oral manifestations of hiv disease

3

Oral manifestations of HIV disease

DON SMITH DAVID CROSER

Pathology involving the oral cavity is extremely common in human immunodeficiency virus (HIV) infection and is particularly relevant for a number of reasons. Firstly, there are a number of conditions that are seen in people with HIV infection that only involve the oral cavity (Greenspan et al, 1984; Winkler et al, 1989). Secondly, disease in the oral cavity often is the first marker of systemic disease elsewhere (Silverman et al, 1986) and the mouth is a region of the gastrointestinal tract that is easily examined by clinicians. Thirdly, the mouth is often the first site of any manifestations of HIV disease (Klein et al, 1984; Schulten et al, 1988).

As a person progresses through the stages of HIV infection, with the eventual development of severe immunosuppression and the opportunistic infections associated with it, pathology in the oral cavity is also noticed. It often occurs in the first stages of the development of minor symptomatic disease-the so-called AIDS related complex (ARC) (CDC stage IV-A or IV-C2) (Anonymous, 1986a). These lesions, as listed in Table 1, are quite numerous and, although a number of them may be present in members of the general population, their presence in a person known or suspected to be HIV positive carries much greater significance and may be the first manifestation of any disease associated with HIV.

The majority of these lesions in the early stages are asymptomatic and this emphasizes the need for a regular careful examination of the oral cavity in patients who are HIV positive or suspected of being so throughout the course of their follow-up. The mouth, therefore, can be a very useful indicator of the degree of immunosuppression found in people with HIV disease.

Generally the majority of conditions such as oral candidiasis, gingivitis and ulceration arise because of impairment of the mucosal immune defence mechanisms at a reasonably early stage of HIV disease before systemic abnormalities have occurred (Yeh et al, 1988).

The treatment for the majority of these conditions does not differ between HIV-positive people and non-HIV patients except in that, although treatment is usually successful, continued recurrence of the problem is the rule rather than its successful eradication. This is not surprising given that the underlying cause of local pathology is a systemic immunosuppression

BailliPre’s Clinical Gastroenterology- 315 Vol. 4, No. 2, June 1990 Copyright @ 1990, by Baillitre Tindall ISBN O-7020-146%9 All rights of reproduction in any form reserved

316 D. SMITH AND D. CROSER

and treating the oral complications that arise will in no way alleviate the immune defect. Conditions that allowed the development of the pathology in the first instance are usually still present, and this creates a need for repeated treatments or continuous suppressive therapy. Not only does the underlying immune deficiency persist after treatment of oral conditions, but over a course of time it usually worsens. In the early stages of disease, patients may respond very quickly and effectively when therapy has been instigated, but as time passes the response becomes less and may become non-existent. Local palliative therapies which have worked in the past for such patients often become ineffective and it is necessary to move on to more aggressive and often systemic treatments for a number of conditions.

Although the above list of possible oral manifestations appears daunting, the number of commonly encountered lesions is in fact quite small. A review of 100 patients referred to our community HIV dental clinic showed the most common problems to be gingivitis (35%), periodontitis (29%), hairy leucoplakia (15%), candidiasis (8%), intraoral Kaposi's sarcoma (5%), parotid swelling (3%) and herpes simplex (1%). These lesions will be discussed in greater depth.

Table 1. Oral lesions associated with HIV infection. Modified from Schiodet & Pindborg (1987).

Fungal infections Candidiasis:

pseudomembranous erythematous hyperplastic angular stomatitis

Histoplasmosis Cryptococcosis Geotrichosis

Bacterial infections HIV-gingivitis HIV-necrotizing gingivitis HIV-periodontitis Actinomycosis Sinusitis Submandibular cellulitis Other:

Mycobacterium avium-intracellulare Klebsiella pneumoniae Escherichia coli Enterobacterium cloace

Viral infections Herpes simplex virus Epstein-Barr virus (hairy leucoplakia) Cytomegalovirus Herpes zoster virus Human papillomavirus

Neoplasms Kaposi's sarcoma Squamous cell carcinoma Non-Hodgkin's lymphoma

Neurological disorders Trigeminal neuropathy Facial palsy

Unknown aetiology Aphthous ulcers Progressive necrotizing ulceration Toxic epidermolysis Delayed wound healing Salivary/parotid swelling Submandibular lymphadenopathy Melanotic hyperpigmentation Xerostomia Immune thrombocytopenia purpura

ORAL MANIFESTATIONS OF HIV DISEASE 317

CANDIDIASIS

Oral candidiasis is probably the most common oral pathology encountered in HIV infection, with estimates that over 90% of patients will develop candidiasis at some stage during the course of the infection (Barr and Torosian, 1986). It was also one of the first conditions noted to be associated with the acquired immunodeficiency syndrome (AIDS) when it was first reported in 1981 (Gottlieb et al, 1981).

Immunology

The presence of Candida albicans in the oral cavity does not always indicate disease, as 30% of the general population carry this organism asympto- matically (Odds, 1988). It is unlikely that the strains of Candida that cause clinical disease in most patients with HIV disease are any more virulent than in other patient groups, but rather the occurrence of disease is accounted for solely by the progressive decline in the local defence mechanisms (Yeh et al, 1988). In some ways it is often quite surprising that severely immune depressed patients with HIV infection do not develop systemic spread of the candidiasis as do other patients with severe immune depression, such as oncology patients undergoing chemotherapy (Bross et al, 1989).

The disease is limited almost entirely to the oral cavity and oesophagus, with little true invasion through the mucosal surface. The reason that systemic invasion does not occur is probably because the immune suppres- sion seen with HIV infection is not total, but limited to defects in certain aspects of cell-mediated immunity. Although classical teaching dictates that the human antibody response is not effective against fungi such as Candida albicans, it has been shown that patients with HIV infection do develop antibodies against a specific 47 kilodalton antigen produced by Candida albicans, and that as patients progress through from asymptomatic to symptomatic through to full-blown AIDS there is increased antibody production of immunoglobulin (Ig) G, A and M in increasing proportions specifically against Candida albicans (Matthews et al, 1987).

This finding may be accounted for by either the protective effect of specific antibodies against key antigenic components of Candida albicans and hence protection of the individual from systemic infection, or may reflect the fact that the ability to mount a strong antibody response is a marker of a somewhat more effective and functional immune system generally and other components of the immune system may be playing more important roles.

Presentation

Infection with Candida albicans in the oral mucosa presents in a variety of ways, from scattered erythematous dot-like lesions seen with erythematous candidiasis to the much more easily recognized pseudomembranous candidiasis with the appearance of creamy, curdish-like coatings on the surface of the mucosa (Figure 1). If pseudomembranous lesions occur they may usually be scraped off the mucosa to reveal an underlying erythematous


Figure 1. Typical appearances of pseudomembranous candidiasis.

mucosal surface, which may be associated with some degree of ulceration in the more severe cases.

All parts of the mouth may be involved to some degree or another, with no special propensity for any particular area, although the soft palate is perhaps the most commonly recognized. The tongue may be spared or conversely may be the sole site. The patients usually complain initially of an alteration in taste sensation, often described as food tasting like pieces of cardboard. This is followed by a feeling or sensation of furriness or a coating inside the mouth, and later may develop into pain and tenderness if inflammation and ulceration become widespread. This can be severe enough to prevent patients being able to eat or drink or in some advanced cases to even swallow their own saliva. If dysphagia is present as well this is almost conclusive of oesophageal involvement, although it is not uncommon for oesophageal candidiasis to be asymptomatic. An endoscopic study of 24 HIV-positive patients without an AIDS diagnosis revealed oesophageal candidiasis in four (17%) despite the absence of oral candidiasis (Clotet et al, 1986). In 24% of cases seen in our department the finding of oral candidiasis is associated with oesophageal candidiasis, although one small study of ten patients with oral candidiasis and an AIDS diagnosis showed that all ten had oesophageal candidiasis at endoscopy, 30% of cases being asymptomatic at presentation (Tavitian et al, 1986). Other investigators have confirmed this finding, showing not only that all patients with oesophageal candidiasis have concurrent oral disease, but also that oral candidiasis plus symptoms of dysphagia is more often associated with dual pathology in the oesophagus (candidiasis plus cytomegalovirus or herpes infection or Kaposi's sarcoma) (Connolly et al, 1989).

Table 2 gives the results of a recent study of 111 HIV-positive patients


Table 2. Features of candidiasis (see text for explanation of categories).

ARC AIDS OESP (n = 22) (n = 63) (n = 26)

Erythema 100% 100% 92% Aphthae 100% 100% 92% Angular cheilitis 64% 73% 81% Mucosal ulceration 41% 52% 39% Mucosal erosion 0% 10% 19% Dysphagia 18% 21% 96%

attending our outpatient department documenting the clinical features of pseudomembranous candidiasis in three patient groups: AIDS-related complex plus buccal candidiasis (ARC), AIDS plus buccal candidiasis (AIDS) and AIDS plus oesophageal candidiasis (OESP).

Diagnosis

Pseudomembranous candidiasis is usually characteristic clinically but must be confirmed microbiologically. Direct staining of swabs from affected sites with either potassium peroxide or gram stain will reveal large numbers of candidal spores and hyphae surrounded by host inflammatory cells and debris. A more quantitative assessment can be made by culturing mouth washings or by imprint culture (Odds, 1988).

Treatment

Topical treatment with nystatin, amphotericin or clotrimazole is of benefit in mild cases of candidiasis occurring at an early stage of immunosuppression, with clotrimazole troches probably being the most useful (Quintiliani et al, 1984). However, there are a number of disadvantages with these topical therapies: response with amphotericin lozenges is often slow or non-existent (DeVries-Hospers and van der Waaiji, 1980), certain strains of Candida may develop resistance to nystatin (Martin and Dinsdale, 1982), any oesophageal disease will not be effectively treated, and as immunosuppression becomes more advanced relapse rates are high and topical therapies appear to no longer control the candidal overgrowth (personal observations). With the development of safe and effective systemic antifungal agents, topical therapies are used much less frequently in these patients.

Ketoconazole was the first systemic imidazole to be evaluated for systemic and mucocutaneous fungal infections. The mechanism of action of the imidazole compounds is one of inhibition of fungal synthesis of ergosterol by selectively blocking the enzyme lanosterol-C14-demethylase. This results in inadequate ergosterol for the stabilization of fungal cell membranes. A dose of 200 mg twice a day is standardly used in immune compromised patients. This is twice the recommended 200 mg once a day regimen, but is necessary as the half-life of the drug is shorter in immune compromised patients compared with normal subjects (Hann et al, 1982; Huang et al, 1986) and, as


an acidic environment is necessary for maximal absorption of ketoconazole, the achlorhydria seen in some AIDS patients may result in suboptimal absorption (Lake-Bakaar et al, 1987, 1988).

Concerns about possible hepatotoxicity with ketoconazole (10% of patients on long-term therapy develop transient elevations of serum trans- aminases and 24 cases of hepatitis have been reported by the FDA; Hayes, 1982) have led to the development of two other azoles: itraconazole-- chemically similar to ketoconazole but with a longer half-life, wider range of antifungal activity and no evidence of hepatotoxicity, and fluconazole--a triazole which is more water-soluble, has a long half-life and better penetration into cerebrospinal fluid and is predominantly eliminated unchanged in urine. All three agents are extremely efficient in clearing both oral and oesophageal candidiasis (Table 3), although almost all information on the efficacy of these agents in HIV-infected patients is currently available as abstracts only. One important feature emerging from these studies is that mycological cures are less common than clinical cures. This is not surprising given that disease appears to be caused by an overgrowth of pre-existing Candida and therefore a reduction of candidal colony-forming units should result in the disappearance of clinical symptoms.

The potential disadvantages with the imidazoles in the AIDS setting is that maximal absorption depends on gastric acidity and that enhanced hepatic metabolism can occur with concurrent usage of hepatic microsomal enzyme inducers such as rifampicin (rifampin USP). The potential disadvantages with

Table 3. Review of treatments for oral/oesophageal candidiasis in HIV-positive patients.

Patient Clinical Mycological Reference Drug Dose numbers response clearance

Gudrun et al, 1989 Flu 200 mg stat then 104 90% NA 100 mg od

Flu 50 mg od 100% 79% Dupont and Drouhet, 42 1988 (86% HIV+)

Meyer and Ching, 1988 Flu 100 mg od 8 63% NA Chave et al, 1989 Flu 400 mg stat 22* 82% NA Cajot, 1989 Flu 150 mg stat 54 87% NA Taelman et al, 1988 Flu 50mg od 20 90% 70% Lim et al, 1989 Flu 50 mg od 15 100% 87% Saballs et al, 1989 Flu 100-200 mg od 17" 100% NA Esposito et al, 1989 Flu 50 mg od 25* 96% 44%

Keto 200mg bd 25* 91% 42% DeWit et al, 1989 Flu 50mg od 17 100% 87%

Keto 200 mg od 16 75% 69% Smith et al, 1989a Keto 200 mg bd 38* 100% 92%

Itra 200 mg od 39* 98% 77% De Beule and Itra 200 mg od 17" 94% NA

Cauwenberg, 1989 Leon, 1989 Itra 200 mg od 25 100% NA Desmet et al, 1989 Itra 100 mg bd 39 100% 100%

(oral solution)

* Oral and oesophageal patients. Flu = tluconazole; Keto = ketoconazole; Itra = itraconazole; od = once a day; bd = twice a day; star = single dose only; NA = not assessable on data presented.


fluconazole are that liver function test abnormalities can occur at higher doses and its water solubility may give rise to intermittent binding and blockage of lanosterol-C14-demethylase in the fungal membrane, stimulating over- production of this enzyme, which could lead to total azole resistance developing. Therefore a logical approach would be to use the most appropriate agent given each individual patient's situation: ketoconazole in the first instance, itraconazole if pre-existing hepatic abnormalities are present, and fluconazole if patients are on concurrent H2-antagonists or rifampicin.

From our own study of 111 cases of pseudomembranous candidiasis, we have shown that, despite successful treatment of an episode (in terms of absence of clinical signs plus negative candidal cultures after 28 days of systemic antifungal therapy), 59% of these patients will have a clinical relapse within one month and 88% of patients will have relapsed within three months (Smith et al, 1989b).

Prognostic implications

The finding of oropharyngeal candidiasis in an HIV-positive individual is a valuable prognostic marker; 59% of HIV-infected patients with pseudomembranous candidiasis will develop an AIDS diagnosis within three months (Klein et al, 1984). Often the diagnosis of candidiasis will be made at the time the patient presents with their first AIDS diagnosis (Gottlieb et al, 1981; Small et al, 1983). Within our own group of patients with oropharyngeal candidiasis, 80% had AIDS at the time of presentation (although it was not the first episode of candidiasis for all patients). Erythematous candidiasis is more difficult to diagnose clinically but is becoming increasingly recognized as a precursor form of pseudomembranous candidiasis which develops at an earlier stage of immunosuppression when CD4 counts are at similar levels to those found with oral hairy leucoplakia (i.e. 370 compared with 345 per cubic millimetre) (Nielsen et al, 1990).

HERPES

Presentation

Reactivation of herpes simplex virus (HSV) is a common problem in symptomatic HIV-infected people. It manifests mainly as cold sores and occasionally intraoral ulceration. Of patients with or at risk of AIDS, 5-9% are seen with herpetic mouth ulcers (Barr and Torosian, 1986; Silverman et al, 1986; Reichart et al, 1987). If the herpetic infection lasts for more than four weeks it then becomes an AIDS defining opportunistic infection (Anonymous, 1986b). In one small study of 22 HIV-positive patients, HSV-2 was the predominant type, accounting for 88% of ulcers either alone (47%) or combined HSV-2, HSV-1 (41%), with HSV-1 alone causing 12% (MacPhail et al, 1989).

Herpes varicella zoster virus (VZV) reactivation involving the second or third branch of the trigeminal nerve can cause unilateral oral vesical

322 D . SMITH A N D D. CROSER

formation which leads to ulceration. These lesions are often extremely painful.

Diagnosis

The diagnosis is usually made clinically, based on the characteristic painful vesicle that ulcerates without purulent exudate. Confirmation of herpes infection can be made by swabbing the lesion with a dry swab placed in special viral transport medium. This is particularly important if atypical lesions cause diagnostic problems and if lesions are not responding to therapy to check for resistant viral strains.

Treatment

High-dose acyclovir (400 mg five times a day) is effective in reducing the duration and severity of HSV infections. However, some patients are prone to frequent recurrences and continuous maintenance therapy of 200-400 mg twice a day is required. Foscarnet (trisodium phosphonoformate) is also effective against herpes viruses and has been used with success in cases of acyclovir-resistant strains (Youle et al, 1988). VZV infections require acyclovir doses of 800 mg five times a day for seven days either orally or intravenously, in conjunction with appropriate analgesia.

ORAL HAIRY LEUCOPLAKIA

Oral hairy leucoplakia (OHL) is a condition thought to be almost patho- gnomonic of symptomatic HIV disease (Greenspan et al, 1984). Although it has been rarely found in bone marrow recipients (Epstein et al, 1988), renal transplant patients (Itin et al, 1988; Greenspan et al, 1989a) and some immunocompetent patients (Likimani et al, 1989), it is seen with much greater frequency in HIV-positive patients. It appears to be more common in HIV-positive homosexual men (15-29 % ) than in other risk groups such as intravenous drug users (7-13%) (Engelman et al, 1988; Ficarra et al, 1988; Sinicco et al, 1988; Loeb et al, 1989) and a higher incidence is associated with oral-genital sexual practices (Feigal et al, 1989). The timing of the development of OHL lesions is related to the decline in numbers of T4 helper cells to below 400/mm 3 (Gaglioti et al, 1989).

Presentation

Clinically OHL is manifested as white corrugated ribbed lesions that do not scrape off (Figure 2). The commonest site is the lateral border of the tongue (87%), followed by the dorsum of the tongue (29%), and less commonly the buccal mucosa (3%) or the soft palate (0.4%) (Greenspan et al, 1989b). It is almost never found on the hard palate but has been described in the oesophagus (Logan et al, 1990). The lesions are almost always asymptomatic and often go unnoticed. Rarely they are painful or irritating to the patient. This feature seems to be more common with oesophageal lesions, in


Figure 2. Bilateral corrugations on the lateral tongue with OHL.

which mucosal ulceration is frequently found (Logan et al, 1990). Over- growth by Candida is frequent, yet this appears to be unrelated to the pathogenesis of OHL, as the lesions persist after successful antifungal treatment.

Pathogenesis The development of OHL seems to be related to the interaction of Epstein- Barr virus (EBV) infected epithelial cells and the removal of cell-mediated immunity (Greenspan et al, 1985). Although human papillomavirus (HPV) infection was purported to be a corequisite for the development of OHL (Greenspan et al, 1984), HPV is not always isolated from the lesions by DNA hybridization, immunostaining or electron microscopy studies, whereas EBV can be detected by various techniques in ballooning epithelial cells as well as within intercellular spaces (Greenspan et al, 1984; Greenspan et al, 1988). EBV DNA can also be found in HIV-positive patients without OHL who later go on to develop clinical lesions as they become more immunocompromised (Naher et al, 1989). The predilection for the lateral border of the tongue may be related to the presence of EBV receptors on the parakeratinized mucosa (Corso et al, 1989). HIV DNA is not present in these altered cells and its relationship with this entity seems to be solely in providing the chronic immunosuppression required for the alteration of the latently EBV-infected epithelial cells.

Biopsy of OHL lesions reveals hyperparakeratosis, acanthosis of epithelial cells, characteristic koilocytotic prickle cells, reduced numbers of Langerhan's cells and few inflammatory infiltrates (Greenspan et al, 1984; Daniels et al, 1987).

324 D . SMITH A N D D. CROSER

Treatment

The majority of cases of OHL are asymptomatic and, as they do not appear to have malignant potential, treatment is usually not necessary. Spontaneous remission can occur with time (Freidman-Klien, 1986). Those occasional lesions that are painful may respond to treatment with antivirals. High-dose acyclovir in doses of 800 mg four times a day for seven to ten days is almost always effective, although lesions may reappear some time after treatment (Resnick et al, 1988) and chronic prophylactic therapy may be necessary. Topically applied vitamin-A-acid also has some effect, but only for the duration of treatment (Ochsendorf et al, 1988). Intravenous ganciclovir (DHPG) or Foscarnet (trisodium phosphonoformate) have been used with good effect in more severe cases of oesophageal disease (Newman and Polk, 1987).

Prognostic significance

OHL is an important clinical entity in HIV disease, not because of any sinister pathological ability within the lesions, but because it is an easily detected marker of developing immunosuppression. Patients with OHL are more likely to have lower T4 helper cell counts and progress to AIDS more rapidly than other asymptomatic HIV-positive patients without OHL (Engelman et al, 1988). One study has shown that 48% of patients with OHL had progressed to AIDS within 16 months and 83% within 31 months (Greenspan et al, 1987). Therefore OHL is an important prognostic indicator for disease progression and a useful clinical marker of when antiretroviral and prophylactic regimens against opportunistic infections should be initiated.

GINGIVITIS/PERIODONTITIS

HIV-associated gingivitis (HIV-G) and HIV-associated periodontitis (HIV-P) appear to be different manifestations of a similar phenomenon, namely the inflammation and destruction of gingival and periodontal tissue caused by the overgrowth of oral microflora in the presence of local and systemic immune dysfunction. HIV-positive patients may present with either condition or a combination of both, although it appears likely that gingivitis occurs at an earlier stage of immunosuppression than does necrotizing gingivitis and periodontitis.

Incidence

Routine oral examination of HIV-positive patients with no known other HIV-related illness will reveal either gingivitis or periodontitis in 3.3% of cases (Melnick et al, 1988). This figure increases to 51% in known AIDS patients (Roberts et al, 1988); 7% of these patients will have acute necrotizing ulcerative gingivitis (ANUG). ANUG is a more severe form of gingivitis and is found in all symptomatic risk groups for HIV infection:


6--12% of homosexual American ARC and AIDS patients (Reichart et al, 1987; Zakarian et al, 1988), 4% of heterosexual African patients (Mugaruka et al, 1989) and 9% of Argentinian patients (Casariego et al, 1989).

Advanced periodontitis is seen in 23% of AIDS patients, 83% of whom were homosexual or bisexual (Roberts et al, 1988). A similar incidence has been reported in heterosexual intravenous drug users (IVDUs), with 21% of IVDUs with AIDS having mild periodontitis, 16% having moderate disease and 21% having severe disease, with a significantly higher proportion in female versus male IVDUs (Quart et al, 1989).

In our own study of 100 HIV-positive patients attending a specialized dental surgery it was found that 12% of patients presented with HIV-G, 23% with ANUG and 29% with HIV-P. CD4 counts in these patients showed that presentation with either HIV-G or HIV-P was related to deteriorating immune status: 42% of patients with periodontitis had a CD4 count less than 200/mm 3 compared with 28% with gingivitis.

Presentation

HIV-G is often defined as erythema of the free gingiva, attached gingiva and alveolar mucosa. It is confined to the soft tissues and can either manifest as a band of erythema 2-3 mm thick between the free gingival margin and the attached gingiva or as diffuse gingival erythema (Winkler et al, 1989). Spontaneous bleeding is common as the disease becomes established. Patients may initially be asymptomatic or complain of generalized oral pain, especially when masticating. ANUG is a more advanced form of gingivitis characterized by gingival pain, swelling and mucosal ulceration, with rapid necrosis of the interdental papilla (Figure 3).

Figure 3. Acute necrotizing ulcerative gingivitis.


HIV-P shows all the features of HIV-G as well as rapid bone loss with possible bone sequestration, loosening and possibly exfoliation of teeth (Winkler and Murray, 1987). Patients often complain of a deep bony pain which may be severe enough to force them to stop eating. Halitosis and pyrexia may occur with either ANUG or HIV-P.

Pathology

Immunological typing of inflammatory cells found in the affected mucosa reveals a high proportion of activated T cells, monocytes and macrophages, with very few B cells in the inflammatory infiltrate (Stern et al, 1989). A number of oral bacteria have been implicated in the development of HIV-G and HIV-P. Rams and colleagues (1989) reported the proportional involvement of a variety of bacteria in ~17 patients with periodontal disease as Peptostreptococcus micros in 21%, Bacteroides intermedius in 16%, Actino- bacillus actinomycetemcomitans in 10%, Fusobacterium species in 9%, Wolinella species in 8% and spirochetes in 15%. When compared with HIV-positive well patients or HIV-negative controls there was a significantly greater isolation of Bacteroides species, Fusobacterium nucleatum and A. actinomycetemcomitans in both HIV-G and HIV-P sites (Winkler et al, 1988). The pathogenic role of these bacteria is supported further by the increased serum IgG antibody response seen in HIV-positive patients to B. gingivalis, B. intermedius, F. nucleatum, Eikenella corrodens and A. actinomycetemcomitans compared with HIV-negative controls (Grieve et al, 1988). Secondary overgrowth by Candida is common, but, as with OHL, treatment of the Candida alone will not improve the gingivitis or periodontitis.

Diagnosis

The diagnosis of HIV-G is made clinically on the typical appearances of inflamed gingival mucosa together with spontaneous bleeding and its failure to respond to normal scaling and polishing in an at-risk or known HIV- positive patient. Ulceration may be superimposed. HIV-P is also diagnosed on the clinical destruction of the interdental papilla, together with rapid bone loss, spontaneous gingival bleeding and acute oral pain (Abel and Andriolo, 1989). X-rays of the mouth are useful in determining the location and extent of bone loss, as periodontitis may not be limited to just one site. Microbiological sampling of gingival crevices is useful in determining the causative organisms and antibiotic sensitivities, and allows more accurate control of the condition (Volpe et al, 1985; Lynch and Naftolin, 1987).

Treatment

Conventional management of gingivitis with scaling, root planing and improved oral hygiene is only effective in some cases of HIV-G (Roberts et al, 1988) and HIV-P (Grassi et al, 1988). Cases which are reluctant to respond will benefit rapidly from a short course of systemic antibiotics.


Metronidazole 200 mg three times daily for five to seven days is extremely effective in relieving symptoms and decreasing the severity of the inflammation.

Areas of acute infection need careful debridement, and the use of povidone-iodine has an antimicrobial effect as well as an apparently topical anaesthetic effect which allows fairly painless mechanical cleaning of the area. After the acute episode has resolved it is necessary to completely remove all plaque and calculus from the necks of the teeth and to debride necrotic soft tissue back to a healthy base. This is done a week later when advice on oral hygiene is also given. The patient should be reviewed at regular intervals (three monthly). The long-term use of 0.12 % chlorhexidine solution in addition to the above regimen has been shown to be effective in some cases of HIV-P (Grassi et al, 1988).

The main aim of long-term management is maintaining the microbial levels low enough for the compromised immune system to handle. In this respect, the chlorhexidine mouthwash can be useful, whilst attention to oral hygiene motivated by regular reviews with the dentist or hygienist are essential.

Further acute exacerbations can usually be controlled by a short course of metronidazole or amoxycillin. Dental extractions are the last resort, usually where patient co-operation over oral hygiene is lacking or never existed.

GIANT APHTHOUS ULCERATION

Aphthous ulceration in the mouth occurs commonly in non-immunocompromised people (Antoon and Miller, 1960). HIV-infected patients appear to be more prone to the development of these ulcers, which are usually very painful and slow to heal.

Incidence

No prospective studies have been performed to document the true incidence of these ulcers and their relationship to the degree of immunosuppression. One study of 346 AIDS patients showed that 1.1% had giant aphthous ulcers persisting for more than two months (Phelan et al, 1988). Occasionally the ulcers may involve the oesophagus as well as the oropharynx (Bach et al, 1988).

Diagnosis

Diagnosis is made clinically on the finding of painful, often multiple ulcers in the oropharynx. The ulcers have an erythematous, clearly defined raised border with a clean white base (Figure 4). Swabs for Candida may be negative, as will viral cultures for herpesvirus. The histology is similar to that found with aphthous ulceration in Beh~et's syndrome, showing acute and chronic inflammation.


Figure 4. Multiple aphthous ulceration.

Treatment

The majority of ulcers will clear with local treatment consisting of cortico- steroid paste and regular chlorhexidine mouth rinses. Tetracycline paste has also been reported to be effective (Phelan et al, 1988). Empirical therapy with acyclovir, antibiotics or antifungals is ineffective. In a small number of patients the ulcers fail to heal with topical treatment and systemic measures are needed. Prednisone 40 mg daily is effective but recurrences can occur if the dose is tapered off too quickly (Bach et al, 1988). Thalidomide (100 mg daily) has also been used with good effect, but can be limited by its sedatory side-effects; again, long-term usage is often required to prevent recurrences (Youle et al, 1989).

WARTS

Incidence and site

HPV infections appear to become more common as people become more immune suppressed with HIV. These intraoral warts may present as oral papillomata, condylomata or focal epithelial hyperplasia (Scully et al, 1985). Papillomavirus was originally implicated as an aetiological agent in the development of OHL (Greenspan et al, 1984), but this is now refuted as HPV DNA is not found in all affected lesions and appears to be an incidental finding (Langford et al, 1988).


Figure 5. Extensive ulceration caused by cytomegalovirus.

Treatment

Local cryothermy or surgical excision are the treatments of choice for these lesions. Sexual partners may also have to be contacted for treatment and to prevent reinfection.

CYTOMEGALOVIRUS ULCERATION

Cytomegalovirus reactivation may present as mucosal ulceration in the oropharynx (Figure 5). This is usually a late stage presentation and the differential diagnosis includes giant aphthous ulcers, herpes ulceration, atypical ulcerative gingivitis and lymphoma. The diagnosis is made on the typical histopathological features at biopsy. Repeated biopsies may be necessary before the diagnosis can be confirmed. Treatment is with either ganciclovir (5 mg/kg twice daily) or Foscarnet (21-200 mg/kg daily depending on renal function) for 14-21 days, depending on clinical response. Repeated courses or continuous maintenance therapy may be required.

KAPOSI'S SARCOMA

Incidence

Kaposi's sarcoma (KS) occurs in approximately one third of HIV-infected homosexuals, and with lesser frequency in other risk groups (Des Jarlais et


al, 1984). Intraoral KS is found in 10-25% of HIV-positive patients (Volberding, 1988) and is the only manifestation in 10-39% of these (Silverman et al, 1986; Reichart et al, 1987). In patients with an AIDS diagnosis, 20-45% of homosexuals and 6% of IVDUs have oral KS (Barr and Torosian, 1986; Silverman et al, 1986).

Pathology

KS is thought to be a neoplasm of endothelial origin. Histologically, spindle cells are enmeshed in a network of proliferating capillaries with a surrounding lymphoid infiltrate (Groopman, 1987).

Presentation

Clinically KS appears as raised reddish-purple macules (Figure 6), often with surrounding bruising from the leakage of red blood cells from the highly vascular lesion. They are often painless until mechanical distortion of normal tissue or ulceration occurs.

The palate is the commonest oral site, accounting for 89% of the lesions in one study (Reichart et al, 1987). Lesions may also be found on the gingiva, tongue, buccal mucosa and lips.

Treatment

As the majority of lesions in the mouth are painless, slow-growing and do not trouble the patient (and as treatments are palliative rather than curative)

Figure 6. Multiple intraoral KS.

O R A L MANIFESTATIONS OF H1V DISEASE 331

most clinicians would adopt a 'watch and see' policy. Treatment is usually reserved for lesions that are painful, bleeding or growing aggressively. Therapy may be either local or systemic, as patients may often be troubled by the effects of lesions in multiple sites.

Local treatment

Solitary small lesions in the mouth may be removed by surgical excision, although this is not feasible for the majority of lesions involving the hard palate as good tissue closure and healing is difficult. Local radiation therapy using fractional treatments up to a total dose of 1500 cGy was shown in one study to cause regression of signs and resolution of symptoms in all 34 patients treated (Ficarra et al, 1989). In an attempt to avoid the mucositis often seen after radiotherapy, some centres have used carbon dioxide laser treatment to good effect, even on lesions on the hard palate, resulting in reduced treatment-associated morbidity and hospital stays (Hadderingh and Meulen, 1989).

Another form of therapy that is effective in reducing tumour size and clinical symptoms with few associated side-effects is intralesional chemotherapy. A number of agents have been used, primarily vincristine or vinblastine. One small study of ten patients showed that 0.2-0.8rag of intralesional vinblastine resulted in a 50% reduction in tumour mass, increasing to 63% if a second injection was given (Epstein et al, 1989).

Systemic treatment

Systemic therapy is usually considered appropriate when symptoms arise from large coalesced lesions with surrounding oedema and painful tissue distension on a scale that would make local radiotherapy or intralesional therapy ineffective. It should be remembered that when oral KS lesions become aggressive this is often a reflection of the activity of other KS lesions throughout the body, and symptoms or cosmetic concerns from these other lesions need to be addressed at the same time. High-dose recombinant interferon-et2 has been shown to cause regression of tumour in approximately half the patients treated, although this response may be associated with the immunomoderatory properties of interferon rather than cytotoxic activity (De Wit et al, 1988). Similarly, we have seen cessation of activity of KS lesions in patients given antiretroviral treatment with zidovudine (Stambuk et al, 1988).

Systemic treatment with chemotherapeutic agents has been used for disseminated lesions with some success, although such therapies are limited by their side-effect profile, especially bone marrow toxicity when the majority of patients will concurrently be subjected to the myelotoxicity of zidovudine. Vinblastine is perhaps the most widely used agent (Volberding et al, 1985), although doxorubicin or etoposide are also useful (Groopman, 1987).

332 D. SMITH A N D D. CROSER

PAEDIATRIC ORAL DISEASE

As well as being a major cause of morbidity in HIV-infected adults, oral pathology causes considerable problems in the paediatric setting. Diseases such as OHL, KS, oral warts and periodontitis appear to be less common in the infant, but there is an increased incidence of candidiasis, parotid and salivary gland enlargement and dental caries. One small study of 24 children revealed that two thirds had some oral pathology: 33% had candidiasis, 16% had parotid gland enlargement, 10% had dental caries, 3% had submandibular gland enlargement and 3% had leucoplakia (Mastrucci et al, 1988). The development of oral pathology in infants perhaps carries greater significance than in adults, as it is often difficult to determine an infant's HIV status, given the persistence of maternal antibodies. In this setting following the disease progression relies more heavily on the emergence of clinical features than on laboratory markers. Clinical follow-up of more than one year in 123 babies born to HIV-infected mothers showed that ten developed ARC or AIDS; of this group, 90% had oropharyngeal markers of HIV disease (persistent oral Candida in nine and parotid swelling in two out of the ten) (European Collaborative Study, 1988). Another study of 165 infected children showed that 11 had parotitis as their clinical marker of HIV infection (Italian Multicentre Study, 1988).

Therefore, the early detection of oropharyngeal disease in children is of great importance, not only in terms of treatment of the local condition but also in its implications for the long-term survival of the infant.

CONCLUSIONS

In conclusion, there are a large number of conditions arising in the oral cavity as a result of HIV infection. Although they are mostly not life- threatening diseases, they do cause considerable morbidity and are important clinical markers for determining an individual's immune status. As a number of these conditions are asymptomatic it is important that regular examination of the oral cavity is carried out on all patients known to be HIV infected.

The diagnosis of each individual condition can usually be made clinically, but confusion can arise when looking at the early stages of a disease, for example erythematous candidiasis may mimic early gingivitis, or in the determination of mucosal ulceration, where the causative disease may be herpes simplex infection, giant aphthous ulceration, cytomegalovirus ulceration or even lymphoma. In these instances appropriate swabs and if necessary biopsies may be needed to make the diagnosis.

The prognostic significance of different oral lesions must not be over- looked. There are now a number of large studies relating the occurrence of various oropharyngeal diseases to progression to an AIDS diagnosis; therefore patients with these diseases may benefit from early intervention with antiretroviral agents or prophylaxis against the more common opportunistic


infect ions such as Pneumocys t i s carinii p n e u m o n i a , toxoplasmosis or d i s semina ted cytomegalovirus .

Perhaps the most impor t an t lessons that can be learn t abou t H I V disease by m a n a g i n g oral mani fes ta t ions is that , a l though therapy may be effective init ial ly, the unde r ly ing causative aet iology persists after t r e a t m e n t and therefore recurrences are to be expected. The impl ica t ion of this is that once an acute exacerba t ion has been managed , con t inuous prophylact ic measures may be required . Also, as i m m u n e suppress ion worsens over t ime, topical therapies may lose their effectiveness and systemic therapy becomes essential .

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