Oral manifestations of viral infections

Introduction

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.

Herpes virus and associated lesions

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)}.

Oral manifestations of aids

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)}.

Papilloma virus

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)}.

Varicella

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)}.

Epstein -Barr virus

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)}.

Acute necrotizing ulcerative gingivitis

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.

Clinical features

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.

Aetiology

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.

Action to be taken

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.

Systemic treatment

Specific local treatment

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.

Cytomegalovirus infection

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)}.

Conclusion

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.

BIBLIOGRAPHY

• ALFORT CA, BRITT WJ. Cytomegalovirus. In : Fiels N, Knippe MM et al., eds. Virology. New York : Raven Press, 1990:1981-2003.
• ALTMEYER R, WEHRENBERG O, HOLZMANN H. Treatment of recurrent herpes labialis using a herpes simplex type 1 subunit vaccine. A prospective randomized double-blind multicenter study. Hautarzt 1991;42:759-763.
• AMSTERDAM JD, MAISLIN G, RYBAKOWSKI J. A possible antiviral action of lithium carbonate in herpes simplex virus infections. Biol Psychiatry 1990;27:447-453.
• ANDERSON R, SCARFFE JH, SUTTON RNP. Oral acyclovir prophylaxis against herpes virus infection in non-Hodgkin's lymphoma and acute lymphoid leukaemia patients receiving remission induction chemotherapy. Br J Cancer 1984;50:45-49.
• APISARIYAKULM A, BUDDHASUKH D, APISARIYAKUL S, TERNAI B. Zinc monoglycerolate is effective against oral herpetic sores [Letter]. Med J Austr 1990;152:54.
• BALARAM P, NALINAKUMARI KR, ABRAHAM E, BALAN A, HAREENDRAN NK, BERNARD HU et al. Human papillomaviruses in 91 oral cancers from Indian betel quid chewers - High prevalence and multiplicity of infections. Int J Cancer 1995;61:450-454.
• BARRETT AP. A long term prospective clinical study of orofacial herpes simplex virus infection in acute leukemia. Oral Surg Oral Med Oral Pathol 1986;61:149-152.
• CHOU S, GALLAGHER JG, MERIGAN TC. Controlled clinical trial of intravenous acyclovir in heart transplant patients with mucocutaneous herpes simplex infections. Lancet 1981;i:1392-1394.
• COEUGNIET EG. Recurrent herpes labialis infections : cellular immunity and immunomodulation. Onkologie 1989;12:48-55.
• COHEN PR, HEBERT AA, ADLER-STORTHZ K. Focal epithelial hyperplasia : Heck disease. Pediatr Dermatol 1993;10:245-251.
• COHEN SG, GREENBERG MS. Chronic oral herpes simplex virus infection in immunocompromised patients. Oral Surg Oral Med Oral Pathol 1989;59:465-471.
• COLLINS R. Viral sensitivity following the introduction of acyclovir. Am J Med 1988;85:129-134.
• CHRISTOPHERS J, SUTTON RNP. Characterisation of acyclovir resistant and sensitive clinical herpes simplex virus isolates from an immunocompromised patient. J Antimicrobiol Chemother 1987;20:389-398.
• CRUMPAKER CS, SCHNIPPER LE, MARLOW SI, CROSS WG. Gum tumours in pregnancy and gingivitis gravidarum. Br Dent J 1988;75:85-89.
• DETIEN PF, PATTERSON R, NOSKIN GA, PHAIR JP, LLOYD SO. Herpes simplex virus associated with recurrent Stevens-Johnson Syndrome. Arch Intern Med 1992;152:1513-1516.
• DHARIWAL SK, CUBIE HA, SOUTHAM JC. Detection of human papillomavirus in oral lesions using commercially developed typing kits. Oral Microbiol Immunol 1995;10:6063.
• DUSSAIX E, BROSSAR Y. Les cytomégalovirus. In : Les virus transmis par le sang. Montrouge : John Libbey Eurotext, 1996:187-203.
• EPSTEIN JB, LOZADA-NUR F, McLEOD WA, SPINELLI J. Oral Kaposi's sarcoma in acquired immunodeficiency syndrome : review of management and report of the efficacy of intralesional vinblastine. Cancer 1989;64:2424-2430.
• EPSTEIN JB, SCULLY C. Herpes simplex virus in immunocompromised patients : growing evidence of drug resistance. Oral Surg Oral Med Oral Pathol 1991;72:47-50.
• EPSTEIN JB, SHERLOCK C, PAGE JL. Clinical study of herpes simplex virus infection in leukemia. Oral Surg Oral Med Oral Pathol 1990;70:38-43.
• FIELD HJ. Persistent herpes simplex virus infection and mechanisms of virus drug resistance. Eur J Clin Microbiol Infect Dis 1989;8:671-680.
• FLAITZ CM, NICHOLS CM, HICKS MJ. An overview of the oral manifestations of AIDS-related Kaposi's sarcoma. Compend Contin Educ Dent 1995;16:136-143.
• FLAITZ CM, NICHOLS CM, HICKS MJ. Herpesviridae-associated persistent mucocutaneous ulcers in acquired immunodeficiency syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endond 1996;81:433-441.
• FOWLER CB. Benign and malignant noeplasms of the periodontiumogy. Periodontol 2000 1999;21:33-83.
• FURMAN RA, COEN DM, SAINT CLAIR MH, SCHAFFER PA. Acyclovir-resistant mutants of herpes simplex virus 1 express altered DNA polymerase or reduced acyclovir phosphorylating activity. J Virol 1981;40:936-944.
• GARLICK JA, TAICHMAN LB. Human papillomavirus infection of the oral mucosa. Am J Dermatopathol 1991;13:386-395.
• GERCHON RR, VLAHOV D, NELSON KE. The risk of transmission of HIV-1 through non-percutaneous, non-sexual modes - A review. AIDS 1990;4:645-650.
• GLUCKMAN E, LOTSBERG J, DEVERGIC A. Prophylaxis of herpes infection after bone marrow transplantation by oral acyclovir. Lancet 1983;706-708.
• GREENBERG MS. Herpes virus infections. Dent Clin North Am 1996;40:359-368.
• HEIRNDAHL A, MATTSSON T, DAHLOF G, LONNQUIST B, RINGDEN O. The oral cavity as a port of entry for early infections in patients treated with bone marrow transplantation. Oral Surg Oral Med Oral Pathol 1989;68:711-716.
• HO M. Interferon as an agent against herpes simplex virus. J Invest Dermatol 1990;95:158S-160S.
• HOLLAND HK, SARAL R. Opportunistic viral infections. Br Med Bull 1985;41:46-49.
• JONES AC, FREEDMAN PD, PHELAMAN JA, BAUGHMAN RA, KERPEL SM. Cytomegalovirus infections of the oral cavity. Oral Surg Oral Med Oral Pathol Oral Radiol Endond 1993;75:76-85.
• JONTELL M, WATTS S, WALLSTROM M, LEVIN L, SLOBERG K. Human papilloma virus in erosive lichen planus. J Oral Pathol 1990;19:273-277.
• LARDER BA, DERSE D, CHENG YC, DARBY G. Properties of purified enzymes induced by pathogenic drug-resistant mutants of herpes simplex virus : evidence for virus variants expressing normal DNA polymerase and altered thymidine kinase. J Biol Chemother 1983;258:2027-2033.
• LEIGH L. Management of non-genital herpes simplex virus infection in immunocompetent patients. Am J Med 1988;85:34-38.
• LINDHE J. Textbook of clinical periodontology. Copenhague : Munksgaard edit, 1983:288-289.
• LOESCHE WJ, SCHMIDT E, SMITH BA, MORRISSON EC, CAFESSE R, HUJOEL PP. Effect of metronidazole on periodontal treatment needs. J Periodontol 1991;62(4):247-257.
• MAMEDOVA SA, GASHIMOV RG, BIKBULATOV RM. The use of the ultrasonic spraying of interferon and larifan solutions for treating acute herpetic stomatitis in children. Stomatologia (Mosk) 1991;5:68-70.
• MAO EJ, SCHWARTZ SM, DALING JR, ODA D, TICKMAN L, BECKMANN AM. Human papilloma viruses and p53 mutations in normal pre-malignant and malignant oral epithelia. Int J Cancer 1996;69:152-158.
• MARSLAND GJ, FOX JM. Histology of oral mucosa. Londres : Academic Press, 1977.
• MATICIC M, POLJACK M, KRAMAR B, TOMAZIC J, VIDMAR A, ZAKOTNIK B et al. Proviral HIV-1 DNA in gingival crevicular fluid of HIV-1-infected patients in various stages of HIV disease. J Dent Res 2000;79(7):1496-1501.
• MILLER CS. Viral infections in the immunocompetent patient. Dermatol Clin 1996;14:225-241.
• MINDEL A. Is it meaningful to treat patients with recurrent herpetic infections ? Scand J Infect 1991;78:27-32.
• MOLIN L, RUHNEK-FORSBECK M, SVENNERHOLM B. One year acyclovir suppression of frequently recurring genital herpes : a study of efficacy, safety, virus sensitivity and antibody response. Scand J Infect 1991;78:33-39.
• MONTGOMERY MT, REDDING SE, LEMAISTRE GF. The incidence of oral herpes simplex virus infection in patients undergoing cancer chemotherapy. Oral Surg Oral Med Oral Pathol 1986;61:238-242.
• NADAL D, CADUFF R, FREY E, HASSAM S, ZIMMERMANN DR, SEIGNEURIN JM et al. Non-Hodgkin's lymphoma in four children infected with the human immunodeficiency virus. Association with Epstein-Barr virus and treatment. Cancer 1994;73:1750-1752.
• NUGIER F, COLIN JN, AYMARD M, LANGOIS M. Occurrence and characterisation of acyclovir-resistant herpes simplex virus isolates : report on a two year sensitivity screening survey. J Med Virol 1992;36:1-12.
• OBALEK S, JANNIGER C, JABLONSKA S, FAVRE M, ORTH G. Sporadic cases of Heck disease in two polish girls : association with human papillomavirus type 13. Pediatr Dermatol 1993;10:240-244.
• PADAYACHEE A. Human papillomavirus (HPV) types 2 and 57 in oral verrucae demonstrated by in situ hybridization. J Oral Pathol Med 1994;23:413-417.
• PALEFSKY IM, SILVERMAN S JR, ABDEL-SALAARN M, DANIELS TE, GREENSPAN JS. Association between proliferative vertucons leukoplakia and infection with human papillomavirus type 16. Oral Pathol Med 1995;24:193-197.
• PORTER SR, FLINT SR, SCULLY C, KEITH O. Recurrent aphthous stomatitis : the efficacy of replacement therapy in patients with underlying hematinic deficiencies. Ann Dent 1992:14-16.
• PRAETORIUS E. 11PV-associated diseases of oral mucosa. J Clin Dermatol 1997;IS:399-413.
• PREMOLI-DE-PERCOCO G, CISTERNAS JP, RAMIREZ JL, GALINDO I. Focal epithelial hyperplasia : human papillomavirus-induced disease with a genetic predisposition in a Venezuelan family. Hum Genet 1993;91:386-388.
• PURANEN M, YLISKOSKI M, SAARIKOSKI S, SYRJANEN K, SYRJANEN S. Vertical transmission of human papillomavirus from infected mothers to their newborn babies and persistence of the virus in childhood. Am J Obstet Gynecol 1996;174:694-699.
• REDDING SW, MONTGOMERY MT. Acyclovir prophylaxis for oral herpes simplex virus infection in patients with bone marrow transplants. Oral Surg Oral Med Oral Pathol 1989;67:680-683.
• REDDING SW, MONTGOMERY MT, LEMAISTRE CF. Acyclovir prophylaxis for oral HSV in bone marrow transplant patients. J Dent Res 1987;66:275.
• REGEZI JA, EVERSOLE LR, BAKER BF, RICK GM, SILVERMAN S. Herpes simplex and cytomegalovirus coinfected oral ulcerations in HIV-positive patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endond 1996;81:55-62.
• REICHART PA. Oral manifestations of recently described viral infections. Curr Opin Dent 1991;1:377-383.
• RIVIERA-HIDALGO F, STANFORD TW. Oral mucosal lesions caused by infective microorganisms. I. Viruses and bacteria. Periodontology 2000 1999;21:106-123.
• ROYCE RA, SENA A, CAES W JR, COHEN MS. Sexual transmission of HIV. N Engl J Med 1997;336:1071-1078.
• SABISTON CB Jr. A review and proposal for the etiology of acute necrotizing gingivitis. J Clin Periodontol 1986;13(8):727-734.
• SACKS SL, WANKLIN RJ, REECE DE et al. Progressive esophagitis from acyclovir-resistant herpes simplex. Clinical roles for DNA polymerase mutants and viral heterogeneity ? Ann Int Med 1989;111:893-899.
• SAFRIN S, ASSAYKEEN T, FOLLANSBEE S, MILLS J. Foscarnet therapy for acyclovir-resistant mucocutaneous herpes simplex virus infection in 26 AIDS patients : preliminary data. J Infect Dis 1990;161:1078-1084.
• SAFRIN S, CRUMPACKER C, CHATIS P et al. A controlled trial comparing foscarnet with vidarabine for acyclovir-resistant mucoccutaneous herpes simplex in the acquired immunodeficiency syndrome. The AIDS clinical trials group. N Engl J Med 1991;325:551-555.
• SCHUBERT MM, PETERSON D, FLOURNOY N et al. Oropharyngeal herpes simplex virus (HSV) infections following bone marrow transplantations. Am Soc Clin Oncol 1985;4:257.
• SCULLY C. Orofacial herpes simplex virus infections : current concepts in the epidemiology, pathogenesis and treatment and disorders in which the virus may be implicated. Oral Surg Oral Med Oral Pathol 1989;68:701-710.
• SEALE L, JONES CJ, KATHPALIA S. Prevention of herpes virus infections in renal allograft recipients by low dose oral acyclovir. JAMA 1985;254:3435-3438.
• SEIGNEURIN JM. Le virus d'Epstein-Barr. In : Les virus transmis par le sang. Montrouge : John Libbey Eurotext, 1996:206-218.
• SHEPP DH, NEWTON BA, DANDILIKER PS. Oral acyclovir therapy for mucocutaneous herpes simplex virus infections in immunocompromised marrow transplant recipients. Ann Int Med 1985;102:783-785.
• SLOTS J, RAMS F. Antibiotics in periodontal therapy : advantages and disadvantages. J Clin Periodont 1990;17:479-483.
• VESPER M, RIETHDORF S, CHRISTOPH E, RUTHKE A, SCHMELZLE R, LONING T. Detection of human papillomavirus (HVP) DNA in oral manifestation of lichen planus. Mund Kiefer Cesichtschir 1997;1:146-149.
• WADE JC, NEWTON B, MCLAREN C et al. Intravenous acyclovir to treat mucocutaneous herpes simplex virus infection after marrow transplantation : a double blind trial. Ann Int Med 1982;96:265-269.
• WEN S, TSUJI T, LI X, MIZUGAKI Y, HAYATSU Y, SHINOZAKI E. Detection and analysis of human papillomavirus 16 and 18 homologous DNA sequences in oral lesions. Anticancer Res 1997;17:307-211.
• WHITLEY RJ, LEVEIN M, BARTON N et al. Infections caused by herpes simplex virus in the immunocompromised host : natural history and topical acyclovir therapy. J Infect Dis 1984;150:323-329.
• YADAV M, ARIVANATHAN M, KUMAR S. HI-IV-6 antigen and viral DNA detected in cervical cells from archived tissue using histochemical staining and hybridization. Clin Diagn Virol 1996;7:23-33.
• YAO QY, ROWE M, MARTIN B, YOUNG LS, RICKINSON AB. The Epstein-Barr virus carrier state : dominance of a single growth-transforming isolate in the blood and in the oropharynx of healthy virus carriers. J Gen Virol 1991;72:1579-1590.
• YOUNG EJ, CHAFIZADEH E, OLIVEIRA VL, GENTA RM. Disseminated herpes virus infection during pregnancy. Clin Infect Dis 1996;22:51-58.
• ZEUSS MS, MILLER CS, WHITE DK. In situ hybridization analysis of human papillomavirus DNA in oral mucosal lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1991;71:714-720.