Articles
Jean-François MICHEL * Guy CATHELINEAU **
*MCU
**Professeur des Universités
Laboratoire de biomatériaux en site osseux,
Rennes, France.
Many viral diseases have oral and/or periodontal manifestations. Those lesions seen most frequently are herpes virus and associated lesions, oral manifestations of AIDS, shingles papilloma virus lesions, varicella, Epstein-Barr lesions, acute necrotising ulcerative gingivitis and cytomegalovirus lesions. If practitioners take care to detect these lesions, they will be called upon to treat them in their daily practice. Some of these lesions are specific, whereas others...
General practitioners, as well as specialists, frequently observe oral lesions of viral origin. These are sometimes dramatic and may be more or less painful. Many viral diseases have oral and/or periodontal manifestations. The lesions most frequently seen are : herpes virus and associated lesions, oral manifestations of AIDS, papilloma virus lesions, zoster virus lesions, lesions related to Epstein-Barr virus, acute necrotising ulcerative gingivitis and cytomegalovirus infections. If practitioners take care to detect these lesions, they will be called upon to treat them in their daily practice. Some of the lesions are specific whereas others are not. Various clinical situations are examined and treatments are suggested in the light of clinical examples and evidence from the literature. The options for treatment are related to the diagnosis, to the amount of pain and to the prognosis. Any prescribed medication must take into account best practice as well as the indications and contra-indications for any agents used.
Many viral diseases have oral and/or periodontal manifestations. Those lesions seen most frequently are herpes virus and associated lesions, oral manifestations of AIDS, shingles papilloma virus lesions, varicella, Epstein-Barr lesions, acute necrotising ulcerative gingivitis and cytomegalovirus lesions. If practitioners take care to detect these lesions, they will be called upon to treat them in their daily practice. Some of these lesions are specific, whereas others are encountered in patients without infection although, in general, they are less dramatic and do not develop to the same extent. This article aims to illustrate various clinical situations and proposes options for treatment using clinical case studies and evidence from the literature.
Oral or gingival ulceration may be due to trauma, viral or bacterial infection, aphthous ulceration, haematological, nutritional or malignant disease (Porter et al., 1992). Amongst the viral causes, herpetic infections are common and their effects on the periodontium most commonly reported. The primary herpetic infection usually occurs in the infant or child and prodromal signs may be fever, malaise or vomiting. Equally, a subclinical infection may pass unnoticed or be accompanied by pharyngitis (Greenberg, 1996). In general, the infection is characterized by vesicles on the mucosa, gingivae or pharynx that break down to form ulcers. An erythematous marginal gingivitis may accompany the lesions (Greenberg, 1996). The classic labial lesions often accompany the mucosal lesions. Associated cervical lymphadenopathy is possible. Primary infection may occur during pregnancy, in which case there may be significant perinatal mortality (Young et al., 1996).
Herpetic lesions have a variable distribution on the oral mucosa and gingivae. The lesions are often unobtrusive but may be painful, sometimes becoming quite large (over 1 cm diameter). The initial lesion is a vesicle, yellowish in colour, with a red border (fig. 1). The onset of the lesion is often preceded by a burning sensation that reduces as soon as the lesions appear. When associated with labial lesions, diagnosis is easy (fig. 2).
In general, immunocompetent patients presenting with oral lesions caused by the Herpes simplex virus (HSV) need only symptomatic treatment, in particular adequate fluid intake, antipyretics, analgesics and topical antiseptics (Scully, 1989). A large variety of other treatments have been suggested for herpetic infections, including antiviral agents, immunomodulators (for example levimasole, inosine, pranobex, interferon) and several other treatments of doubtful efficacy, including antibiotics, topical steroids, laser and acupuncture (Scully, 1989 ; Coeugniet, 1989 ; Ho, 1990 ; Amsterdam et al., 1990 ; Apisariyakulm et al., 1990 ; Mamedova et al., 1991 ; Mindel, 1991).
Antiviral therapy is only indicated in severe infections (fig. 3) or when the patient presents with an immunodeficiency or immunosuppression, and when there is the risk of the infection spreading to the skin, oesophagus or systemically (Schubert et al., 1985 ; Barrett, 1986 ; Montgomery et al., 1986 ; Redding et al., 1987 ; Cohen and Greenberg, 1989 ; Epstein et al., 1990). Oral or intravenous acyclovir is the antiviral of choice for controlling herpes simplex infections (Mindel, 1991), because it provides a substantial reduction in the shedding of the virus and of the duration of signs and symptoms (Chou et al., 1981 ; Wade et al., 1982 ; Whitley et al., 1984 ; Shepp et al., 1985). Acyclovir may be given as prophylactic cover for immunodepressed patients in oral doses of 200 g 4 times per day. This reduces the chances of recurrence as well as the severity of the infection and prodromal symptoms (Gluckman et al., 1983 ; Anderson et al., 1984 ; Seale et al., 1985 ; Redding and Montgomery, 1989). Acyclovir prophylaxis is particularly indicated in immunodepressed patients with Ac HSV because 9 % of these cases present with particularly severe secondary infections (Heirndahl et al., 1989 ; Holland and Saral, 1985 ; Epstein et al., 1990 ; Redding et al., 1987), whereas only 7 % of HSV seronegative patients develop this type of infection.
Resistance to acyclovir following prophylactic therapy is now becoming a major problem and occurs in a minority of immuno-depressed patients (Epstein and Scully, 1991 ; Molin et al., 1991 ; Crumpacker et al., 1988 ; Sacks et al., 1989). Resistance occurs in those patients receiving higher doses of acyclovir (Christophers and Sutton, 1987 ; Collins, 1988 ; Field, 1989 ; Safrin et al., 1990). Usually, resistance to acyclovir is due to residual mutant forms that produce non-functional thymidine kinase (Collins, 1988 ; Field, 1989), present an altered thymidine or an altered DNA polymerase (Furman et al., 1981 ; Larder et al., 1983). Patients carrying strains resistant to acyclovir are usually carriers of strains that are sensitive to high dose intravenous acyclovir (Nugier et al., 1992). Nevertheless, in unresponsive cases it may be necessary to resort to trisodium hexahydrate phosphoformate (foscarnet) or treatment based on vidarabine (Safrin et al.,1990 and 1991).
There is no effective vaccine available (Altmeyer et al., 1991). Some patients presenting with erythema multiforme associated with HSV may respond favourably to acyclovir, but this is not the case with all of them (Leigh, 1988 ; Detien et al., 1992).
Numerous epidemiological studies have shown that the human immunodeficiency virus (HIV) is not transmitted by simple contact but usually by parental exposure to infected blood, by sexual intercourse with an infected person and by babies born from a seropositive mother (Royce et al., 1997). The transmission of HIV by saliva has never been demonstrated. The presence of HIV-1 in the saliva of infected patients has been recorded (Gershon et al., 1990). Nevertheless, the oral cavity has rarely been cited as a site of HIV transmission, despite the presence of the virus in saliva, the high prevalence of periodontal disease in infected patients and the large numbers of mononucleocytes in gingival fluid (Maticic et al., 2000).
The oral manifestations vary according to the stage of infection. With reference to the International Classification of 1993, category A seropositive subjects are asymptomatic or with lymphadenopathy. There are no oral manifestations. Patients in category B present with minor clinical signs such as pharyngeal candidosis or hairy leucoplakia of the tongue. Faced with these signs of disease, the practitioner must immediately investigate for HIV. Patients in category C are defined as suffering AIDS. At this stage, oral lesions are much more frequent : candidosis (commonly), cytomegalovirus infections, herpetic infections, Kaposi sarcoma (fig. 4), Burkitt's lymphoma.
In infected patients, Kaposi sarcoma typically presents as multiple haemorrhagic lesions. The palate and gingivae are frequently the sites of oral lesions (Flaitz et al., 1995). However, the clinical appearances are variable as the lesion becomes larger, haemorrhagic and with extensive necrotic areas (fig. 5 and 6) (Fowler, 1999).
Treatment depends on the extent of the lesion, it location and the level of CD4+ lymphocytes. If the CD4+ count is above 500/ml, only symptomatic treatment is necessary. The lesions respond well to radiotherapy. If the CD4+ count is below this threshold, the use of alpha interferon or systemic chemotherapy is recommended. The oral lesions can be treated by injecting them with chemotherapeutic agents or sclerosing solutions in order to control bleeding (Epstein et al., 1989).
Human papilloma virus comprises more than 60 serological types (Dhariwal et al., 1995). They are the cause of lesions in many parts of the body especially the genital, nasal, gastro-intestinal and oral mucosas. Diagnosis is usually established by histology. The characteristics are koilocytosis, acanthosis and papillomatosis which, together with the clinical lesions, confirm the diagnosis (Marsland and Fox, 1977 ; Dhariwal et al., 1995). The majority of the lesions are squamous (Reichart, 1991 ; Yadav et al., 1996), have the appearance of a condyloma (Garlick and Taichman, 1991), a verruca or of epithelial hyperplasia (Garlick and Taichman, 1991 ; Reichart, 1991).
Squamous cell papilloma is classically described as a cauliflower-like growth on a narrow base. It is relatively small, pink and situated on the buccal mucosa or gingiva (fig. 7 and 8). The condyloma is often similar but multiple and discoloured. These lesions would be mostly due to human papilloma virus types 6 and 11 (Praetorius, 1997 ; Zeuss et al., 1991). These lesions should be treated by surgical excision.
The appearance of a verruca is that of an excrescence, on a broad (sessile) base and with a firm texture. The lesion appears most often on the gingivae, labial mucosa, the commissure, the hard palate and the tongue (Miller, 1996 ; Praetorius, 1997). The human papilloma virus types 2 and 57 have been detected in these lesions (Padayachee, 1994). There again, surgical excision is the general rule.
Hyperplasic forms have been described as Heck's disease. Flat papular or convex lesions appear, usually in children (Cohen et al., 1993). Their colour varies from red-grey to white and they are exclusively on the oral mucosa (Praetorius, 1997). It would appear that there is a genetic predisposition but, contrary to initial reports, it seems that the occurrence of these forms is not linked to any ethnic groups (Premoli-de-Percoco, 1993). The lesions are benign and may undergo spontaneous regression. Human papilloma virus types 13 and 32 are cited as the initiating cause (Obalek et al., 1993 ; Praetorius, 1997). Other lesions that have been associated with human papilloma virus are : erythematous plaques (HPV-16) (Praetorius, 1997), verrucous leucoplakia (HPV-16) (Palefsky et al., 1995) candidal leucoplakia (Wen et al., 1997), squamous carcinoma (HPV-16 and HPV-19) (Balaram et al., 1995 ; Mao et al., 1996 ; Praetorius, 1997 ; Wen et al., 1997) and lichen planus (HPV-6, -11 and -16) (Jontell et al., 1990 ; Praetorius, 1997 ; Vesper et al., 1997). Types 2, 4, 6, 11, 13, and 32 are associated with benign lesions, whereas types 16 and 18 are more often associated with malignant lesions (Garlick and Taichman, 1991). The transmission of the virus may occur by direct contact and/or at birth (Puranen et al., 1996).
The agent responsible for this disease is the varicella-zoster virus (VZV) (international nomenclature : HHV-3). The primary infection caused by the varicella-zoster virus usually occurs in children. Later reactivation in the adult causes a similar condition, accompanied by high fever. Varicella is a highly contagious infection transmitted by inhalation of infected droplets and by direct contact with the lesions. The disease develops into a more severe form in adults.
Skin lesions consist of a pruritic rash manifesting as macules, papules, vesicles and finally as crusts before finally healing, which occurs in 2 or 3 weeks.
Oral lesions show as vesicles on the lips and hard and soft palate (Miller, 1996). After the primary infection, the virus remains dormant in the dorsal root ganglia. Whether it is located in the neurones or in the surrounding cells prior to reactivation is not clear. Herpes zoster results from reactivation of the latent virus. In immunodepressed individuals, especially HIV carriers, there is an increase in the occurrence of herpetic infection (Rivirea-Hidalgo and Stanford, 1999).
The Epstein-Barr virus (EBV) belongs to the Herpes viridae family of viruses (herpes virus type 4 or HHV-4). It is transmitted by saliva and blood. EBV gains entry through the pharynx where it typically attaches to epithelial cells. Multiplication at this site explains the high level of virions in saliva. After the primary infection, EBV persists in the body throughout life, probably due to replication in seats of infection in the oro-pharynx (Yao et al., 1991). During reactivation, large quantities of salivary virions are liberated together with many infected B lymphocytes.
The clinical features are variable. Infectious mononucleosis shows the following signs : fever, weakness, tonsillitis, rhinopharyngitis and generalised lymphadenopathy. The oral manifestations are sometimes unobtrusive : ulceration, petechiae on the palate, gingival ulceration. Healing takes place in 2 or 3 weeks with rest and analgesics.
The pathology of EBV in the immunodepressed patient is also unobtrusive : immunosuppressed organ transplant patients have a predisposition to malignant B lymphoma as have HIV positive patients at the stage of AIDS (Nadal et al., 1994).
Finally, mention should be made of malignant syndromes associated with EBV in the immunocompetent patient : Burkitt's lymphoma which is endemic in Africa, naso-pharyngeal cancer which is common in China and other oral carcinomas sometimes associated with EBV (Flaitz et al., 1995). In 40 % of cases, Hodgkin's disease is associated with EBV (Seigneurin, 1996).
The dental practitioner may be confronted with acute necrotizing ulcerative gingivitis (ANUG). Even if the life of the patient is not immediately endangered because of this emergency, systemic repercussions can lead to major problems. Pain, infection and the risk of systemic involvement necessitates accurate diagnosis and appropriate treatment.
Acute onset, severe recurrent gingivitis, usually occurring in young adults, sometimes in epidemics. It is accompanied by severe, radiating pain which causes the patient to seek immediate attention. There are usually three groups of signs :
- local : bright red gingivae covered with a greyish slough, surrounded by a red margin. The papillae are blunted and the gingival contour is altered (fig. 9) ;
- local/regional : cervical and/or submandibular lymphadenopathy ;
- general : constant fever (39-40 °C), weakness and anorexia are usual. Digestive upsets are possible and sometimes tachycardia can lead to headaches or collapse.
In all cases there is a combination of local initiating factors, together with a general predisposition. Local initiating factors : bacteriology of the plaque associated with acute necrotizing ulcerative gingivitis reveals the presence of a fuso-spirochaetal complex, otherwise described as Vincent's flora. These particularly virulent anaerobic organisms are responsible for the severity of the lesions.
Lindhe (1983) and Sabiston (1986) have also implicated viruses in the aetiology of acute necrotizing ulcerative gingivitis (cytomegalovirus, AIDS), especially in recurrent acute necrotizing ulcerative gingivitis. Defective oral hygiene is evidently an aggravating factor.
General predisposing factors : a patient's response to stress is very variable and it is a question of their perceived sensitivity to it (emotional stress, professional stress, confined situations). If accepted by the patient, a psychologist or a psychiatrist may investigate this component.
As in all cases of infection where prompt action is necessary, it is desirable to combine systemic treatment (antibiotics) with specific local treatment. When virus infection is associated with the aetiology, antibiotics will only prevent super infection by bacteria.
The three questions to be posed in this connection are : what to prescribe, why and for how long ? We know from evidence in the literature that we must prescribe antibiotics : that they should be active against the anaerobes responsible for the infection, that they should be present in adequate concentration in saliva and gingival fluid and that they should have low toxicity and low risk of allergy (Loesche et al., 1991). Also, they should have a low MIC for the bacteria concerned.
All studies agree on the importance of using antibiotics in the treatment of acute necrotizing ulcerative gingivitis : the systemic administration of antibiotics allows their penetration into the pocket via gingival fluid and therefore directly reaching the bacteria at that site. In all cases, it is possible by systemic administration to achieve a sufficient concentration of antibiotic to inhibit the growth of the majority of bacterial species that are implicated in the disease (table I).
Three antibiotics seem to be particularly useful because of their normally therapeutic concentrations in gingival fluid and in serum : the cyclines, metronidazole and amoxycillin (in combination with clavulanic acid). Nevertheless, in order to achieve the desirable spectrum of activity, the prescription of choice would be amoxycillin (in combination with clavulanic acid) or metronidazole in preference to the cyclines.
Many studies have shown that topical antiseptics (chlorhexidine) cause a reduction in the clinical indicators of inflammation (bleeding on probing, gingival index) which justifies their use in combination with systemic antibiotics.
Non-salicylate analgesics can be prescribed according to the severity of the pain (paracetamol or paracetamol in combination with codeine). A follow-up appointment can be arranged for 8 to 15 days later, in order to re-evaluate the situation and to decide on subsequent treatment :
- oral hygiene methods should be reviewed and accompanied by a written prescription ;
- if the acute inflammation has resolved, the level of attachment can be measured ;
- bacteriological sampling could be undertaken ;
- a decision may be made on surgical treatment of any residual lesions.
Maintenance treatment should be undertaken every 3 to 6 months with a review of oral hygiene methods, scaling and root planing and radiographic assessment of healing.
This consists of cleaning the necrotic lesions with a swab soaked in 10 volumes hydrogen peroxide or chlorhexidine or, if not too painful, with an ultrasonic scaler. After the emergency treatment, management is comparable to that of a patient with chronic gingivitis or adult periodontitis - if the acute necrotising ulcerative gingivitis was not treated early enough and therefore allowed to progress to the periodontal ligament.
In cases with viral infection, especially AIDS, the prevention of recurrence is more problematic and the services of a medical team is essential for this.
Agent responsible : human cytomegalovirus (international nomenclature : HHV-5).
The cytomegalovirus (CMV) belongs to the ß-herpes virinae sub-family of the Herpetoviridae family that comprises many viruses with the characteristic of a narrow host spectrum and a long cycle of replication (Dussaix and Brossar, 1996).
Human CMV (HCMV) have a structure and morphology resembling those of other viruses. With electron microscopy, particles of HCMV cannot be distinguished from those of herpes simplex virus (HSV) or from varicella or shingles (VZV) (Alford and Britt, 1990). Infection with HCMV is pandemic and the seroprevalence very high : 30 to 70 % of adults in western Europe, United-States and Canada.
Acquisition of the infection commences in utero (congenital infection), it then increases during the first year of life from mother to baby contacts (Dussaix and Brossar, 1996). Continued infection regularly occurs. Blood and all secretions (milk, saliva, etc.) may contain the virus. The location of the dormant virus is not clear, nevertheless in 25 % of cases it can be found in the salivary glands. The targets for the HCMV seem to be endothelial and ciliated epithelial cells (Jones et al., 1993).
The primary infection in healthy subjects is, in 90 % of cases, asymptomatic or nearly so (flu-like symptoms). Typically, the clinical form presents as a fever that persists for 3 or 4 weeks without any other general symptoms. The clinical picture can resemble glandular fever, although there is no sore throat and there is little cervical or maxillary lymphadenopathy.
In HIV positive subjects with advanced immunosuppression (less than 100 CD4/µl), the infection may be serious. In the majority of cases it shows itself as a retinitis and then as haemorrhagic lesions of the digestive tract.
It should be mentioned that there is a greater risk of lesions after bone marrow grafts that are taken while the virus is dormant in the recipient or in the graft itself. The use of blood products tested for HCMV prevents the transmission of primary infection.
Ulcerative oral lesions have been described in HIV positive patients (Jones et al., 1993 ; Regezi et al., 1996). The diagnosis is effected by biopsy : histological examination demonstrates intranuclear inclusion bodies or specific immune antigens.
Treatment consists of a combination of oral acyclovir and systemic gancyclovir (Flaitz et al., 1996).
Viral infections constitute a panoply of oral and periodontal conditions whose symptoms must be well known to the practitioner and which are being encountered more and more frequently in dental practice. Their early diagnosis allows appropriate treatment to be undertaken.
Demande de tirés à part
Jean-François MICHEL, Laboratoire de biomatériaux en site osseux, 2, place Pasteur, 35000 RENNES - FRANCE. E-mail : jfmichel.rennes@wanadoo.fr