Oral Manifestations of HIV Infection

Studies have estimated that more than 90% of persons with human immunodeficiency virus (HIV) infection will have at least one oral manifestation at some time during the course of their disease [1, 2]. A summary of these studies has shown that the frequency and type of oral lesion varies with the patient's stage of disease and degree of immunosuppression [2]. The studies often contradict each other about when a particular manifestation may first appear and about the relative frequency of a given lesion; the discrepancies seem to be a function of the populations studied. All, however, agree that the risk for oral complications increases as further immunologic impairment develops [3-9]. Table 1 summarizes our impressions of the consensus of these studies. Data also identify oral diseases as a marker for deteriorating immune function independent of CD4+ lymphocyte count. The identification of such lesions may, therefore, have prognostic significance for the development of the acquired immunodeficiency syndrome (AIDS) in affected patients [10-13]. Table 1. Occurrence of Oral Lesions during the Stages of HIV Infection* Severely compromised oral health has serious implications for the general health of patients with HIV infection. Left untreated, oral disease can result in odynophagia and dysphagia, which may interfere with talking, chewing, and swallowing. Persons with severe pain reduce their oral intake of nutrients, resulting in weight loss, dehydration, malnutrition, and the HIV wasting syndrome. Prevention and treatment of oral disease are important in maintaining quality of life and preventing more serious complications. Thus, it is important that physicians recognize the earliest signs of the most common oral diseases so that they can diagnose and treat the disease and provide appropriate dental referrals. 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. Table 2. Presenting Signs and Symptoms of Oral Health Problems 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). Table 3. The 4-Minute Oral Examination 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. Figure 1. White or yellowish white lesions associated with human immunodeficiency virus infection. Top. Upper middle. Lower middle. Bottom. 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. Table 4. Characteristic Clinical Features and Locations of Oral Manifestations of Human Immunodeficiency Virus Infection 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]. Table 5. Diagnosis of Oral Diseases Associated with Human Immunodeficiency Virus Infection and Management and Referral of Patients with These Diseases* 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 tech