6: Viral Infections of the Oral Cavity

Viral Infections of the Oral Cavity

The Latin word virus means venom or poison. Viruses are ultramicroscopic, metabolically inert, infections organism. They live and multiply in the living cells. Viruses are almost infinite in distribution, affecting not only plants and animals, including man, but also insects and even bacteria. The size of viruses has been measured by various techniques and ranges between 10 millimicrons or less to more than 200 millimicrons. Virus consists of a central core of DNA or RNA (but never both) surrounded by a capsid made up of proteins or an ensheathed outer envelope made of glycoproteins and lipids derived from the host cell membranes. It has been suggested that virally infected cells produce the nucleic acid characteristics of the virus and that, therefore, the susceptibility of cells to viral infection may depend upon the availability of suitable nucleic acid within the cell to sustain the virus.

Viruses have long been known to cause certain infectious diseases, and many of them produce a long-lasting immunity against reinfection by the same virus. In addition, there are many neoplasms in animals that have been transmitted by cell free extracts of the tumor to other animals, establishing a viral etiology. More recent proof of the viral origin of certain animal leukemias has given impetus of the search for specific viruses in the cause of human cancer and the possibility of immunization against this disease.

The classification of viral diseases is difficult because of the size of viruses and their incompletely understood metabolic systems. However, their classification based on the biologic, chemical and physical properties of the animal viruses, separating them into groups according to the type of nucleic acid, and the size, shape and substructure of the particle, has been undertaken by the International Committee on Nomenclature of Viruses of the International Association of Microbiological Societies. This classification, with examples of human diseases in the various groups, is shown in Table 6-1.

Diagnostic confirmation of viral infection by laboratory investigations is slow and difficult. Thus, most viral infections are diagnosed by their clinical presentation.

Herpes Simplex: (Acute herpetic gingivostomatitis, herpes labialis, fever blisters, cold sores)

Herpes simplex, an acute infectious disease, is probably the most common viral disease affecting man, with the exception of viral respiratory infections. The tissues preferentially involved by the herpes simplex virus (HSV), often referred to as herpes virus hominis, are derived from the ectoderm and consist principally of the skin, mucous membranes, eyes, and the central nervous system. HSV is composed of double stranded DNA, protein capsid, tegument and lipid envelope, which contains glycoproteins derived from the nuclear membrane of host cells. There are two immunologically different types of HSV: type 1 and type 2. They differ antigenically and biologically, but share 50% of the nucleotide sequence. Many types of specific regions exist in both HSV 1 and 2 and are responsible for host immunity. These subtypes can be distinguished serologically or by restriction endonuclease analysis of the DNA. A state of latency and reactivation is common in many viral infections, especially the herpes group. The incubation period is 1–26 days and can occur throughout the year. Transmission is mainly through close contact, kissing, sharing of glasses, cutlery or crockery, etc.


The primary HSV infection is usually acquired through direct contact with affected area or through secretions. The virus once attached to the cells at inoculation site through specific receptors; it replicates too many virions to the maximum number and discharges to neighboring cells. Subsequently it affects adjacent cells, spreads to distant sensory nerve endings and autonomic axons, further to adjacent related ganglia, and remains latent there. The lymph node is involved through viral proteins by mobile dendritic cells and begins its primary immune response. The reason for the wide anatomical distribution and multiple crops may be due to descending spread of virions back to periphery from various neuronal site. Initial or primary infection is asymptomatic and occurs commonly in childhood or infancy. This disease manifests as characteristic vesicles containing desquamated cells, multinucleated giant cells, and free viruses with edema fluid. Though both subtypes produce orofacial and genital lesions, which are clinically indistinguishable, HSV-1 predominantly affects the face, lips, the oral cavity, and upper body skin; and HSV-2 usually affects the genitals and skin of the lower half of the body. Primary infection resolves and the virus can no longer be recovered from ganglia but viral DNA can be found in the ganglion cells. Both humoral and cell mediated immunity is responsible for the clinical manifestation, latency, and recurrence of the disease. Immune-compromised individuals, especially with impaired cellular immunity, are more prone for dissemination and recurrence of the primary disease.

An in-depth summary of the structure, composition, growth cycle, and cytopathogenic effects of HSV-1 has been published by Hicks and Terezhalmy. Gruter was among the first to offer evidence that the herpes simplex infection was caused by an infectious agent and that the fluid of vesicles from patients with herpes simplex would produce keratitis when inoculated on scarified rabbit cornea. Subsequently, the virus has been found to multiply well on the chorioallantoic membrane of the chick embryo. Andrews and Carmichael, in 1930, found that neutralizing antibodies against the herpes simplex virus were present in the circulating blood of most normal adults and persisted throughout life, but that recurrent herpetic lesions frequently developed in these persons.

These and other studies have finally led to the established principle that two types of infection with the herpes simplex virus occur. The first is a primary infection in a person who does not have circulating antibodies, and the second is a recurrent infection in persons who have such antibodies. It is impossible to differentiate clinically between the lesions of a primary and a recurrent attack, although the primary infection is accompanied more frequently by severe systemic manifestations and is occasionally fatal. It has been shown; however, that most adults have circulating antibodies in the blood, but have never exhibited a severe primary illness. Thus, it is reasoned, subclinical primary infections must be common. The relation between the primary and secondary forms of the herpes simplex infection is shown in Figure 6-1.

Herpes genitalis, caused by HSV-2, is a relatively common disease of the uterine cervix, vagina, vulva, and penis. The incidence of this form of the infection has increased precipitously in the United States within the past decade, and in fact, is now often termed the ‘new epidemic venereal disease,’ since it is transmitted through sexual contact. This virus differs immunologically from type 1 herpes virus, which is responsible for most cases of herpetic infection of the oral cavity. The type 2 virus of genital herpes is somewhat more virulent than type 1, and significantly, has been associated repeatedly with carcinoma of the uterine cervix, thus suggesting a possible cause and effect relationship. However, because of changing sexual practices, there has been rather widespread translocation in the usual habitats of type 1 and type 2 HSV. Thus, it is not unusual today to find HSV-2 on the lips or oral mucous membranes and HSV-1 on the genitalia.

Herpetic meningoencephalitis is a serious form of this infection, characterized by sudden fever and symptoms of increased intracranial pressure. Paralysis of various muscle groups occurs, while convulsions and even death may ensue. It is difficult to differentiate clinically between meningoencephalitis caused by the herpes virus and that produced by other viruses.

Herpetic conjunctivitis, or keratoconjunctivitis, is a rather common disease and is characterized by swelling and congestion of the palpebral conjunctiva, although keratitis and corneal ulceration also may occur. Herpetic vesicles of the eyelids are typical, but these eye lesions usually heal rapidly.

Herpetic eczema (Kaposi’s varicelliform eruption) is an epidermal form of the herpetic infection superimposed upon a pre-existing eczema (possibly an example of anachoresis) and is characterized by diffuse vesicular lesions of the skin, usually of an extremely serious nature. In addition to this atopic dermatitis, the herpetic infection may also be superimposed on severe seborrheic dermatitis, impetigo, scabies, Darier’s disease, and pemphigus vulgaris or foliaceus. It is most frequently due to the primary herpetic attack and may be fatal. The patients, usually children, exhibit a high fever, coincident with the typical umbilicated vesicles as well as other systemic manifestations.

Disseminated herpes simplex of the newborn is a relatively uncommon disease in which the newborn baby acquires the infection during passage through the birth canal of a mother who is suffering from herpetic vulvovaginitis. However, occasional cases of transplacental infection by the virus have been reported. These infants usually manifest the disease by the fourth to seventh day of life, exhibit a wide variety of signs and symptoms of the disease and with few exceptions, usually die on the 9th to 12th day of life. Surviving infants frequently show residual neurological involvement.

Herpetic whitlow occurs in fingers due to autoinoculation.

Herpes gladiatorum occurs in wrestlers.

Primary Herpetic Stomatitis

Dodd and her coworkers reported that the herpes simplex virus could be isolated from patients suffering from a gingivostomatitis with a particular clinical configuration. Burnet and Williams reported similar findings, and in addition, demonstrated that infants with this disease developed circulating antibodies during the convalescent period.

Clinical Features

Herpetic stomatitis is a common oral disease transmitted by droplet spread or contact with the lesions. It affects children and young adults. However, it has been suggested by Sheridan and Herrmann that the primary form of the disease is probably more common in older adults than was once thought. It rarely occurs before the age of six months, apparently because of the presence of circulating antibodies in the infant derived from the mother. The disease occurring in children is frequently the primary attack and is characterized by the development of fever, irritability, headache, pain upon swallowing, and regional lymphadenopathy. Within a few days, the mouth becomes painful and the gingiva which is intensely inflamed appears erythematous and edematous. The lips, tongue, buccal mucosa, palate, pharynx, and tonsils may also be involved. Shortly, yellowish, fluid-filled vesicles develop. These vesicles rupture and form shallow, ragged, extremely painful ulcers covered by a gray membrane and surrounded by an erythematous halo (Fig. 6-2). It is important to recognize that the gingival inflammation precedes the formation of the ulcers by several days. The ulcers vary considerably in size, ranging from very tiny lesions to lesions measuring several millimeters or even a centimeter in diameter. They heal spontaneously within 7–14 days and leave no scar.

Utilizing culture techniques, August and Nordlund found that the HSV-1 could be isolated from facial, labial, and oral herpetic lesions for a mean duration of three-and-a-half days, with a range of 2–6 days, after the onset of the lesions, while HSV-2 could be isolated from genital lesions for a mean duration of five-and-a-half days, with a range of 2–14 days, after onset. They also noted that viral persistence in lesions did not seem to differ between mild primary infection and recurrent infection. In addition, Turner and his colleagues have shown that HSV could survive for two to four hours on environmental surfaces such as cloth and plastic as well as on the skin of the hands contaminated by direct contact with labial or oral lesions.

It is now well established that the HSV does not remain latent at the site of the original infection in the skin or oral mucosa. Instead, the virus reaches nerve ganglia supplying the affected areas, presumably along nerve pathways, and remains latent there until reactivated. The usual ganglia involved are the trigeminal for HSV-1 and the lumbosacral for HSV-2. Viral DNA can be demonstrated in these ganglia. Unfortunately, this incorporation of viral DNA into host DNA ensures a lifelong infection beyond the reach of antibody, cell mediated immune responses or chemotherapy.

Mode of Transmission

The fact that the herpes virus may be recovered from the saliva of patients during the course of the disease leads to the assumption that transmission may occur by droplet infection, although some workers believe that direct contact is necessary. There is no animal reservoir for this virus. It has been reported in one series of patients that a history of contact with affected persons was present in nearly 50% of the cases. After such contact, the incubation period appears to range from 2–20 days, with an average of six days before development of lesions. There also have been occasional epidemics of herpetic stomatitis, such as that reported by Hale and his associates in an orphanage nursery. In addition, it has been noted that primary herpetic eruptions are commonly associated with pneumonia, meningitis, and common cold.

Histologic Features

The herpetic vesicle is an intraepithelial blister filled with fluid. The infected cells are swollen and have pale eosinophilic cytoplasm and large vesicular nuclei, described as ‘ballooning degeneration,’ while others characteristically contain intranuclear inclusions known as Lipschütz bodies. These are eosinophilic, ovoid, homogeneous structures within the nucleus, which tend to displace the nucleolus and nuclear chromatin peripherally. The displacement of chromatin often produces a peri-inclusion halo. Cytoplasm of the infected cells forms giant cells. The subjacent connective tissue is usually infiltrated by inflammatory cells. When the vesicle ruptures, the surface of the tissue is covered by exudates made up of fibrin, polymorphonuclear leukocytes, and degenerated cells. The lesions heal by peripheral epithelial proliferation.


Antiviral drugs have significant impact on the course of the disease, if it is diagnosed early. Antibiotic therapy helps in the prevention of secondary infection. Nonsteroidal anti-inflammatory drugs and topical anesthetic gel may relieve the discomfort considerably.

Recurrent or Secondary Herpetic Labialis and Stomatitis

Recurrent herpetic stomatitis is usually seen in adult patients and manifests itself clinically as an attenuated form of the primary disease. It has been reported by Nahmias and Roizman that between 80 and 100% of adults in the lower socioeconomic levels have HSV-1 and/or HSV-2 circulating antibodies, whereas only 30–50% of adults in the higher socioeconomic levels, including medical, dental, and nursing personnel, have such antibodies. Those without antibodies are at higher risk of contact and infection, especially the latter groups because of the nature of their occupation. Also, as pointed out by Rowe and his coworkers, recurrent lesions of the fingers or hands (herpetic whitlow) and eyes may be encountered in these professional groups more frequently than in the general population.

The recurrence is related to reactivation of infection and various theories namely (i) ganglionic trigger theory due to nerve section, surgery, or fever (ii) skin trigger theory due to UV light or trauma and (iii) emotional theory due to stress, have been put forward for reactivation. The recurrent form of the disease is often associated with other factors like fatigue, menstruation, pregnancy, upper respiratory tract infection, allergy, or gastrointestinal disturbances. The mechanism through which these various precipitating factors elicit an outbreak of lesions is unknown. The viruses, once introduced into the body, appear to reside dormantly within the regional ganglia, and when reactivation is triggered, spread along the nerves to sites on the oral mucosa and skin where they destroy the epithelial cells and induce the typical inflammatory response with the characteristic lesions of recurrent infection.

Clinical Features

Recurrent herpes simplex infection may occur at widely varying intervals, from nearly every month in some patients to only about once a year or even less in others. The lesions may develop either at the site of primary inoculation or in the adjacent area supplied by the involved ganglion. It may develop on the lips (recurrent herpes labialis, Fig. 6-3) or intraorally (Fig. 6-4). In either location, the lesions are frequently preceded by a burning or tingling sensation and a feeling of tautness, swelling or slight soreness at the location in which the vesicles subsequently develop. These vesicles are generally small (1 mm or less in diameter), tend to occur in localized clusters, and may coalesce to form somewhat larger lesions. These gray or white vesicles rupture quickly, leaving a small red ulceration, sometimes with a slight erythematous halo. On the lips, these ruptured vesicles become covered by a brownish crust. The degree of pain present is quite variable.

It has been emphasized by Weathers and Griffin that the recurrent intraoral herpetic lesions almost invariably develop on the oral mucosa that is tightly bound to periosteum. Seldom do they occur on mobile mucosa, in contrast to the recurrent aphthous stomatitis (q.v.) which almost invariably occurs only on mobile mucosa. Thus, the most common sites for the recurrent intraoral herpetic lesions are the hard palate and attached gingiva or alveolar ridge. Interestingly, herpes labialis is seldom seen concurrently with intraoral lesions.

The lesions gradually heal within 7–10 days and leave no scar.

Histologic Features

A number of investigators, beginning with Blank and his associates, have shown that the Papanicolaou smear, using fresh scrapings from the base of a vesicle, is a reliable technique for the diagnosis of active herpes simplex infection if herpes zoster/varicella infection is ruled out, since no other conditions produce a similar cytopathic effect. ‘Ballooning degeneration,’ chromatin margination and typical Lipschütz bodies as described earlier are all seen in smears from these lesions, as well as characteristic multi-nucleated giant cells originally observed by Tzanck (Fig. 6-5). Nowakovsky and her coworkers have thoroughly reviewed the manifestations of viral infections in exfoliated cells. The histologic findings in biopsy specimens from the recurrent lesions are identical to those described under the primary form of the disease.

Laboratory Findings

Isolation of the herpes simplex virus can be accomplished in tissue culture, particularly in the early stages of the recurrent infection. According to Tokumaru, the virus is easily isolated when there is a low production of γ-A globulin, but there is a rapid clearing of the virus, often within one day, after a rebound production of γ-A globulin. Similarly, smears would be positive for only a short time after the virus has cleared because of the rapid degeneration of the affected cells.

Current diagnostic methods for herpes viral diagnosis have been reviewed by Burns. These have included:

Herpangina: (Aphthous pharyngitis, vesicular pharyngitis)

Herpangina is a specific viral infection, which was described by Zahorsky in 1920 and later named by him. Studies by Huebner and coworkers proved that Coxsackie group A viruses are the cause of the disease, with types 1 through 6, 8, 10, 16, and 2, as well as other enteroviruses, being isolated at various times. Infection occurs through ingestion, direct contact, or through droplet spread and multiple cases in a single household are common.

Clinical Features

The incubation period is probably 2–10 days. It is most commonly seen in young children; older children and adults are only occasionally affected. Herpangina is chiefly a summer disease, and many children may actually harbor the virus at this time without exhibiting clinical manifestations of the disease.

The clinical manifestations of herpangina are comparatively mild and of short duration. It begins with sore throat, cough, rhinorrhea, low-grade fever, headache, sometimes vomiting, prostration, and abdominal pain. The patients soon exhibit small vesicles which rupture to form crops of ulcers, each showing a gray base and an inflamed periphery on the anterior faucial pillars and sometimes on the hard and soft palates, posterior pharyngeal wall, buccal mucosa; and tongue (Fig. 6-6). Vesicles preceding the ulcers are small and of short duration, and are frequently overlooked by the examiner. The ulcers do not tend to be extremely painful, although dysphagia may occur. The systemic symptoms resolve within few days. Ulcers generally heal within 7–10 days.

Children have been affected several times in one season by infection with different strains of the Coxsackie virus. A permanent immunity to the infecting strain usually develops rapidly, and most adults have neutralizing antibodies against numerous strains.

Acute Lymphonodular Pharyngitis

Acute lymphonodular pharyngitis is an acute febrile disease, first reported by Steigman and coworkers in 1962. It is caused by a strain of Coxsackie virus A10. The first recognized outbreak of the disease occurred in the vicinity of Louisville and Fort Knox, Kentucky, during the fall of 1960. Since then it has been recognized as occurring with a wide distribution. Delay in recognition of the disease as an entity may have occurred because of the marked resemblance between this and herpangina.

Hand, Foot and Mouth Disease

Hand, foot and mouth disease is an epidemic infection, first reported by Robinson and coworkers in 1958. It is caused by the enterovirus Coxsackie A16 and has been reported to be caused less frequently by types A5 and A6, and occasionally even by B2, B5 or enterovirus 71. This first recognized outbreak of the disease occurred in Toronto, Canada, but since then it has appeared in many parts of the United States, as well as in many other countries around the world. Despite the similarity in names, it bears no relationship to foot-and-mouth (hoof-and-mouth) disease, another viral disease with an animal vector.

Foot-and-Mouth Disease: (Aphthous fever, hoof-and-mouth disease, epizootic stomatitis)

Foot-and-mouth disease is a viral infection, which only rarely affects man, but does affect dogs and sheep as well as cattle. Transmission of the disease occurs through contact with infected animals; in human beings this is usually through the use of milk from affected animals or through the handling of tissues from these animals. An excellent review of foot-and-mouth disease in human beings was published by Roset. This disease should not be confused in nomenclature with hand, foot and mouth disease, a Coxsackie virus infection previously discussed.

Measles: (Rubeola, red spots, morbilli)

Measles is an acute, contagious, dermatropic and endemic viral infection, primarily affecting children and occurring many times in epidemic form. It is caused by paramyxovirus belonging to the family paramyxoviridae, which is a RNA virus. Outbreaks are often cyclic in their appearance and are seen commonly at two- or three-year intervals. Spread of the disease occurs by direct contact with an affected person or by droplet infection, the portal of entry being the respiratory tract.


Measles has a worldwide distribution but incidence is more in developing countries. In Asia, incidence was reduced after the introduction of a vaccine schedule, but resurgence of measles may be due to failure to immunize infants and young children, and failure of vaccination or waning immunity. The mortality rate is high among children and adults. It varies from 1–10% in developing countries. It is contagious from first or second day even before the onset of serious illness or appearance of rash. It is transmitted mainly through respiratory secretions and also through direct contact of droplets. The incubation period is generally from 8–12 days. It is mainly transmitted in large families, crowded homes and slums. It is a self-limiting disease in healthy immune competent children, but morbidity and mortality is high in malnourished and immunocompromised individuals.

Oral Manifestations

The oral lesions are prodromal, frequently occurring two to three days before the cutaneous rash, and are pathognomonic of this disease. These intraoral lesions are called Koplik’s spots and have been reported to occur in as high as 97% of all patients with measles. The Koplik’s spots are white papules resembling table salt like crystals with red base which appear usually on the buccal mucosa opposite to first and second molar teeth. Immune reaction to the virus in the endothelial cells of dermal capillaries plays a role in the development of spots. The spots disappear after the onset of rash. In actual practice, they are seldom seen unless the affected child has had a known contact with measles and the dentist or parent watches carefully, since the child is often well at the time they appear. These characteristic spots are small, irregularly shaped flecks which appear as bluish, white specks surrounded by a bright red margin. These macular lesions increase in number rapidly and coalesce to form small patches. Palatal and pharyngeal petechiae as well as generalized inflammation, congestion, swelling, and focal ulceration of the gingiva, palate and throat may also occur.

Histopathological features show pathognomonic multinucleated giant cells called Warthin–Finkeldey giant cells.

Rubella: (German measles)

Rubella or the German measles should not be confused with rubeola. In rubella, Koplik’s spots do not occur, and the oral mucous membranes are not usually inflamed, although the tonsils may be somewhat swollen and congested and red macules may appear on the palate. Complications following this disease are rare except when the disease occurs in women during the first trimester of pregnancy. In such cases, the offspring has a high incidence of congenital defects such as blindness, deafness, and cardiovascular abnormalities, if miscarriage does not occur.

Occasionally reports in the literature have suggested that rubella affecting women during the first trimester of pregnancy can cause a number of developmental defects, including enamel hypoplasia, a high caries incidence, and delayed eruption of deciduous teeth. However, a study by Grahnen provided some evidence that maternal rubella did not give rise to any clinically detectable defects in either the deciduous or permanent dentition of the offspring.

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Jan 12, 2015 | Posted by in Oral and Maxillofacial Pathology | Comments Off on 6: Viral Infections of the Oral Cavity

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