Viral Infections of the Mouth

Human herpesvirus infection

HHVs are icosahedral DNA viruses measuring approximately 100 nm without an envelope or 150 nm with an envelope. They replicate in the host cell nucleus. HHVs are spread in the oral cavity via infected saliva or droplets; they may also be transmitted via oral-genital contact. Viral shedding has been detected before, during, and after the appearance of clinical lesions in patients with recurrent HHV-1 and HHV-2 infections; therefore, lack of visible lesions does not correlate with lack of potential infectivity. ^{[20, 21]}  In a localized primary infection, the virus penetrates the mucosal epithelium and invades the cells of the basal layer, where the viral DNA inserts into the host DNA.

In HHV-1 and HHV-2 oral infections, viral replication within the oral epithelium may cause lysis of epithelial cells, with vesicle formation. Shallow ulcers with scabs that then heal without scarring follow the formation of vesicles. HHVs establish latent permanent infections in their hosts, though clinical signs of disease may not be apparent.

Human papillomavirus infection

HPV is a 50-nm virus composed of double-stranded DNA with no envelope. The virus penetrates the mucosal epithelium and invades the cells of the basal layer, where the viral circular DNA inserts into the host DNA.

Coxsackievirus infection

Enteroviruses infect humans mainly via the fecal-oral route. Spread of enteroviruses can also occur via direct contact with nasal and throat secretions from individuals who are infected.

Enteroviruses attach to and replicate in susceptible areas of the pharynx or the distal gastrointestinal (GI) tract. After multiplying in the submucosal lymphoid tissues, they move to the regional lymph nodes (cervical and mesenteric) and produce a minor viremia that is transient and undetectable. Most infections are subclinical, and viral replication stops or is halted by host defense mechanisms. Oral and cutaneous lesions result from secondary infection of the small blood vessels during viremia.

The incubation period can range from 2 days to 2 weeks but is generally 3-5 days. A patient who is infected sheds the virus several days before symptoms appear and can continue to excrete the virus several weeks after the illness.

Mumps

The mumps virus is a member of the Paramyxoviridae family and of the Rubulavirus genus. This genus includes the mumps virus; Newcastle disease virus; and human parainfluenza virus types 2, 4a, and 4b. Transmission of the mumps virus occurs via direct contact, via droplets, or via fomites, and it enters through the nose or mouth. More intimate contact is necessary for the spread of mumps than for the spread of measles or varicella.

During the incubation period (~16-18 d), the virus proliferates in the upper respiratory tract and regional lymph nodes. Viremia follows with secondary spread to the glandular and neural tissues. Inflammation of infected tissues leads to the manifestations of parotitis and aseptic meningitis. Patients are most contagious 1-2 days before the onset of parotitis.

Measles (rubeola)

The measles virus is a paramyxovirus belonging to the Morbillivirus genus. It can survive for as long as 2 hours in the air and on surfaces. Measles is spread by direct contact via droplets from respiratory tract secretions in patients who are infected. It is considered one of the most communicable infectious diseases.

The initial site of infection is the respiratory tract epithelium. Multiplication of the measles virus in the respiratory tract epithelium and regional lymph nodes is followed by a primary viremia, with spread to the reticuloendothelial system. A secondary viremia occurs upon breakdown and necrosis of the reticuloendothelial cells, and the virus infects the leukocytes. During the secondary viremia, infection may spread to the thymus, spleen, lymph nodes, liver, skin, and lungs.

Rubella

The rubella virus is an RNA virus belonging to the Togavirus family and the Rubivirus genus. It is related to the group A arboviruses (specifically, Eastern and Western encephalitis viruses). The virus is unstable and is killed by lipid solvents, trypsin, formalin, ultraviolet (UV) light, and extremes in temperature and pH.

The virus is spread via respiratory tract droplets from individuals who are infected. The virus replicates in the nasopharyngeal tissues and lymph nodes. A viremia results 5-7 days after initial exposure to other areas of the body. Patients are believed to be contagious when the rash is emerging. The virus may also be shed from the throat from 10 days before to 15 days after the onset of the rash. In congenital rubella infections, transplacental spread of virus occurs during viremia.

Rubella is moderately contagious. It is most transmissible when the rash begins. Infants with congenital rubella syndrome (CRS) shed large amounts of the virus in their body secretions for many months and can spread rubella to caregivers who are vulnerable to rubella infection.

Outbreaks of rubella continue to occur in susceptible populations, including those exposed to certain individuals who have religious or philosophic beliefs regarding personal exemption from vaccination. Other outbreaks have occurred in workplaces with employees who were born in countries outside of the United States that do not advocate routine immunizations, including some Latin American and Caribbean countries. ^[22]

Human herpesvirus infection

Seroprevalence for the eight HHV types has been estimated as follows:

• HHV-1 - Approximately 80% in North American adults
• HHV-2 - Approximately 20% in North American adults
• HHV-3 - Approximately 95% in North American adults
• HHV-4 - Approximately 90% in North American adults
• HHV-5 - Approximately 70% in North American adults
• HHV-6 - Approaching 100% in North American adults
• HHV-7 - Approximately 85% in adults
• HHV-8 - Globally, 2-10% (but >28% in Albanian adults, 25% in Albanian children, 18% in Kosovar adults, and >16% in Kosovar children ^[23] )

Primary herpes infections occur most frequently during childhood or youth, though occasional cases are observed in older individuals. Recurrent HHV-1 infections typically occur throughout life and are particularly triggered by stress, illness, immune compromise, or other factors. Herpes zoster usually affects patients older than 40 years and has similar triggers, though the triggering conditions usually must be more pronounced.

Human papillomavirus infection

HPV has been detected in the oral cavity of approximately 6-10% of children and adolescents. Estimates of the frequency of HPV in the oral cavity of healthy adults have ranged from 5% to 80%. Persistent oral HPV infection in one spouse appears to predict similar infection in the other spouse, regardless of oral sex habits. ^{[24, 25, 26]}  The evidence is conflicting as to whether oral HPV infection may denote an increased risk of vaginal HPV infection and vice-versa. ^{[27, 28]}

In a landmark study (N = 5579; age range, 14-69 y) by Gillison et al, the prevalence of HPV in oral rinses approached 7%; the prevalence of the HPV-16 subtype (by far the most relevant subtype for oral cancer) was around 1%. ^[29]  A study of Northern Italian men who have sex with men (MSM) found much higher levels of oral HPV detected by PCR: About 21% of the men had HPV, and about 24% of those men had high-risk HPV. ^[30]

HPV-16 has been linked to the development of dysplasia and carcinoma of the uterine cervix. Oral HPV-16 has been found to be more commonly detected in women with HPV-associated cervical dysplasia. ^[31]  Oral HPV-16 detection is much less common in children than in adolescents and adults; however, persistence of HPV-16 and other high-risk HPV types is more common in infants of parents with persistent oral HPV infections and high-risk behaviors.

The presence of HPV in patients with oropharyngeal cancers is believed to be on the rise, and this increase may be more pronounced in HIV-positive patients. ^[32]  In patients with these types of cancer, the prognosis is better when HPV is present than when it cannot be detected. ^{[33, 34]}

HPV lesions are more common in immunocompromised patients, especially in HIV-infected patients and in solid-organ transplant recipients. ^{[35, 36]}  Oral HPV may also be more common in renal dialysis patients. The development of effective preventive HPV vaccines may eventually have a significant impact on these rates. ^{[37, 38, 39]}

Coxsackievirus infection

Hand-foot-and-mouth disease most often occurs in children younger than 5 years. Herpangina most frequently occurs in children aged 3-10 years. Acute lymphonodular pharyngitis also most frequently occurs in children. No sexual predilection is apparent. No racial predilection is reported.

Hand-foot-and-mouth disease

In the United States, most cases (individual and outbreaks) occur in the summer and early fall.

Internationally, major outbreaks of hand-foot-and-mouth disease related to enterovirus 71 (EV-71) occurred in Malaysia in 1997, ^[40]  with periodic epidemics since then, ^[41]  and in Taiwan in 1998. More than 75,000 cases were reported in Qingdao, China, between 2007 and 2014, with peak incidence in the warmer months. ^[42]  In 2008, 387 severe cases of hand-foot-and-mouth disease and 14 deaths were reported in Taiwan. ^[43]  

In Vietnam between 2011 and 2012, there were more than 200,000 hospitalizations and 207 deaths from hand-foot-and-mouth-disease. ^[44]  Between 2008 and 2014, 10,717,283 cases of hand-foot-and-mouth-disease were reported in China; there were 3046 deaths, with a fatality rate of 0.03%. ^[45]

Hand-foot-and-mouth disease is not a reportable disease in the United States. During the period from November 7, 2011, to February 29, 2012, 63 cases of hand-foot-and-mouth disease were reported to the Centers for Disease Control and Prevention (CDC). ^[46] Regionally, these cases were concentrated in Alabama, California, Connecticut, and Nevada. Of the 63 cases, a significant percentage (63%) were in children younger than 2 years, and 24% were in adults older than 18 years. Coxsackievirus A6 was seen in 74% of the cases in which clinical specimens were obtained. International importation was not believed to be a contributing factor.

Herpangina and acute lymphonodular pharyngitis

In the United States, illness usually occurs as summer outbreaks, peaking between August and October. Infections occur with higher frequency in younger age groups, in people who live in crowded areas, and in people who are economically disadvantaged. Under these conditions, the rate of infection with one or more enteroviruses can exceed 50%.

There was a significant outbreak of herpangina in Hangzhou, China, during the summer of 2015. ^[47] Between May and August 2015, 210 cases of herpangina were diagnosed among children, with 91% occurring in children younger than 5 years.

Mumps

Epidemics related to the mumps paramyxovirus have occurred in military populations and other communities, including prisons, boarding schools, ships, and remote islands. The spread of mumps in a community is also postulated to occur via children in schools and via those who secondarily infect their family members. Past outbreaks of mumps have occurred despite vaccination, possibly related to vaccine failure from the use of only one dose of the vaccine.

In the United States, before the introduction of the live-attenuated mumps vaccine in 1967, epidemics occurred every 2-5 years, most frequently between January and May. Since the introduction of the vaccine, the annual incidence of mumps in the United States has declined by more than 99%. In 1986 and 1987, a resurgence of mumps occurred, with 12,848 cases reported in 1987. ^[48] Most cases involved pediatric patients between the ages of 10 and 19 years who were born before the institution of recommendations for routine mumps vaccination.

In 2006, a mumps outbreak occurred that involved 45 US states and the District of Columbia. ^[49]  From January 1 to October 7, 2006, 5783 cases of mumps were reported, of which 3113 (54%) were confirmed, 2612 (45%) were probable, and 58 (1%) were of unknown classification. ^{[50, 51]}  The median patient age was 22 years, and 3644 cases (63%) occurred in females.This was the largest outbreak of mumps since 1991, when 4264 cases were reported.

In the 2006 outbreak, most cases were reported in individuals who had received two doses of measles, mumps, rubella (MMR) vaccine. ^[49] It is known that two doses of MMR are not totally effective in preventing disease. Another contributing factor is the college campus environment, where close contact among students can spread mumps through respiratory and oral secretions. Yet another factor is that only 25 states have a college admission requirement of two doses of MMR vaccine.

In 2009, another US outbreak of mumps occurred, the most significant one since 2006. This outbreak occurred in the northeastern United States, specifically in the New Jersey–New York area. Between June 2009 and the end of the year, 1776 cases were identified. ^[52] Most occurred in the Orthodox Jewish community, and a significant number of these (77%) were in males. Furthermore, 36% of cases were seen in adolescents aged 13-17 years. Of the individuals who had been vaccinated against mumps, 88% had received one or more doses of mumps vaccine, and 76% had received two doses. ^[52]

In 2016, 4975 cases of mumps were reported in Arkansas, accounting for 78% of all mumps cases in the United States during that year. ^[48] Of these 4975 individuals, 73% had received two doses of the mumps vaccine.

Internationally, mumps is endemic throughout the world.

Mumps is uncommon in infants younger than 1 year because of passive immunity acquired via placental transfer of maternal antibodies. Before the vaccine was instituted in 1967 and during the initial period of vaccination, most cases occurred in children aged 5-9 years, with 90% of cases in children younger than 15 years. In the late 1980s, a shift toward older individuals aged 5-19 years occurred. More recently, the number of cases in infants and elderly persons has increased.

Males and females are affected equally. No racial predilection is reported.

Measles (rubeola)

Before the introduction of the measles vaccine in 1963, approximately 500,000 cases and 500 deaths were reported annually in the United States, and epidemic cycles occurred every 2-3 years. More than 50% of the population had had measles by age 6 years, and more than 90% had had it by age 15 years. After licensure of the vaccine in 1963, the number of reported cases of measles dropped by more than 98%, and the 2- to 3-year epidemic cycles no longer prevailed. Most cases now occur in unvaccinated individuals. When vaccination rates fall in the United States, measles is often the first disease to occur.

Between 1989 and 1991, the incidence of measles rose significantly. Approximately 55,000 cases were reported during this 3-year period, with the greatest number occurring in children younger than 5 years. ^[53] The disease was particularly prevalent in Hispanic and African American populations as a consequence of low vaccination rates among preschool-aged children in these groups. After this period, the incidence of measles decreased, and since 1993, fewer than 500 cases have been observed in most years. By 2002, the measles rate had fallen to 0.15 cases per million individuals.

Persons who are at higher risk for measles include the following ^[54] :

• Unvaccinated students in colleges and postsecondary institutions, where there are large concentrations of susceptible people
• Workers in medical facilities, regardless of whether they are medical or nonmedical staff
• People who have refused vaccination for personal or religious reasons
• Individuals traveling outside the United States

Unvaccinated individuals returning from travels abroad are the most likely causative factor for measles outbreaks in the United States; subsequently, the virus is transmitted to those who are intentionally unvaccinated, with resulting clusters of outbreaks.

As an example, in March 2004, the Iowa Department of Public Health informed the CDC that a 19-year-old college student had flown from India to the United States during the infectious stage of measles. ^[55] Because of a nonmedical exemption, the students at this college had not been previously vaccinated, and six of them had become infected with measles during a trip to India. The measles infection in these students while traveling abroad demonstrates how easily measles can be transmitted to unvaccinated individuals.

Since 1993, the largest US outbreaks have occurred in groups of individuals who refused vaccination. Between January 1 and July 31, 2008, 131 cases were reported to the CDC, compared with an average of 63 cases per year from 2000 to 2007. ^[56] Of these 131 cases, 76% were in individuals younger than 20 years, and 91% were in those who were not vaccinated or whose immune status was unknown. Additionally, 89% of these cases were associated with importations from other countries. Many of the imported cases were from Europe, where outbreaks were occurring at the time.

In 2009, 71 reported cases of measles occurred in the United States. ^[57] Of these, 21 were deemed to have been imported; 14 of these cases occurred in US residents who had traveled internationally, and the remaining seven were in individuals from other countries. Countries of origin of measles included United Kingdom, India, China, Philippines, Vietnam, Italy, and Cape Verde. Of the US residents who had nonimported cases of measles in 2009, 44% had personal or religious beliefs against vaccination, and 22% had parents who had delayed MMR vaccination.

In 2011, 222 cases of measles were reported in the United States. ^[58] Seventeen outbreaks (three or more cases linked in time or place) occurred, and 112 cases (50%) were associated with outbreaks. Furthermore, 200 cases were reported to be imported, with 52 occurring in US residents who had traveled internationally. A significant percentage (85%) of individuals with measles were not vaccinated or were not sure as to their past vaccination history.

In 2014, 667 cases of measles occurred in the United States. ^[59]

Internationally, measles is endemic or epidemic in many parts of the world. An estimated 20 million cases occur globally each year. ^[60] Ongoing outbreaks have been occurring in Europe, where vaccination rates are lower than in the United States. The main countries involved have been Austria, Italy, and Switzerland. In 2008, the United Kingdom reported endemic levels of measles cases as a result of a drop in vaccination levels.

Before vaccination against measles became routine, the disease primarily affected school-aged children. After that, other groups were more frequently affected, including preschool-aged children younger than 5 years and adults older than 20 years. No sexual predilection is apparent. No racial predilection is reported.

Rubella

In the United States, the incidence of rubella infections historically was higher in late winter and spring. Before the licensure of the rubella vaccine in 1969, the number of rubella cases was high, and epidemics occurred every 6-9 years. The largest annual number of cases of rubella reported in the United States was 57,686, in 1969.

After 1969, the incidence of rubella dropped significantly. Fewer than 1000 cases per year were reported after 1983. In 1988, the number of cases of rubella in the United States fell to an all time low of 223. However, in 1989, the number of cases nearly doubled from the previous year to 396. This was thought to have occurred together with the rise in measles cases, because of failure to perform timely vaccination of preschool children. After this resurgence, the number of cases of rubella fell steadily.

The demographics of rubella cases in the United States have changed since the 1990s. It now occurs more frequently in foreign-born Hispanic adults who are unvaccinated or in those who have unknown vaccination status. Furthermore, rubella infection continues to occur in women of childbearing age who were born outside the United States. ^[61]

Since 2001, the annual numbers of rubella cases in the United States have been the lowest in recorded history. Twenty-three cases were reported in 2001, 18 in 2002, 7 in 2003, and 9 in 2004. Approximately half of these cases occurred in persons born outside the United States, of whom most were born outside the Western Hemisphere.

In 2005, the United States declared that it had eliminated endemic rubella transmission. ^[62]  Between 2005 and 2007, 34 cases of rubella were reported in the United States. A median of 25% (range, 18-45%) of cases were imported between 2005 and 2007. The countries of origin included Brazil, France, Russia, Uganda, Philippines, Malaysia, and Bangladesh. ^[63]

Whereas rubella is endemic in many other parts of the world, the United States has continued to maintain high vaccination rates in children, encouraged vaccination in women of childbearing age (especially in those born outside the United States), and maintained surveillance for and response to future outbreaks of rubella. ^[64]

Internationally, rubella infections occur worldwide.

Rubella is considered a childhood disease; however, it can affect adolescents and adults. No sexual predilection is apparent. No racial predilection is reported.

Human herpesvirus infection

In children and adults who are immunocompetent, primary herpetic infections may be annoying and uncomfortable, but they rarely cause significant morbidity or mortality. In individuals who are immunosuppressed, however, primary herpetic infections can be severe and occasionally can cause esophagitis, encephalitis, keratoconjunctivitis, and other diseases. The other forms of HHV infection can result in death. Herpes infections occasionally trigger erythema multiforme.

Human papillomavirus infection

The prognosis for patients with HPV infection is excellent. Most oral lesions caused by HPV are benign. Lesions are usually painless and not ulcerated, though they may be secondarily ulcerated by trauma. Lesions may be more common and severe in immunocompromised patients than in other patients. In extreme conditions, the treatment objective is limited to control of the HPV lesions rather than eradication.

Coxsackievirus infection

Oral symptoms of coxsackievirus infection (eg, mild pharyngitis and erythema of the oral mucosa) occur with hand-foot-and-mouth disease, herpangina, and acute lymphonodular pharyngitis. In hand-foot-and-mouth disease, an accompanying rash also occurs. Aside from the oral discomfort and general malaise that accompany herpangina, acute lymphonodular disease, and most forms of hand-foot-and-mouth disease, mortality and morbidity are low.

Hand-foot-and-mouth disease caused by EV-71 is often accompanied by more life-threatening manifestations, such as respiratory distress and aseptic meningitis. A major outbreak of hand-foot-and-mouth disease caused by EV-71 was reported in Taiwan in 1998. The outbreak resulted in a number of deaths; most patients who were hospitalized developed rapid cardiopulmonary failure and died soon afterward. This event was the third known EV-71 outbreak leading to rapid deterioration and death in children. Previous outbreaks in young children occurred in Bulgaria in 1975 and in Malaysia from April through June 1997. ^[65]

Mumps

The prognosis for patients with mumps is good. Deaths related to mumps are rare; more than half occur in individuals older than 19 years. Fetal deaths are increased when mumps infection occurs during the first trimester.

Approximately one third of people infected with the mumps virus are asymptomatic. Although as many as 50% of patients with mumps demonstrate inflammation of the central nervous system (CNS), fewer than 10% present with manifestations of CNS infection. Adults are at higher risk for aseptic meningitis. Orchitis is a common complication of mumps infection, but sterility is rare. Other less common complications include pancreatitis and deafness.

Measles (rubeola)

The prognosis is good for well-nourished children. Complications have occurred in as many as 30% of patients with measles. They are typically more severe in young children and adults. During the period 1985-1992, the most commonly reported complication was diarrhea, followed by otitis media and pneumonia.

In the United States, the fatality rate has been approximately 1-2 deaths per 1000 cases of measles. Young children and adults are at higher risk. Pneumonia causes approximately 60% of measles-related deaths, especially in children. In adults, encephalitis-related deaths are more common. Measles-related fatalities are increased in children with leukemia or HIV infection, who are immunocompromised.

Developing countries have higher rates of measles in children younger than 1 year. Malnourishment, particularly vitamin A deficiency, is a factor that influences the severity of measles. Mortality due to measles in populations with malnutrition can be as high as 25%. In Africa, measles is the leading cause of blindness in children.

Rubella

The prognosis is good in cases of postnatal rubella. In cases of CRS, the prognosis is more guarded, depending on the severity of the manifestations.

Complications of rubella infection occur more frequently in adults than in children. Arthritis or arthralgias occur in as many as 70% of adult women  with rubella. Joint involvement occurs at the same time as the rash and may last as long as 1 month. Encephalitis is observed in one in 5000 cases, more often in adults than in children; rates of death related to encephalitis in the setting of rubella have ranged from 0% to 50%. Hemorrhagic complications occur in approximately one in 3000 cases, manifesting more often in children than in adults. Thrombocytopenic purpura is common and likely due to low levels of platelets and vascular damage. GI and cerebral hemorrhage may also occur.

Congenital rubella syndrome

In 1964, 12.5 million cases of rubella were reported, including 20,000 infants born with CRS. In early pregnancy, rubella infection can lead to serious complications, including fetal death, premature delivery, and congenital defects. Spontaneous abortions and stillbirths are common. As many as 85% of fetuses infected during the first trimester are affected. Complications are rare when rubella infection occurs after the 20th week of pregnancy.

All organ systems may be affected in CRS. Although some investigators have reported developmental defects (eg, enamel hypoplasia and delayed eruption of deciduous teeth), others have questioned the validity of such findings in CRS. Deafness is the most common, and occasionally the only, manifestation of congenital rubella infection. Ocular defects (eg, glaucoma, cataracts, and retinopathy) are possible sequelae. Cardiac defects (eg, patent ductus arteriosus, ventricular septal defect, pulmonary stenosis, and coarctation of the aorta) may be observed. Neurologic manifestations (eg, microcephaly and intellectual disability) are also potential complications.

For patient education resources, see the Oral Health Center and the Infections Center, as well as the patient education articles Oral Herpes, Canker Sores, Measles, Mumps, Coxsackievirus, Chemical Burns, and Allergic Reaction.

Human papillomavirus infection

Patietns should be educated regarding the etiology and the route of transmission to prevent reinfection. This should include information about safer genital, anal, and oral sex.

Given the association between sexual behavior and the rate of HPV infection as measured by HPV detection in oral rinses (discussed above), oral HPV must be considered a sexually transmitted virus. Counseling of patients by healthcare providers is required; this must include informing the patients of the up-to-date knowledge on the mode of transmission of oropharyngeal HPV and the possible risks associated with it. This issue is pertinent to deciding on HPV vaccination, especially for male patients. For this reason, younger adolescents and their parents should be included in counseling efforts.

The involvement of dentists in this educational process has been a relatively new direction for these providers, who had not traditionally discussed sexual matters with their patients. At a 2009 consensus meeting, the oral and maxillofacial pathology section of the American Dental Education Association decided that when a dentist and a patient discuss the patient’s history, this should include a discussion of possible exposure to high-risk HPV types, as well as information about safer sex practices, for all patients judged to be sexually active. 

Mumps

Parents of children with mumps should be informed that their children should not attend school or daycare centers until 9 days after the onset of parotitis.

When attempting to control outbreaks, schools should exclude susceptible students from attending affected schools; the susceptible students may return to school after immunization. Students who are exempt from mumps vaccination for medical, religious, or other reasons should avoid affected schools for at least 26 days after the onset of parotitis in the last person who was infected.