Oral Manifestations of HIV Infection

Methods

To identify these conditions and develop a guide to assist physicians in the diagnosis of the oral manifestations associated with HIV infection and the management and referral of patients with these manifestations, we did a comprehensive search of the medical and dental literature. Our principal data source was the National Library of Medicine's AIDSLINE database, which was searched using the term “mouth diseases.” More than 600 abstracts were located, and these were reviewed by at least two of the authors. We then reviewed the articles associated with these abstracts, which addressed the frequency of the conditions, the physical appearance of the lesions, diagnostic methods, or treatment or referral guidelines. The bibliographies of these articles occasionally included other, related articles or books; these were also reviewed. We report on those oral conditions that the literature indicates are likely to appear in more than 1% of patients with HIV infection. Sixteen such conditions were identified.

History and Oral Examination

Our review indicated that the major oral manifestations of HIV infection can all be seen or palpated during the physical examination. In addition, almost all of these conditions produce subjective symptoms that are noticeable to patients. Therefore, the first steps in the recognition of these conditions are the history and the physical examination. Patients who have HIV (whether they are known to be infected or not) often present with symptoms of oral disease. They may not voice these concerns to their physicians because they believe that the mouth is the province of the dentist. Therefore, the physician may have to prompt the patient with some basic questions. The areas that should be covered when a history is taken are shown in Table 2. Physicians should also note the general oral affect of the patient.

Any symptom voiced by the patient and any suggestive affect observed by the physician indicate the need for a thorough oral examination. Such an examination should also be done periodically in any HIV-infected patient who is receiving continuing care. Physicians typically limit oral examinations to the dorsum of the tongue and the visible pharynx, but the patient who is known to be or is suspected of being infected with HIV requires more systematic and thorough attention. This is necessary to avoid overlooking any problems and thereby missing important information that may affect diagnosis and treatment plans. This examination need not be time-consuming; it can be done in a few minutes (Table 3).

The oral examination may show numerous lesions. One of the 16 oral conditions commonly seen in HIV-infected patients, angular cheilitis (Figure 1, top), is diagnosed through simple observation, without an examination of the oral cavity. It is characterized by macerated tissue in the corners of the mouth, which results from an overgrowth of Candida albicans. The procedures for a definitive diagnosis of candidal infection are described below. Uncomplicated angular cheilitis is treated with nystatin cream; refractory cases may require systemic antifungal therapy. Treatment is almost always successful, but the condition is likely to recur.

Other HIV-related oral conditions may be noted during the oral examination. Lesions are most easily classified according to their physical appearance or color, or both. On the basis of these factors, a differential diagnosis can be developed. The physical characteristics of interest are 1) white or yellowish white nonulcerative lesions of the oral mucosa, 2) red or reddish purple nonulcerative lesions of the oral mucosa, 3) ulcers, and 4) oral structures with abnormal appearance.

White or Yellowish White Nonulcerative Lesions

Oral candidiasis is the most common cause of white lesions in the mouth. This condition is rare in patients who are not infected with HIV, and it is usually associated with the use of broad-spectrum antibiotics or steroid-based therapies. However, it is a common feature of HIV infection and occurs in as many as 75% of HIV-infected patients [14]; it has been shown to be a precursor to the development of AIDS [15-18]. Oral candidiasis may present in several clinically distinct forms, the most common being pseudomembranous candidiasis, often referred to as “thrush” (Figure 1, upper middle), and hyperplastic candidiasis, also known as candidal leukoplakia (Figure 1, lower middle). The clinical features of these conditions are described in Table 4.

Diagnosis of these forms of candidiasis is often presumptive and made on the basis of clinical appearance [19-21]. Yet when clinical manifestations are subtle or uncertain, direct examination using a potassium hydroxide preparation may help to confirm the diagnosis [22]. The presence of fungal hyphae distinguishes infection from colonization. Hyperplastic candidiasis represents a superficial invasion of C. albicans; thus, tests done using potassium hydroxide preparations may have false-negative results. Positive cultures for Candida do not provide absolute evidence of oral candidiasis because C. albicans is a common oral commensal organism [23]. The clinician may choose to initiate empirical therapy and refer the patient to an oral pathologist for tissue biopsy, which is useful in distinguishing candidal leukoplakia from other white lesions, such as oral hairy leukoplakia (note the similarity between the lower middle and bottom panels of Figure 1).

Once identified, all forms of oral candidiasis should be treated as uncontrolled infections with the potential for local and even esophageal extension. This infectious process may be accompanied by pain and altered taste sensation, both of which interfere with nutrition and hydration. Management begins with the elimination of potential predisposing agents, such as broad-spectrum antibiotic therapy. Treatment involves both topical and systemic antifungal agents (Table 5) and may include the use of nystatin or clotrimazole suspension, ointment, or troches [24]. Oral candidiasis in HIV-infected patients usually responds to initial topical therapy, but recurrences are common and often require the use of systemic agents for both treatment and maintenance therapy [25, 26]. Ketoconazole has been used for systemic treatment but is poorly absorbed in patients with achlorhydria, a condition present in many patients with advanced AIDS [27]. Fluconazole has gained favor as the systemic azole of choice because of its rapid response rate, longer half-life, and better side-effect profile [28-30]. Several recent reports of resistance to fluconazole have been published [31-33]; itraconazole and ketoconazole have been used successfully in cases of resistance to fluconazole [34-36]. Refractory cases may require topical or intravenous amphotericin B [23, 28, 37].

In the absence of any other identified cause of immunosuppression, oral hairy leukoplakia can be considered diagnostic of HIV infection [38] (Figure 1, bottom). The reported prevalence of this lesion can be as great as 42%, depending on the stage of HIV infection [8]. Rapid progression to AIDS in a significant proportion of patients with oral hairy leukoplakia has been described [13, 39]. The lesion is thought to be virally induced as a result of the reactivation of latent Epstein-Barr infection [40].

A presumptive diagnosis based on typical clinical appearance and location of the lesion is usually adequate (Table 4). However, if confirmation is sought to rule out other leukoplakic lesions, then a mucosal biopsy specimen that shows Epstein-Barr virus DNA is required [41]. An alternative, noninvasive technique that uses either filter or cytospin in situ hybridization can show the presence of Epstein-Barr virus [42]. The differential diagnosis of oral plaques includes hyperplastic candidiasis (also known as candidal leukoplakia) (Figure 1, lower middle), tobacco-associated leukoplakia, epithelial dysplasia, and lichen planus [20, 23]. Because oral hairy leukoplakia is benign and usually asymptomatic, treatment is elective (Table 5) [22]. Topical application of trichloracetic acid or glycolic acid has been reported to be effective therapy for this condition [43]. Good results have also been reported with the topical application of podophyllum resin, 25% solution [44]. Oral acyclovir also suppresses oral hairy leukoplakia [37]. None of these treatments eliminate the Epstein-Barr virus, and they should be considered palliative because the condition recurs after treatment is discontinued. The benefit of continuous treatment with acyclovir is questionable because of this drug's potential to promote the emergence of acyclovir-resistant herpes simplex virus.

Red or Reddish Purple Nonulcerative Lesions of the Oral Mucosa

Smooth, red patches on the hard or soft palate, buccal mucosa, or tongue characterize the erythematous or atrophic form of oral candidiasis (Figure 2, top). Diagnosis and treatment are the same for this condition as they are for the other forms of candidiasis (Table 5).

Kaposi sarcoma is a multifocal neoplastic proliferation of endothelial cells that is predominately found in men with HIV infection (Figure 2, upper and lower middle). Historically, this sarcoma has been found only in elderly men of Mediterranean descent and in persons living in Africa. Several recent studies [45-47] have implicated a newly discovered herpesvirus as a possible cause of this neoplasm. The recent demonstration of fragments of this virus in semen suggests that the disease may be sexually transmitted [48]. As a manifestation of HIV infection, Kaposi sarcoma has been reported in 15% of patients with AIDS [49], and a high proportion of these patients have an oral or perioral lesion [50]. These lesions may actually be the initial manifestation of Kaposi sarcoma in as many as 60% of cases [51].

If cutaneous or visceral Kaposi sarcoma has already been shown, oral Kaposi sarcoma may be diagnosed clinically [52]. However, if a solitary oral lesion is noted as a potential, initial manifestation of this malignant condition, then biopsy is needed to establish the diagnosis and rule out lesions of similar appearance, such as hemangioma or hemorrhage. Intraoral Kaposi sarcoma lesions are frequently asymptomatic, but, as they progress, patients may have pain associated with ulceration, bleeding, or superinfection.

Treatment decisions are made on the basis of the extent of disease. For lesions confined to the oral cavity, local therapy may include surgical excision, radiotherapy, or intralesional chemotherapeutic injections. A recent report [53] also suggests that a sclerosing agent, 3% sodium tetradecyl sulfate, may be beneficial. Systemic therapy is usually reserved for patients with widespread progressive disease [54]; in this setting, dentists are considered to be cotherapists, working in close consultation with both the primary physician and the oncologist. Intralesional injections of vinblastine [52, 55] or interferon-α are reported to be effective in the palliation of oral Kaposi sarcoma [56, 57], but treatment usually requires several visits to a dentist before a response is achieved. Repeated treatments are possible because of a lack of cumulative side effects, but local pain and mucosal ulceration may occur [51]. Liposomal doxorubicin has also been shown to be effective in the treatment of this condition [58].

Non-Hodgkin lymphoma is the second most common malignant condition associated with HIV infection (Figure 2, bottom). The oral form of this condition is rarely found in persons who do not have HIV infection and, when present, is not nearly as aggressive as it is in those with HIV infection. It is less common than Kaposi sarcoma, but its incidence continues to increase [59, 60]. Lymphomas present as a focal soft tissue swelling that may be red and inflamed. These lesions can be painful and progress rapidly. Suspected lesions are diagnosed through tissue biopsy. Management of these conditions requires systemic combination chemotherapy. For large exophytic or pedunculated lesions, surgical debulking is useful for relieving pain and reducing interference with chewing and speaking. Because of their large size and location, some lesions may be hard to access. In such cases, radiotherapy—preferably delivered in fractionated doses to reduce the frequent complication of mucositis—is the treatment of choice [61]. Treatment is almost always palliative and not curative.

Physicians need to encourage good oral hygiene and frequent professional cleanings for patients with Kaposi sarcoma lesions or lymphomas because these lesions may become infected in advanced stages [20]. Patients require ongoing dental consultation to help prevent and manage the specific oral complications of mucositis, xerostomia, and the increased risks for bacterial or fungal superinfection that are associated with both chemotherapy and radiotherapy [62].

Table 4 summarizes the recognition of these disorders; the diagnosis and management of the neoplastic manifestations associated with HIV infection are shown in Table 5.

Oral Ulcers

Oral ulcers occur in as many as one half of HIV-infected persons at some time during the course of infection. The differential diagnosis includes ulcers caused by herpesvirus infections, idiopathic ulcers (“recurrent aphthous ulcers”), and iatrogenically induced ulcers secondary to drug therapy.

Various viruses produce mucosal lesions in patients infected with HIV [63]. Human herpesvirus infections are seen throughout the clinical course of HIV infection, with recurrent oral vesicular lesions that are usually attributed to herpes simplex virus (Figure 3, top). Intraoral, perioral, and cutaneous outbreaks affect approximately 10% to 25% of persons with HIV infection [37]. Oral herpes simplex infections (such as cold sores and fever blisters) are common throughout the general population, but recurrent herpes simplex virus disease manifests as a more aggressive and protracted illness in HIV-infected persons [64]. These erosive, painful ulcerations may persist for several weeks and can extend to the esophagus [21, 23]. Although a presumptive diagnosis is most often made on clinical grounds, oral ulcerations may represent several opportunistic conditions. Confirmation is made on the basis of the appearance of characteristic giant cells on a cytologic smear or viral isolation in tissue culture [19]. Some studies [65, 66] suggest that the results of viral culture may be imprecise; therefore, tissue biopsy and the use of monoclonal antibodies may be required.

Herpes simplex virus lesions often heal spontaneously, but some patients have prolonged bouts of frequent recurrences that are accompanied by severe pain and local tissue destruction. Initiating treatment at the onset of symptoms is therefore recommended. Oral acyclovir remains the standard first-line therapy and is usually given for 10 to 14 days. Therapy reduces viral shedding and hastens the course of healing. Parenteral therapy may be necessary for more severe cases, and maintenance therapy is often required to suppress further recurrences [26, 37]. If lesions do not respond to standard therapy, resistance to acyclovir may be present [26, 67]. In patients with acyclovir-resistant herpes simplex virus, foscarnet therapy has been shown to have good clinical efficacy [68].

Other herpes viruses that should be included in the differential diagnosis of oral ulcers are mucocutaneous varicella-zoster virus and cytomegalovirus (Figure 3, upper middle and lower middle). Conditions caused by these viruses are almost unknown in immunocompetent persons but occur in a small percentage of HIV-infected patients. Varicella-zoster virus is usually treated with oral acyclovir, but severe cases may require prolonged parenteral acyclovir therapy [26]. Unfortunately, this treatment is suppressive, and the condition may recur. Punched-out, nonhealing oral ulcers may be a manifestation of disseminated cytomegalovirus infection. Patients should be referred for tissue biopsy to confirm the diagnosis [19, 20]. If cytomegalovirus is suspected or diagnosed, an ophthalmologic consult should be obtained to rule out cytomegalovirus-associated retinitis. The treatment for oral cytomegalovirus has not been established. Foscarnet and ganciclovir are known to be effective therapies for cytomegalovirus-associated retinitis and may be useful in treating the oral condition.

Shallow, well-circumscribed lesions, known as recurrent aphthous ulcers, are commonly found in both the general and the HIV-infected populations, but they occur more frequently and are far more severe in the latter. The cause of recurrent aphthous ulcers has not been determined, but no evidence suggests an infectious organism. Recurrent aphthous ulcers are described as minor or major according to size, depth of ulceration, and duration. Minor recurrent aphthous ulcers are less than 1 cm in diameter and are typically self-limiting. They are rarely associated with odynophagia or dysphagia. In contrast, major recurrent aphthous ulcers (Figure 3, bottom) are greater than 1 cm in diameter, extend deep into connective tissue, are prolonged in duration, and heal with scarring. They are progressive, chronic, and slow to heal [19]. They are painful and may interfere with speech and swallowing; thus, they may contribute to inadequate oral intake and rapid weight loss [69]. When recurrent aphthous ulcers mimic other lesions, referral for biopsy to confirm the diagnosis is indicated [21]. The histologic appearance of a lesion is that of a nonspecific ulcer with diffuse inflammation.

Treatment regimens for recurrent aphthous ulcers include topical steroids to reduce inflammation and accelerate healing, topical anesthetic to reduce pain, and adherent dressings to minimize incidental trauma [20, 26, 70]. A Decadron (Merck & Co., West Point, Pennsylvania) elixir rinse is an alternative for inaccessible lesions [20]. If these lesions do not respond to topical corticosteroid therapy, systemic prednisone can be used [37, 71]. As they must with all steroid-based therapies, clinicians should remain alert to the potential development of oral candidiasis. A recent double-blind trial reported by the National Institute of Allergy and Infectious Diseases has shown that thalidomide is effective for treating recurrent aphthous ulcers. The drug should not be used in pregnant women or in women at risk for pregnancy because it has a high potential for causing serious birth defects [72]. Successful treatment of recurrent aphthous ulcers does not eliminate the possibility of recurrence.

Other ulcerative lesions to consider include those of iatrogenic origin. Oral ulcers may occur after the use of foscarnet [73], interferon [74], or zalcitabine [75, 76]. Severe oral ulcerations have also been described as a consequence of radiation therapy for lymphoma, intralesional vinblastine injections, and the use of vincristine for intraoral Kaposi sarcoma lesions [55, 56]. Discontinuing therapy often eliminates the ulcer, but the value of discontinuation must be weighed against the patient's need for the causative agent and the availability of other drug regimens.

Table 4 shows the clinical characteristics of the ulcerative oral lesions associated with HIV infection. The diagnosis and management of these conditions are described in Table 5.

Structures with Abnormal Appearance

These include the gums, teeth, salivary glands, and other perioral structures. There are two categories of these conditions: periodontal disease and salivary gland disorders.

Periodontal Disease

This is a common condition that usually takes many years to develop and is typically pronounced only in elderly persons. Rapidly progressive and painful periodontitis is frequently an early symptom of HIV infection [77]. Published prevalence rates among HIV-infected persons range from 16% to 52% [78]. Patients with HIV infection who have periodontal disease often present with deep pain and spontaneous bleeding that usually occurs at night or with tooth brushing. Without appropriate and timely medical and dental intervention, untreated periodontal disease can progress to a serious and life-threatening infection.

Periodontal disease in HIV-infected patients has four distinct phases. The earliest periodontal manifestations are usually confined to the soft tissues of the mouth and are characterized by profound erythema of the free gingival margin adjacent to the teeth (linear gingival erythema) (Figure 4, top). This can be followed by necrotizing gingivitis (Figure 4, upper middle), which may progress and involve the underlying alveolar bone (necrotizing periodontitis) (Figure 4, lower middle). Occasionally, this condition progresses to involve adjacent soft tissue and underlying nonalveolar bone (necrotizing stomatitis) (Figure 4, bottom) [23]. These conditions are described in Table 4.

The disease process is thought to be caused by mixed aerobic and anaerobic bacterial flora, but severe cases are usually caused by gram-negative bacilli such as Klebsiella pneumoniae and Enterobacter cloacae[2]. Recent reports [79, 80] suggest that a previously unidentified spirochete may also be a causative organism. Standard therapies for the typical, indolent forms of gingivitis and periodontitis are ineffective in persons with HIV infection. Control and management of this aggressive and potentially destructive process require frequent dental visits in addition to a committed, at-home, daily oral hygiene routine [22, 26]. Clinicians should encourage patients to brush and floss meticulously to achieve a maximum level of oral health. Further management is solely the province of the dentist [77] and requires a multistep regimen of debridement, local and systemic antimicrobial therapy, immediate follow-up care, and regular long-term maintenance [78]. The dental referral also requires close communication between the physician and the dentist to avoid conflicting advice and prescriptions.

Intervention is usually intensive curettage and debridement of all involved tissues. A regimen of topical antiseptic agents, such as povidone-iodine solution and chlorhexidine (Peridex; Proctor & Gamble Pharmaceuticals, Inc., Cincinnati, Ohio) mouth rinses, is often initiated as adjunct therapy. This regimen should be continued until all diseased hard and soft tissues are removed and the patient is no longer symptomatic [19, 20]. Despite such intense intervention, patients may develop necrotizing stomatitis. In such cases, curettage, debridement of involved tissue, and topical antimicrobial therapy should be supplemented by a short course of systemic antimicrobial therapy, usually metronidazole [23, 78]. Clindamycin and amoxicillin have also been recommended [81]. Long-term antimicrobial therapy is not recommended because the potential for candidal superinfection is always present. Recurrences are common and result in delayed healing and continued destruction of soft tissues and bones. The importance of regular and long-term oral hygiene cannot be overemphasized by the primary physician [24] because tooth extraction is required after bony necrosis and sequestration have occurred. However, if overall periodontal health can be stabilized after extraction, major restorative dental work can be initiated. These treatments are summarized in Table 5.

Salivary Gland Disorders

Several salivary gland disorders have been noted in patients with HIV infection. Notably, parotid gland enlargement, an unusual condition in immunocompetent persons, often accompanies a syndrome of persistent generalized lymphadenopathy. This condition is thought to be caused by lymphoid proliferation in response to HIV infection. A recent study [82] linked this condition to the presence of antibodies to human T-cell lymphoma virus type 1 [82]. It may manifest as unilateral or bilateral non-tender gland enlargement with xerostomia [83, 84]. The prevalence rate among children with HIV infection ranges from 0% to 58%, depending on the population studied [64, 85]. The condition is seen considerably less often in adults [85-87].

The nature of any parotid mass should be evaluated to differentiate cystic from solid lesions. This is best accomplished with computed tomography [88]. Often, patients are referred to a head and neck specialist for fine-needle aspiration that serves both diagnostic and therapeutic purposes. This procedure provides tissue for microbiological evaluation and effective decompression of painful recurrent cystic masses. Although malignant conditions and infection are always a concern, tissue sampling is likely to show the histologic appearance of a benign lymphoepithelial process [88]. If sampling does not confirm the diagnosis, biopsy by superficial parotidectomy can be done [83].

No definitive treatment is indicated for HIV-related salivary gland disease, but efforts should be made to relieve the symptoms of xerostomia. This includes using sugarless chewing gum to stimulate salivary flow and artificial saliva to provide lubrication. Pilocarpine is also useful for stimulating any residual functional salivary acini. Frequent dental cleanings and the use of topical fluoride should be encouraged to help maintain optimal oral hygiene and prevent xerostomia-associated dental caries [2] (Table 5).

Discussion

Sixteen oral manifestations related to HIV infection were found to occur frequently. Seven of these conditions are caused by specific infectious organisms (such as C. albicans, herpes simplex virus, herpes-zoster virus, and Epstein-Barr virus) and can be suppressed with systemic drug therapies. All, however, are likely to recur after cessation of treatment. No therapy has yet been approved for cytomegalovirus-associated ulcers. Topical treatments are helpful in suppressing candidiasis, recurrent aphthous ulcers, and oral hairy leukoplakia. These conditions are also likely to recur after successful treatment. No specific cures have been shown for the oral malignant conditions (Kaposi sarcoma and non-Hodgkin lymphoma) associated with HIV infection, but palliative treatments for these conditions are available. These treatments not only make the patient more comfortable but also improve the patient's ability to drink, eat, and speak, which allows the patient to maintain hydration, nutritional status, and social interaction. Periodontal disease associated with HIV infection is likely to be severe, leading to pain, an inability to eat and drink, and tooth loss, which will further compromise general health. Management of this condition is difficult and is the province of the dentist. Treatment is seldom completely successful, but these conditions can be stabilized. Salivary gland disease is also found in patients with HIV infection and has no specific treatment. However, the resulting lack of saliva can be alleviated, thereby preventing dental caries and discomfort.

Patients with HIV infection may not have a regular source of dental care, or their dentists may lack experience with the oral manifestations of this infection. Therefore, the physician must aggressively examine patients for oral manifestations and assume the responsibility of diagnosing and treating these conditions or arranging for appropriate referral. This requires a systematic approach to history taking, examination, diagnosis, and treatment or referral. The physician plays an important role in educating the patient about the need for good oral hygiene in the prevention and treatment of these conditions.

The care of patients with HIV infection also necessitates a strong working relationship with the dentist, who should be considered a copractitioner who can provide diagnostic insight and valuable treatment. An appreciation of the dentist and his or her role in diagnosis and treatment will help physicians coordinate care and ensure that patients receive the best possible treatment.

Dr. Grimes: University of Texas, School of Public Health, RAS 345, PO Box 20186, Houston, TX 77225-0186.

Dr. Lynch: Office of the Dean, College of Dentistry, University of Tennessee, 875 Union Avenue, Memphis, TN 38163-2110