Essential Microbiology for Dentistry. 5th ed.

Chapter 21. Viruses of relevance to dentistry

This chapter gives an outline of the viruses that are of special relevance to dentistry. The DNA viruses are described first, followed by the RNA viruses (see Table 4.1).

DNA viruses

Papovaviruses

These DNA viruses infect both humans and animals; however, human disease is infrequent.

Human papillomavirus

Human papillomavirus (HPV) mainly causes skin warts (ver- rucae); it is also associated with a number of lesions including oral papillomas, oral verrucous carcinomas and focal epithelial hyperplasia. There are more than 70 serological types of HPV, some of which are more closely associated with lesions (both benign and cancerous) than others.

Skin warts

 Clinical features: warts typically are benign epithelial tumours. Specific serological types of HPV are associated with anogenital warts (condylomata acuminata) and are seen in all cervical biopsies that show precancerous change.

 Epidemiology: warts are generally more common in children than in adults. The virus is likely to be transmitted by direct contact or autoinoculation.

Oral infections with HPV

Over 40% of healthy individuals have HPV in the normal oral mucosa, suggesting that this is a reservoir of the virus.

Oral squamous papillomas and warts

 Clinical features: most are single, small (1 cm), pedunculated, exophytic lesions (Fig. 21.1). They rarely, if ever, progress to carcinomas.

 Epidemiology: occur mainly in the third to fifth decade of life, with a male preponderance.

Verrucous carcinoma

There is evidence to indicate that HPV is associated with human carcinomas, on the basis of:

 the frequent malignant change in virus-induced warts in epidermodysplasia verruciformis

 the frequent association of HPV-16, -18 and -33 with invasive cervical cancer

 development of cancer in vulvar warts in women with lymphoma.

Adenoviruses

These DNA viruses induce latent infections of the tonsils, adenoids and other lymphoid tissues of humans. However, most infections caused by adenoviruses are acute and self-limiting.

Adenoviral diseases

Acute respiratory disease is the most common adenovirus infection. It is an influenza-like illness seen commonly in military training camps. Clinically, the main symptoms are pharyngitis and conjunctivitis. Although self-limiting, acute respiratory disease may be complicated by pneumonia in some cases. Other infections caused by these viruses include pharyngoconjunctival fever (a disease of infants and children), epidemic keratoconjunctivitis, pneumonia and gastroenteritis.

Epidemiology

Adenoviruses are ubiquitous, and human beings are the only known reservoir for the human strains. The infections are spread from person to person by respiratory and ocular secretions. Adequate chlorination of pools may help decrease the spread of pharyngoconjunctival fever.

Fig. 21.1 a papilloma at the angle of the mouth.

Herpesviruses

There are a range of different human herpesviruses (HSVs), currently numbered 1-8 (Table 21.1). All of them are structurally similar (enveloped, icosahedral with double-stranded DNA) and infect both humans and animals. They are the most common causes of human viral infections. All have the important property of remaining latent, with the ability to re-infect the host a variable period after the primary infection. Important human pathogens include herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV) and cytomegalovirus (CMV; see Chapter 4). Students of dentistry should be thoroughly conversant with the herpes group of viruses as the majority of them either cause oral infection or are intimately associated with orofacial tissues and saliva.

Structure

See Chapter 4.

HSV (human herpesviruses 1 and 2)

There are two types of HSV: human herpesvirus type 1 (HSV-1) and type 2 (HSV-2). They can be differentiated by serotyping, by DNA homology and, to some extent, by clinical disease pattern.

Clinical disease

Disease due to HSV can be either a primary infection, due to first encounter with the virus, or a reactivation or recurrent infection, due to activation of the latent virus.

Primary infection

There is an incubation period of 2-20 days, depending upon the infected site and the infecting strain of virus. The lesions include:

 primary gingivostomatitis with lesions on the lips and mouth; very common (see Chapter 35)

Fig. 21.2 A herpetic whitlow in a dentist caused by herpes simplex virus.

 genital herpes: vesicular eruption of the genitalia, mostly due to HSV-2 (but up to a third of the cases may be due to HSV-1)

 herpetic whitlow: infection of the fingers, acquired by dentists and nurses as a result of contamination of the hands by virus-laced saliva or other secretions (Fig. 21.2)

 conjunctivitis and keratitis: less commonly, HSV infections involve the eyes, sometimes leading to blindness

 encephalitis: a result of either primary or recurrent infection; may lead to permanent defects or death.

Recurrent infections

Recurrence or reactivation of HSV entails activation of the non-infectious form of the latent virus residing in the neurons of either the trigeminal ganglion (Fig. 21.3) or the sacral ganglia. Reactivation is provoked by menstruation, stress, sunlight (possibly ultraviolet rays), local trauma, etc.; the lesions tend to recur at the site of the primary lesion. HSV has been implicated in Bell's palsy.

Epidemiology

Humans are the only known reservoir for HSV-1 and HSV-2; experimental infection can be induced in animals and cell cultures. As the virus is highly labile, most primary infections are acquired through direct contact with a lesion or contaminated secretions. In general, HSV-1 causes orofacial lesions or lesions 'above the belt', whereas HSV-2 causes lesions 'below the belt', that is, genital herpes (Fig. 21.4). However, because of sexual promiscuity or for other reasons, this may not be always true. HSV-1 is acquired early in life, whereas HSV-2 appears after the onset of sexual activity.

As recurrent infection is common in the presence of high antibody titres, circulating antibodies appear to be unhelpful in controlling HSV infection. One reason for this may be the contiguous cell-to-cell spread of the virus, which cannot be prevented by antibody. Reactivation is not accompanied by a rise in herpes antibody titre.

Diagnosis

Diagnosis is usually achieved clinically; laboratory diagnosis is useful to confirm infection, especially in compromised patients. This entails:

■ performing polymerase chain reaction (PCR) assays, which are sensitive and specific assays that are now commonly used for diagnosis; the most reliable diagnostic method

 direct demonstration of viral antigens in vesicular fluid or scrapings by electron microscopy or immunofluorescence (Fig. 21.5)

 demonstration of characteristic multinuclear giant cells in scrapings from lesions, simple but not always successful

 propagation of virus in tissue culture.

However, the foregoing traditional techniques are now supplanted by PCR-based rapid diagnostic methods.

Fig. 21.3 Herpes labialis: (A) recurrence of facial herpes infection due to reactivation of the latent virus in the trigeminal ganglion; (B) clinical presentation of herpes labialis on the mucocutaneous junction of the upper lip.

Fig. 21.5 Positive immunofluorescence of a smear taken from the lip lesion shown in Fig. 21.3B (stained with anti-herpes antibody tagged to a fluorescing chemical), indicating that the patient has herpes labialis.

Prevention

Control is difficult because of the high frequency of asymptomatic infection. It is important to avoid contact with acute herpetic lesions and contaminated body fluid (e.g., saliva) by routine wearing of gloves. No vaccine is available.

Treatment

The course of primary infection can be altered significantly with drugs that interfere with viral DNA synthesis, such as aciclovir and vidarabine, but these should be administered in the early prodromal phase of the disease for best results (see also Chapter 35).

Varicella-zoster virus (human herpesvirus 3)

This organism causes both varicella (chickenpox) and herpes zoster (shingles): two different diseases due to an identical organism. Chickenpox is the primary infection, and herpes zoster is the reactivation of illness.

Fig. 21.4 Predominant distribution of infection with herpes simplex virus types 1 and 2 (HSV-1 and HSV-2, respectively), in different age groups.

Clinical disease

Varicella

A common childhood fever, varicella is mild and self-limiting. The disease is more severe if contracted in adulthood. After a 2-week incubation period, fever develops, followed by a papular rash of the skin and mucous membranes, including the oral mucosa. The papules rapidly become vesicular and itchy but painless (in contrast to the rash in zoster).

Zoster (shingles)

Occurs primarily as a reactivation of the virus in dorsal root or cranial nerve (usually trigeminal) ganglia (Fig. 21.6). The disease usually affects adults, and the virus is reactivated despite circulating antibodies. Zoster is triggered by trauma, drugs, neoplastic disease or immunosuppression.

The virus remains latent in ganglionic nerve cells and, after activation, travels back along the nerve fibre to the skin. Thoracic nerves supplying the chest wall are most often affected, and the lesion presents as a unilateral, painful vesicular rash, which extends in a horizontal strip from the middle of the back around the side of the chest wall (belt of roses from hell). Fever and malaise accompany the lesion. The rash may last for 2-4 weeks, with pain (post-herpetic neuralgia) persisting for weeks or months.

Fig. 21.6 pathogenesis and sequelae of varicella-zoster virus (VZV) infection.

The trigeminal nerve is affected in about 15% of cases, with involvement of the ophthalmic, maxillary and mandibular divisions (in that order of precedence). Severe localized oral pain precedes the rash and may be easily confused with toothache (see Chapter 35). Involvement of the ophthalmic nerve may lead to eye lesions and sometimes blindness.

Ramsay Hunt syndrome is a rare manifestation of zoster, with a vesicular rash on the tympanic membrane and the external auditory canal, together with unilateral facial nerve palsy.

Epidemiology

Shingles is primarily a disease of older adults and immunocompromised persons; it is rare in children. The incidence increases with advancing age and with decreasing degree of immunocompetence. It is a highly contagious infection in a host not previously exposed to the virus. Transmission occurs by direct contact with skin lesions or droplet infection from infectious saliva.

Diagnosis

The clinical picture is pathognomonic, as the lesion distribution overlaps and accurately maps the distribution of the sensory nerve (Figs 21.7 and 21.8). Laboratory diagnostic methods include:

 Sensitive and specific PCR.

 Serology if needed, entails detecting a fourfold rise in antibody titre in paired sera (compare herpes simplex reactivation, where antibody rise is not significant).

Fig. 21.7 Herpes zoster infection of the tongue in an elderly patient: note the sharp midline demarcation of the lesion (due to reactivation of the virus travelling via the lingual branch of the right trigeminal nerve).

Fig. 21.8 Vesicular rash of herpes zoster infection of the dermatome of the right mandibular division of the trigeminal nerve in an elderly patient. Note the sharp demarcation of skin infection accurately reflecting the distribution of the nerve, a feature pathognomonic of herpes zoster infection.

 Cytopathology investigations include staining (Tzanck smear) a scraping from the base of vesicles for the presence of multinucleated giant cells.

Treatment

Chickenpox is self-limiting and requires symptomatic treatment, if any. Disseminated zoster in immunocompromised patients requires antiviral drugs (e.g., aciclovir, vidarabine), which interfere with herpesvirus DNA replication. VZV is less sensitive to aciclovir than is HSV, and hence, a higher dosage is required; therapy should start within 72 h of onset. Systemic acyclovir may reduce the duration of the early infective phase and the associated pain. In addition, it may reduce the prevalence of post-herpetic neuralgia.

Prevention

Passive immunization with varicella-zoster immune globulin (VZIG) may be indicated for persons at high risk of severe infection. A vaccine for chickenpox, which is extremely effective against developing severe disease, is now available. An efficacious new vaccine for herpes zoster is also available for adults with chronic medical conditions and recurrent sufferers.

EBV (human herpesvirus 4)

EBV is widespread in humans. Up to 20% of healthy adults will yield virus-positive throat washings, and most adults have antibody to the virus; it is present in the saliva of many immunosuppressed patients. The virus persists in latent form within lymphocytes after primary infection (lymphotropic, unlike HSV and VZV, which are neurotropic). The genome resides in a latent form in B cells; latent EBV infection is common in the population. It is the aetiological agent of a number of diseases:

 infectious mononucleosis (glandular fever)

 Burkitt's lymphoma and other B cell lymphomas

 nasopharyngeal carcinoma (especially in southern Chinese populations)

 oral hairy leukoplakia

 post-transplant lymphoproliferative diseases.

Infectious mononucleosis

An acute infection affecting lymphoid tissue throughout the body, infectious mononucleosis is commonly seen in teenagers, with a peak incidence at 15-20 years of age. The organism is present in saliva and is postulated to be transmitted during kissing, and hence it is called the 'kissing disease'.

Incubation period

Incubation is 4-7 weeks; possibly shorter (10-40 days) in young children.

Signs and symptoms

Low-grade fever with generalized lymphadenopathy and abnormal lymphocytes in the blood (note that a similar illness, glandular fever-like syndrome, develops during the first fortnight after infection with human immunodeficiency virus (HIV)). Fever, tonsillitis and fatigue are common, and many patients have splenomegaly. Lymphocytosis is a characteristic feature, hence the term 'mononucleosis'; some 10% of the lymphocytes are atypical, with enlarged misshapen nuclei and increased cytoplasm (Fig. 21.9).

Chronic, persistent or reactivated EBV infection

This may take many clinical forms and is less common than acute mononucleosis, described earlier. The syndrome is characterized by persistent fatigue, with or without physical or laboratory findings.

Epidemiology

The virus is ubiquitous, and humans are its only known host. Spread of EBV is via respiratory secretions, primarily through oral contact. Those from lower socioeconomic classes are exposed to EBV at an early age and typically develop asymptomatic infections, whereas in higher socioeconomic classes, particularly in developed countries, primary infection is usually delayed to adolescence or young adulthood.

Fig. 21.9 Infectious mononucleosis: characteristic blood film with many mononuclear cells.

Diagnosis

As EBV cannot be easily propagated in culture, serological diagnosis is common:

 PCR assays have supplanted traditional virus isolation techniques.

 Indirect immunofluorescence is used to detect EBV-specific immunoglobulin M (IgM); the antibody is directed against both the capsid antigen and a non-capsid early antigen.

 Haematology: a blood film is useful for demonstrating atypical lymphocytosis in infectious mononucleosis.

 Serology: heterophile antibody (non-specific): infectious mononucleosis is characterized by the appearance of heterophile (hetero: other, phile: liking) antibodies in the patient's serum, which agglutinate sheep or horse red blood cells. This property is made use of in the Paul- Bunnell diagnostic test.

Treatment

Infectious mononucleosis is generally mild and self-limiting; hence, therapy is usually symptomatic.

Burkitt’s lymphoma

Burkitt's lymphoma is a highly malignant tumour that spreads rapidly, with widespread metastases; it is particularly common in African children. The disease is especially common in areas of Africa with endemic malaria. Hence, it is thought that the effect of the malarial parasite on the reticuloendothelial system could cause an abnormal response to infection with EBV. Under these conditions, the EBV may become frankly oncogenic, producing a malignant transformation in lymphoid tissue (lymphoma) instead of the benign proliferation seen in infectious mononucleosis.

Nasopharyngeal carcinoma

A tumour with a remarkable geographic and probably racial distribution, it is particularly common among the southern Chinese. EBV DNA is regularly present in the malignant epithelial cells of the tumour.

Hairy leukoplakia

The term 'hairy leukoplakia' is given to raised, white areas of thickening, particularly on the lateral border of the tongue (see Fig. 30.3). Although this new clinical entity was first described in HIV-infected patients, other immunosuppressed patients may develop the lesion, which is very closely associated with EBV. The DNA of EBV is present in the epithelial cells of hairy leukoplakia. The lesion is non-malignant but about a third of HIV-infected individuals who develop hairy leukoplakia may develop acquired immune deficiency syndrome (AIDS) in 3-5 years. Demonstration of EBV in biopsy tissue of hairy leukoplakia is essential for a definitive diagnosis.

CMV (human herpesvirus 5)

CMV rarely causes disease unless other precipitating factors, such as immunocompromising states, are present. However, it can infect the foetus during pregnancy.

Clinical disease

Symptomless infection

The majority of infants show no signs of infection, and diagnosis is made by serology. Although a large proportion of the infants are unharmed, a significant number of neonates with congenital infection show neurological sequelae, such as deafness and mental retardation, later in life. A minority develop a severe, often fatal illness associated with infection of the salivary glands, brain, kidneys, liver and lungs.

Post-natal infection

Later in life, the virus may be activated by pregnancy, multiple blood transfusions or immunosuppression. Infection in immunocompromised patients can be severe and involve many organs, such as the lungs, liver, gastrointestinal tract and eyes.

Epidemiology

Infection appears to increase during the perinatal period and during early adulthood; patients with neoplastic disease or AIDS and transplant recipients often have local and disseminated CMV disease. The route of CMV transmission is not clear.

Diagnosis and treatment

Diagnosis is by viral isolation in human embryonic fibroblast tissue cultures; it is confirmed using immunofluorescence and DNA hybridization.

There are no proven regimens for therapy and prevention of CMV infections.

Human herpesvirus 6 (Roseola virus; herpes lymphotropic virus)

A DNA virus closely related to CMV, human herpesvirus 6 (HHV-6) was originally isolated from peripheral blood cells of immunocompromised patients, such as those with AIDS. The virus shows affinity for T and B cells in particular. Infection with HHV-6 is common in childhood, and most primary infections are asymptomatic followed by latency. The pathogenicity of HHV-6 is as yet unclear. Recently, it has been found in active plaques in patients with multiple sclerosis.

Exanthem subitum (roseola infantum)

A common childhood disorder characterized by mild fever and a facial rash, and appears to be associated with HHV-6 infection. The disease, exanthema subitum is also called roseola infantum, or 'sixth disease'.

Mononucleosis with cervical lymphadenopathy

This is a febrile illness in adults with bilateral cervical lymphadenopathy, somewhat like glandular fever; thought to be a primary infection with HHV-6.

HHV-6 and the oral cavity

The virus is present in the saliva of most healthy adults, and it can also be demonstrated in ductal and alveolar epithelium of major salivary glands. There are no specific oral lesions reported for HHV-6, though erythematous papules seen in soft palate and uvula (Nagayama's spots) and in the pharynx are thought to be due to this organism. No occupational hazard from HHV-6 has been proved in dentistry, but the virus may well be transmitted in saliva.

Human herpesviruses 7 and 8 (Kaposi’s sarcoma-associated herpesvirus)

These viruses have been recently identified: human herpesvirus 7 (HHV-7) is a T-lymphotropic virus and is implicated in rashes; human herpesvirus 8 (HHV-8) is the agent responsible for Kaposi's sarcoma, a vascular endothelial tumour commonly seen in HIV disease (see Chapter 30); it is also implicated in sarcoidosis.

The relatively recent discovery of these new herpesviruses in individuals with HIV disease suggests that there are more herpesviruses yet to be uncovered. These viruses appear to be evolving in humans and primates. HHV-6 and HHV-7, in particular, are found in 70%-90% of the population and hence considered universal herpesviruses.

RNA viruses

Orthomyxoviridae

These RNA viruses cause worldwide epidemics of influenza. They are subdivided into types A, B and C on the basis of the antigenic properties of their major nucleocapsid protein (NP) and viral envelope matrix protein (M protein). In addition to these antigenic differences, they are characterized by a unique mechanism of frequent immunological variations within the subtypes. These variations are due to structural changes in the surface spike glycoproteins: haemagglutinin (H antigen) and neuraminidase (N antigen). The nomenclature of influenza viruses is based on the H and N antigens. For instance, the first pandemic influenza virus was called H1N1 and the current avian flu virus is H5N1. Influenza epidemics are due to the

emergence of a new virus strain containing a haemagglutinin (and sometimes a neuraminidase) that differs from that of previously circulating viruses, so that the population has no (herd) immunity to the new haemagglutinin. Antigenic variation may occur due to:

 antigenic drift, as a result of minor changes in the amino acid sequence of the haemagglutinin. These viruses survive because they are less susceptible to the antibodies most common in the population at the time

 antigenic shift, which constitutes the appearance of a new antigenic type unrelated or only distantly related to earlier types because of genetic reassortment. It occurs infrequently and has only been identified in influenza A (four major antigenic shifts have occurred since 1933). These antigenic shifts are critically important in the production of vaccines for influenza: the vaccine used in previous years may have little or no effect because of these phenomena.

Influenza

Clinical features

Symptoms are sudden and appear 1-2 days after exposure. Major symptoms are high fever, accompanied by myalgia, sore throat, headache, cough and nasal congestion. Pneumonia is the most common serious complication of influenza; it is caused by secondary bacterial infection of the respiratory tract with weakened defences.

Epidemiology

Epidemic illness is common in non-immune or partially immune populations. Transmission occurs by aerosolization and subsequent inhalation of virus-laden respiratory secretions during sneezing and coughing (droplet spread). Rapid spread of illness may occur in confined populations (e.g., nursing homes, classrooms).

Treatment and prevention

Only symptomatic treatment is indicated. Amantadine is helpful for relieving symptoms and enhancing the effectiveness of immunization. The low success rate (about 70%) of the vaccination is mainly due to the difficulty of predicting the proper antigenic profile of the influenza strain; this unfortunately cannot be determined until the onset of the particular disease cycle.

Avian influenza or bird flu (H5N1 virus)

The first known cases of avian influenza caused by H5N1 were discovered in Hong Kong in 1997, and since then, there have been sporadic outbreaks, mainly in South-East Asia. Usually, such infections are preceded by lethal outbreaks of H5N1 influenza in waterfowl, which are the natural hosts of these viruses and therefore normally have asymptomatic infection. The acquisition by the viruses of characteristics that enhance virulence in humans and their potential for wider distribution by infected migrating birds have caused renewed pandemic concern. The factors that account for the severe symptoms of viral influenza are still not well understood. However, it is believed that the cytopathic effects of the virus itself and the cytokines evoked by the infection account for both local and systemic effects that are life-threatening.

Clinical features

H5N1 infection and its replication in the respiratory tract have been shown to injure directly the nasal and tracheobronchial epithelium, possibly due to virus-induced cellular apoptosis and resulting loss of respiratory epithelial cells. These may account for symptoms such as cough, depressed tracheobronchial clearance and altered pulmonary function.

Incubation is thought to be 7-12 days after exposure. Major symptoms are high fever, sore throat, headache, chest pain and cough, bleeding nose and gums, and diarrhoea. These may lead to pneumonia, encephalitis and organ failure. The predicted death rate of avian flu ranges from 60% to 90%.

Epidemiology

From 2003-2014 a total of 407 have died due to bird flu worldwide, mainly in South East Asia (death rate 58%).

Treatment and prevention

Preventive measures include good personal hygiene, thorough adherence to routine hand-washing, respiratory precautions such as wearing masks and avoiding crowded places during an outbreak. The routine flu vaccine is ineffective against avian flu. Drugs such as Tamiflu reduce the severity of infection if taken within 2 days of initial symptoms. Patients may need quicker and larger doses. In dentistry, additional precautions or transmission-based precautions must be implemented during an outbreak situation (Chapter 36).

Paramyxoviridae

The paramyxoviruses are enveloped, RNA viruses with an unsegmented genome, which cause major diseases of infancy and childhood. There are four groups of paramyxoviruses:

1. parainfluenza virus

2. mumps virus

3. measles virus

4. respiratory syncytial virus (RSV).

Parainfluenza and mumps viruses are antigenically related.

Parainfluenza viruses

The parainfluenza viruses cause human respiratory infections, especially in autumn and winter.

Clinical features

The major diseases caused by parainfluenza viruses, particularly in young children and infants, are laryngotracheobronchitis (croup), bronchiolitis and pneumonia. When adults are infected with any parainfluenza type, the common cold is the usual result.

Epidemiology

Spread through respiratory/droplet secretions. Closed populations, including young children, are especially at risk.

Mumps virus

Mumps, measles, rubella and varicella (chickenpox) are the common childhood fevers. Mumps virus typically causes arotitis (mumps) of acute onset involving one or both parotid glands. The attenuated form of the mumps virus, incorporated in the combined measles-mumps-rubella (MMR) vaccine, leads to the development of antibody in 95% of vaccines (see also Chapter 35).

Measles virus

Another agent of common childhood fever, measles virus causes one of the most highly infectious diseases known. Infection results in permanent immunity.

Clinical features

Measles is an acute febrile illness with a characteristic exanthematous rash. The virus enters through the respiratory tract and multiplies in the respiratory epithelium and regional lymphoid tissue for up to 12 days. In the next (viraemic) phase, the virus spreads throughout the lymphoid tissues and skin. This stage is accompanied by prodromal symptoms: conjunctivitis, nasal discharge, headache, low-grade fever, sore throat and Koplik's spots. These are bluish-white, pinpoint spots surrounded by dark-red areolae, which appear on the buccal mucosa opposite the molar teeth and sometimes near the orifice of the parotid duct. The measles rash appears to result from the interaction between virus-infected cells and either sensitized lymphocytes or antibody-complement complexes. The rash consists of fine, sparse, discrete macules. As the rash develops, the Koplik's spots disappear.

Complications

The complications of measles virus infection are serious and could be:

 Respiratory complications (bronchopneumonia): the most serious; seen in 4% of patients, with or without secondary bacterial infection. Otitis media occurs in a smaller percentage.

 Neurological complications: these include encephalomyelitis (with a mortality rate of some 10%) and subacute sclerosing panencephalitis. The latter is a rare, progressive, degenerative neurological disease of children and adolescents, causing mental and motor deterioration and death within a year.

 Gangrenous stomatitis and noma: seen in certain sub-Saharan African countries. A number of cofactors such as malnutrition, oral ulceration and acute necrotizing ulcerative gingivitis together with concurrent measles infection lead to progressive gangrene and gross destruction of the orofacial tissues, and consequent disfigurement (see Fig. 33.7).

Epidemiology

Measles is readily transmissible, usually via respiratory secretions and urine, especially during the prodromal phase and when the rash appears.

Prevention

The measles component of the MMR vaccine is a live attenuated virus that induces immunity for up to 10 years. However, in developing countries such as West Africa, where universal vaccination in childhood is not feasible, measles remains a severe disease and a major cause of death in childhood.

Respiratory syncytial virus

A major agent of lower respiratory tract disease, RSV causes worldwide epidemics of respiratory tract infection in infants and young children. Adults, although infected, develop only mild or non-apparent symptoms. The virus can cause colds, bronchiolitis and pneumonia, especially during the first 6 months of life. Approximately one-third of infants develop antibodies in the first year of life.

Picornaviridae

Picornaviridae are non-enveloped, RNA viruses with an unsegmented genome. Four members of this family cause significant human disease: polioviruses, coxsackieviruses, echoviruses and rhinoviruses. The first three of these are collectively termed enteroviruses.

Polioviruses

Polioviruses are agents of paralytic poliomyelitis.

Clinical features

Poliovirus infection is initiated by ingestion of infectious virions, after which primary replication occurs in oropharyngeal and intestinal mucosa. The virus drains into the cervical and mesenteric lymph nodes and then into the systemic circulation. Subsequent replication continues in a number of non-neural sites, leading to a persistent viraemia and spread into the central nervous system.

Paralytic poliomyelitis is unusual and depends on host factors that may predispose to neural infection. The incidence and severity of paralytic disease increase with age (e.g., teenagers are more likely than younger children to develop crippling disease).

Epidemiology

Polioviruses have a wide geographic distribution and spread rapidly, especially in densely populated areas with poor sewage control, such as in developing countries. Infection occurs mainly in the hot season and is spread in the faeces. Transmission is primarily by person-to-person contact through pharyngeal secretions, although the disease may spread by infected water.

Prevention

Spread of poliovirus disease has been successfully prevented through widespread immunization with either killed (Salk vaccine) or live attenuated virus (Sabin vaccine). However, poor immunization practices have led to recent resurgence of the disease in some developing countries.

Coxsackieviruses

Coxsackieviruses are subdivided into two major groups, A and B, on the basis of the lesions they induce in suckling mice. Each group also has several serologically distinct subgroups. Most human coxsackievirus infections are mild and frequently asymptomatic. Serious infection, although rare, results in severe disease. Two diseases caused by group A coxsackieviruses are of particular dental interest: (i) herpangina and (ii) hand, foot and mouth disease.

Herpangina

Herpangina, caused by group A coxsackievirus, is common in children but may affect any age group.

Clinical features

The disease is characterized by fever, headache, sore throat, dysphagia, anorexia and occasionally a stiff neck. These symptoms are accompanied by herpes-like oropharyngitis, where the ulceration is predominantly on the tonsil, soft palate and uvula. The small, papulovesicular lesions are about 1-2 mm in diameter, with a greyish-white surface surrounded by red areolae. The disease is self-limiting and lasts for 3-4 days (see also Chapter 35).

Hand, foot and mouth disease

Hand, foot and mouth disease, also caused by group A coxsackievirus, is a relatively common infection in children. It is easily diagnosed because of its classic distribution in the hands, feet and mouth. The incubation period is about 3-5 days and resolution occurs within a week.

Clinical features

The disease may begin with facial pain, with tenderness along the course of the parotid duct and a few vesicles around the duct orifice. The onset of the oral and skin eruptions is accompanied by headache, malaise and sore throat, but in many, there is little systemic upset. The oral lesions are generally bright-red macules, which later form oval or grey vesicles with red areolae (see Chapter 35). The plantar surface of the feet and the palmar surface of the hands and sometimes the buttocks may be affected. These skin lesions are bright-red macules with pale centres, which develop into thin-walled bullae or small ulcers with surrounding erythema. The lesions in the mouth, and on the hands and feet, are not always seen.

All serotypes of coxsackievirus have a worldwide distribution. They are highly infectious within families and closed communities, and the greatest epidemic spread occurs in the summer and autumn. Viral transmission is by the faecal-oral route and from nasal and pharyngeal secretions. They enter through the mouth and nose, multiply locally and spread viraemically (compare polioviruses).

Rhinoviruses

The aetiological agents of the 'common cold' and a group of acute, afebrile upper respiratory diseases, rhinoviruses are readily inactivated at low pH conditions and require an incubation temperature of 33°C for maximal replication; hence they multiply well in the upper respiratory tract where the incoming air provides low temperature conditions suited to the virus.

Antigenicity

There is a vast array (more than 100) of immunologically distinct groups of rhinoviruses based on a single type-specific antigen,

hence the reason for recurrent colds, as the succeeding infective virus is likely to be antigenically different from the virus that caused the previous episode (i.e., immunity is only effective against homologous challenge).

Epidemiology

In a family unit, rhinovirus transmission is usually initiated when a child introduces the virus, which spreads rapidly via nasal secretions. The disease is most common in the autumn, winter and early spring. Note, however, that rhinoviruses are not the only agents of the common cold, although they are the major culprits.

Togaviridae

Rubella

The agent of rubella (German measles) is a togavirus. Rubella is a childhood fever resembling measles, except that it has a milder clinical course and shorter duration. If rubella is contracted in early pregnancy, the virus can cause severe congenital abnormalities and may cause the death of the foetus.

Epidemiology

Rubella is a highly contagious disease spread by nasal secretions. Because of its mild clinical symptoms, the infection is often non-apparent, and viral dissemination may be widespread before it is recognized. The disease may spread in the dental clinic environment. Females (especially of child-bearing age) should be immunized against the virus: the rubella component of the combined MMR vaccine contains a live attenuated virus, which confers adequate protection.

Other RNA viruses

Other RNA virus families that have not been discussed here include the Arenaviridae, Bunyaviridae, Coronaviridae, Reoviridae, Rhabdoviridae and Retroviridae. HIV, which is in the Retroviridae family, is discussed in detail in Chapter 30 because of its major relevance to dentistry.

Viruses and cancer

Viruses that have the ability to cause cancer are called oncogenic viruses. A number of DNA viruses are oncogenic, but only one RNA virus is known to have this potential. The virus groups and the cancers they cause are summarized in the following sections.

Papovaviruses

HPVs cause benign warts, malignant carcinomas and cervical cancers.

The polyomavirus and the simian virus 40 (SV40) are oncogenic in laboratory animals.

Adenoviruses

Adenoviruses are oncogenic in newborn hamsters, but not in humans.

Herpesviruses

These are implicated in human cancers (also see earlier discussion):

 HSV-2 is a likely coagent of certain variants of cervical cancer

 EBV is associated with Burkitt's lymphoma and nasopharyngeal carcinoma

 HHV-8 is closely associated with the aetiology of Kaposi's sarcoma (an endothelial tumour), which is a well-recognized oral manifestation of HIV infection.

Hepadnaviruses

Hepatitis B virus is a well-known agent of human hepatocellular carcinoma (Chapter 29).

Retroviruses

Retroviruses include the human T cell leukaemia viruses (HTLVs):

 HTLV-I is the agent of adult T cell leukaemia, which is endemic in south-western Japan and the Caribbean region.

 HTLV-II is associated with human lymphomas.

Key facts

DNA viruses

 Human papillomaviruses (HPVs) are associated with benign epithelial tumours.

 Adenoviruses cause acute respiratory disease and are ubiquitous, and humans are the only known reservoirs.

 Up to eight different types of human herpesviruses are described; they are neurotrophic and epitheliotropic.

 All herpes virus infections lead to lifelong viral latency.

 Herpes simplex and zoster viruses cause primary and reactivation infection (post-primary infection).

 In general, herpes simplex virus (HSV) types 1 and 2 (HSV- 1 and HSV-2, respectively) cause infections above’ and ‘below the belt’, respectively (i.e., oral and genital infections).

 Herpetic gingivostomatitis is the primary infection, and herpes labialis is the reactivation infection caused by HSV-1.

 Varicella-zoster ((herpes simplex virus type 3 (HSV- 3)) causes chickenpox (primary) and zoster/shingles (reactivation) affecting well-defined dermatomes (belt of roses from hell).

 Epstein-Barr virus (human herpesvirus 4) causes infectious mononucleosis or glandular fever, oral hairy leukoplakia, nasopharyngeal carcinoma, Burkitt’s lymphoma and posttransplant lymphoproliferative diseases.

 Cytomegalovirus (human herpesvirus 5) causes asymptomatic infection in adults; if infection occurs during pregnancy, transplacental passage of the virus may cause serious developmental defects or abortion.

 Human herpesvirus 6 causes sixth disease’ (or roseola infantum, exanthem subitum), a rash seen in young children.

 Human herpesvirus 7 is isolated from lymphocytes carrying CD4, not yet associated with disease.

 Human herpesvirus 8 is the agent of Kaposi’s sarcoma, a vascular endothelial tumour common in human immunodeficiency virus (HIV) disease.

RNA viruses

 Orthomyxoviruses cause pandemics of influenza.

 Their success is due to the ability to undergo rapid antigenic changes (antigenic shifts and antigenic drifts) of haemagglutinin component of the outer surface spikes of the virus.

 Paramyxoviruses include parainfluenza virus, mumps virus, measles virus and respiratory syncytial virus.

 Mumps virus is the major agent of parotitis (mumps).

 Measles is an acute febrile infection with an exanthematous rash; prodromal symptoms of measles include Koplik’s spots on the buccal mucosa.

 Complications of measles include bronchopneumonia, neurological complications and gangrenous stomatitis or noma.

 The measles-mumps-rubella (MMR) vaccine prevents measles, mumps and rubella.

 Group A coxsackieviruses cause hand, foot and mouth disease of children and herpangina; oral lesions are papulovesicular, small and greyish-white.

 Rhinoviruses are the agents of the common cold.

 Oncogenic or cancer-causing viruses include papillomaviruses, polyomavirus, simian virus, Epstein-Barr virus and human herpesvirus 8, human T cell leukaemia viruses (retroviruses) and hepadnaviruses (causing hepatitis B).

Please indicate which answers are true, and which are false.

Review questions (answers on p. 365)

21.1 Adenoviruses:

A. are DNA viruses

B. cause acute upper respiratory infections

C. primarily cause zoonotic diseases, and humans are accidental hosts

D. varicella-zoster virus

E. measles virus

21.2 Human herpesviruses include:

A. rubella virus

B. cytomegalovirus (CMV)

C. Epstein-Barr virus (EBV)

D. infections have a seasonal incidence

E. infections are often treated with antiviral agents

21.3 Primary herpesvirus infections may cause:

A. gingivostomatitis

B. herpes labialis

C. herpetic whitlow

D. chickenpox

E. herpes zoster

21.4 Which of the following statements on herpes zoster in the maxillofacial region are true?

A. it is triggered by reactivation of human herpesvirus 3 in the trigeminal ganglion

B. it can lead to blindness

C. pain mimics toothache

D. it is difficult to diagnose without laboratory testing

E. patient needs to be kept isolated to prevent the disease from spreading

21.5 Epstein-Barr virus (EBV):

A. is a human herpesvirus

B. achieves latency in sensory ganglia

C. infections will produce a blood film with atypical lymphocytosis

D. humans are the only known host

E. diagnosis has to be confirmed by serological methods

21.6 With regard to Epstein-Barr virus (EBV) infection, which of the following are true?

A. Burkitt's lymphoma is highly prevalent in Africa

B. nasopharyngeal carcinoma is common among Caucasians

C. EBV DNA is regularly isolated from nasopharyngeal carcinomas

D. hairy leukoplakia is a malignancy of the oral cavity

E. EBV is associated with post-transplant lymphoproliferative disorders

21.7 With regard to human herpesvirus infections, which of the following are true?

A. cytomegalovirus (CMV) can incur foetal damage in pregnant women

B. disseminated CMV infections are seen in immunocompromised patients

C. human herpesvirus 6 infection is an occupational hazard to the dentist

D. human herpesvirus 8 is responsible for Kaposi's sarcoma

E. human herpesvirus 6 causes a facial rash in children

21.8 Cancrum oris:

A. is a complication of mumps

B. is more common in African populations

C. has malnutrition as a contributory factor

D. may lead to gross disfigurement

E. is a sequela of fusospirochetal infection

21.9 Papulovesicular oral lesions are seen in:

A. measles

B. herpangina

C. hand, foot and mouth disease

D. rubella

E. mumps

Further reading

Bagg, J. (1994). Virology and the mouth. Rev Med Microbiol, 5, 209-216. Cleator, G. M., & Klapper, P. E. (2009). The Herpesviridae (Chapter 2A). In A. J. Zuckerman, J. E. Banatvala, P. Griffiths, et al. (Eds.), Principles and practice of clinical virology (6th ed.). Chichester: John Wiley.

Greenberg, M. D. (1996). Herpesvirus infections. Dental Clinics of North America, 40, 359-368.

Scully, C., & Samaranayake, L. P. (1992). Clinical virology in oral medicine and dentistry. Cambridge: Cambridge University Press.

Scully, C., & Samaranayake, L. P. (2015). Emerging and changing viral diseases in the new millennium. Oral Diseases, 22, 171-179.



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