe that the characteristic appearance and distribution of skin lesions are the sine qua non for the diagnosis of EM. Nevertheless, cases of oral EM without skin involvement have been reported.¹³¹ Intraoral lesions are irregular bullae, erosions, or ulcers surrounded by extensive erythema. Crusting and bleeding of the lips are common, but not always present.^124,132

Differential Diagnosis

Primary HSV gingivostomatitis with its viral prodrome and erosions and ulcerations may resemble oral EM, but these lesions are culture positive for HSV and do not usually present with the typical skin rash. Oral ulcers of HSV are usually smaller, well circumscribed, and clustered, whereas EM lesions are larger and irregular. Autoimmune vesiculobullous disease such as pemphigus and pemphigoid may have oral ulcers and skin lesions, although skin lesions are bullous in nature and not maculopapular, without the centripetal progression seen in EM. They are chronic, slowly progressive diseases that usually persist for months, whereas EM heals within weeks.

Hemorrhagic crusts on the lips are seen in paraneoplastic autoimmune multiorgan syndrome/paraneoplastic pemphigus (associated with malignancies, see below) and Stevens‐Johnson syndrome (often drug‐induced, see below). The latter may be difficult to distinguish from EM.

Recurrent oral EM in the absence of skin findings may be confused with recurrent aphthous ulcers (see below), but aphthous ulcers present as discrete ovoid or round ulcers, whereas ulcers of EM are more diffuse and irregular with marked erythema.

Laboratory Findings

The diagnosis is made primarily on clinical findings and a recent history of recrudescent HSV infection. IgG and IgM levels are not a reliable test for recrudescence or asymptomatic reactivation although they may be suggestive. A negative IgG level rules out HSV as an etiologic agent.

Early lesions show lymphocytes and histiocytes in the superficial dermis around superficial dermal vessels. This is followed by hydropic degeneration of basal cells, keratinocyte apoptosis and necrosis, subepithelial bulla formation, and a lymphocytic infiltrate.¹³³ Leukocyte exocytosis is also usually noted.

Management

Mild oral EM can be managed with systemic or topical analgesics for pain and supportive care since the disease is self‐limiting and resolves within a few weeks. More severe cases are usually managed with systemic corticosteroids although patients often worsen on discontinuation of steroid therapy. Topical steroids may also help resolve lesions. Cases suspected of being HSV‐associated should be treated with antiviral medications, and prophylaxis may prevent recurrences. Treatment with acyclovir at the first sign of disease in recurrent EM controls disease in approximately half of patients.¹²⁵ Other treatment modalities include dapsone, hydroxychloroquin, mycophenolate mofetil, azathioprine, colchicines, methotrexate, and intravenous immunoglobulin. ¹³⁴

Continuous acyclovir at 400 mg twice a day prevents development of EM in most patients with HSV‐associated recurrent disease, whereas EM not related to HSV responded well to azathioprine (100–150 mg/d).¹²⁷ Other studies have also shown good suppression of recurrent HSV‐associated EM using 500 mg of valacyclovir twice a day or 250 mg of famcyclovir twice daily.^44,135 Dapsone (100–150 mg/d) and antimalarials are partially successful in suppressing recurrent outbreaks but may be associated with significant side effects.¹²⁷

Etiology and Pathogenesis

This is a group of conditions that have protean manifestations. Oral hypersensitivity reactions may take the following forms:

1. Acute onset of ulcers such as in oral EM (discussed above).
2. Red and white reticulated lesions of a lichenoid hypersensitivity reaction (discussed in Chapter 4, “Red and White Lesions of the Oral Mucosa”).
3. Fixed drug eruption.
4. Marked erosion and erythema especially on the gingiva with or without ulceration called plasma cell stomatitis (PCS).
5. Swelling of the lips/angioedema (see Chapter 19, “Immunologic Diseases”).
6. Oral allergy syndrome that presents mainly with symptoms of itching with or without swelling of the oral structures and oropharynx.

This discussion concentrates on lesions of PCS. PCS generally causes erythema and less often ulcers, but is included here for completeness.

PCS is a hypersensitivity reaction that was first described in the late 1960s and early 1970s and was likely a contact stomatitis to a component of chewing gum.¹⁴³ Since then, sporadic cases have continued to be reported, and these are all likely caused by a sensitizing contactant, whether or not the contactant is identified. These include khat (Catha edulis),¹⁴⁴ components of toothpaste,^144,145 mint candies,¹⁴⁶ and household cleaners.¹⁴⁷ Sometimes, the terms mucous membrane plasmacytosis and plasma cell orificial mucositis are used because there may be involvement of the upper respiratory tract.¹⁴⁸ Because of the intense plasma cell infiltration, it is believed that this is a B cell‐mediated disorder, with T cells augmenting the response. Some believe that this is caused by components of plaque bacteria, although this is not a universally accepted concept.¹⁴⁹

Clinical Findings

PCS occurs within days of exposure to the contactant, with most signs and symptoms limited to the oral cavity. Some lesions may affect the periorificial tissues or the oropharynx, leading to upper airway symptoms of hoarseness, dysphagia, and mild airway obstruction.¹⁴⁸ Endoscopy may reveal erythematous and thickened mucosa, often with a cobblestoning pattern from the edema. An obvious allergen/contactant is not always identified.^148,150

Oral Manifestations

PCS occurs within a few days of exposure. It presents as brightly erythematous macular areas of the oral cavity, almost always involving the marginal and attached gingiva or alveolar mucosa and often involving other soft tissues, such as the maxillary and mandibular sulcus, tongue, or buccal mucosa (Figure 3‐22). Ulcers may be present, and there may be epithelial sloughing and desquamation. The gingiva may also be swollen and edematous. Patients may complain of pain and sensitivity and bleeding of the gingiva on brushing. Angular cheilitis with fissuring and dry, atrophic lips have been reported.^143,151

Some cases reported as PCS consisted of a very localized area of erythematous gingiva, usually around a single tooth and measuring usually < 1 cm.¹⁴⁹ Interestingly, two adults in this series also demonstrated plasma cell balanitis. It is unclear if this represented classic PCS since most cases of PCS tend to be diffuse.

Differential Diagnosis

The differential diagnosis for PCS includes any of the desquamative gingivitides, such as erythematous/erosive lichen planus, and the autoimmune vesiculobullous disorders, such as mucous membrane pemphigoid and pemphigus vulgaris. The lesions will become chronic if the patient continues to be exposed to an undetected allergen. A biopsy for both routine histology and direct immunofluorescence studies to rule out mucous membrane pemphigoid and pemphigus vulgaris is necessary to make the diagnosis.

Another condition that PCS can mimic is pubertal or pregnancy‐induced gingivitis and plaque‐associated gingivitis. The difference in the histopathology is in the density of plasma cells since nonspecific gingivitis generally also is associated with a plasma cell infiltrate. The clinical appearance of diffuse red gingiva with a history of recent exposure to a new topical agent helps make the diagnosis, especially if discontinuation of the agent leads to resolution. Some previous cases reported as PCS may constitute such plaque‐associated and pubertal gingivitis.¹⁴⁹ Chronic granulomatous gingivitis caused by components of polishing agents such as pumice also often present with sensitive or painful erythematous gingiva. A biopsy will show the presence of particulate matter in the gingival connective tissue.

Mouth‐breathers often present with erythematous and sometimes edematous gingiva, usually around the upper anterior teeth. A good history and correlation with the histopathologic findings help differentiate this from PCS.

Erythematous candidiasis may present with marked gingival erythema (often linear) without the usual white curdy papules of “thrush” or pseudomembranous candidiasis and will resolve with anti‐fungal therapy. Candida may also secondarily infect an area of PCS.

Fixed drug eruptions are rare in the oral cavity and present as areas of ulceration or erosion that recur at the same site whenever exposed to a certain medication.¹⁵²

PCS should not be confused with a direct contact irritation of the tissues such as from strongly flavored foods and dentifrices.¹⁵³ This would occur in any individual and does not represent a hypersensitivity reaction because ulcers are caused by the noxious and caustic nature of the chemical causing a mucosal burn.

Laboratory Findings

A biopsy is the most useful diagnostic test for this condition, followed by patch testing to identify the allergen.

A biopsy of the gingiva in PCS shows parakeratosis, epithelial hyperplasia, neutrophilic exocytosis, and numerous spongiotic pustules in the absence of Candida.^143,154 The most significant finding is dense sheets of plasma cells in the lamina propria; many dilated capillaries lie close to the surface, accounting for the marked erythema. Eosinophils are not seen usually.¹⁴⁸ Immunoperoxidase stains will invariably show the plasma cell infiltrate to be polyclonal, typical for a reactive/inflammatory process, and not monoclonal, which typifies neoplastic lesions.⁷³

Management

PCS is self‐limiting and will generally, but not always, regress if the contactant is identified and removed. Nevertheless, pain control and anti‐inflammatory agents may be helpful during the healing process. Topical steroids may help reduce inflammation and speed healing.¹⁵⁵ Some lesions have resolved with intralesional triamcinolone injections, although the gingiva is a particularly difficult location for such injections.¹⁵⁶ Cases have also responded well to prednisone.¹⁵⁰ Gingivectomies may be needed to recontour lesions that are long‐standing and more fibrotic. One case showed improvement with 2% fusidic acid.¹⁵⁷

Etiology and Pathogenesis