HIV-related oral disease

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HIV series

HIV-related oral disease Deborah Greenspan, John S Greenspan Few people with HIV infection fail to experience oral lesions during the course of their disease. Oral mucosal and salivary gland manifestations include several that were not seen before the AIDS epidemic, while others are more severe in this population. Oral lesions reflect HIV status and the stage of immunosuppression, are important elements in HIV staging and classification schemes, raise pertinent questions about mucosal aspects of immunosuppression, and provide therapeutic challenges. Their pervasive nature and biological significance emphasise the importance of a careful oral examination as part of the general clinical evaluation. The years of the AIDS epidemic have taught us many lessons about oral disease. New oral lesions have been discovered, while old diseases have appeared in new guises. Certain oral lesions play a specific part in diagnosis and staging of HIV infection.1 Their presence in individuals whose HIV serostatus is unknown strongly suggests HIV infection; in patients known to be HIV infected, development of oral candidosis or hairy leukoplakia—often the first identifiable HIV-associated lesions—indicates that the battle between HIV virion production and infection of immunologically important cells on the one hand, and replacement of those cells on the other hand, has shifted in favour of the retrovirus. These observations have led to the almost universal inclusion of oral lesions in natural history studies and in staging and classification schemes for HIV infection. The oral lesions can cause pain, discomfort, and other symptoms and in most cases warrant treatment. The panel shows the wide variety of HIV-related oral lesions; this review concentrates on those encountered most commonly.

Oral candidosis Oral candidosis, the commonest oral fungal disease, is often a part of the acute HIV syndrome2 as well as a common problem when the CD4 count falls.3 Candida albicans is the predominant species, but C tropicalis, C glabrata, and C krusei occur occasionally and this diversity has implications for choice of and response to therapy. Oral candidosis has several distinct clinical forms. Pseudomembranous candidosis (thrush) is characterised by removable white or creamy plaques consisting of a mixture of fungal hyphae, desquamated epithelium, and inflammatory cells. These plaques can appear anywhere on the oral and pharyngeal mucosa. Erythematous candidosis is less obvious, manifesting as smooth depapillated areas on the palate and dorsal surface of the tongue. This type is easily missed but it is just as important a marker of progression of HIV infection Lancet 1996; 348: 729–33 Department of Stomatology and the Oral AIDS Center, School of Dentistry, University of California San Francisco, San Francisco, CA, USA (D Greenspan DSc , J S Greenspan FRCPath) Correspondence to: Dr Deborah Greenspan, Department of Stomatology, Room S612, Box 0422, 513 Parnassus Avenue, University of California San Francisco, San Francisco, CA 94143-0422, USA

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as the more obvious pseudomembranous form.4 Hyperplastic candidosis, which presents as nonremovable white patches, is rare; hairy leukoplakia is sometimes misdiagnosed as this lesion, but the white patches of hyperplastic candidosis are homogeneous, lacking the corrugations seen in hairy leukoplakia, and may disappear with antifungal therapy. Angular cheilitis, another form of oral candidosis, occurs as cracking, fissuring, and redness at the commissures; these lesions may be unilateral or bilateral and may be seen in association with any of the intraoral presentations. Changes in taste and complaints of a burning sensation are common symptoms. Reports early in the AIDS epidemic suggested a frequent concurrence of pseudomembranous oral candidosis and oesophageal candidosis, an AIDS diagnosis. Subsequent studies have failed to confirm this association—oral candidosis is commonly detected even in otherwise apparently healthy HIV-positive individuals, with a point prevalence in such populations approaching 20% when both erythematous and pseudomembranous forms are considered.5 As the CD4 count falls, the prevalence increases.6 Oral candidosis is also common in HIV-positive children.7 Among such children who are symptom free, the prevalence ranges from 11% to 20%, rising to over 70% in those with advanced HIV disease. How the fungus Panel: HIV-related oral disease Fungal Oral candidosis Pseudomembranous candidosis Erythematous candidosis Hyperplastic candidosis Angular cheilitis Histoplasmosis Cryptococcosis Penicillinosis Viral Herpes simplex Primary herpes Recurrent herpes labialis Recurrent intraoral herpes Herpes zoster CMV ulcers* Hairy leukoplakia* Warts

Bacterial Periodontal disease Linear gingival erythema* Necrotising ulcerative periodontitis† Tuberculosis Mycobacterium avium complex Autoimmune/idiopathic Recurrent aphthous ulcers† Salivary gland disease DILS* Immune thrombocytopenia Neoplastic Kaposi’s sarcoma Non-Hodgkin lymphoma

*Not recognised before the AIDS epidemic. †Unusual presentation of previously known lesions. DILS=diffuse infiltrative lymphocytosis.

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converts from a commensal to a pathogenic form in response to HIV infection is unclear but possibilities include (a) increased adhesiveness and invasion; (b) acquisition of virulent strains; and (c) phenotypic switching.8 Several studies have shown persistence of a single strain over time whereas others have shown that new strains may be acquired.9,10 The choice of therapy for oral candidosis depends on several factors.11 Topical agents available vary from country to country and include amphotericin oral lozenges (10 mg four times a day), nystatin vaginal tablets (100 000 units three times a day), nystatin oral pastilles (200 000 units four to five times a day), and clotrimazole oral troches (10 mg five times a day). The last two agents contain sugars and so could induce dental caries. These topical medications should be dissolved slowly in the mouth over 20–30 min. All depend on full compliance for effectiveness. The systemic agents seem to overcome this problem with dose regimens of one tablet a day, but they in turn may have limitations because of drug interactions and poor absorption. Ketoconazole (200–400 mg a day) and fluconazole (100 mg a day) are commonly used, and itraconazole (200 mg a day) is also helpful. Fluconazoleresistant oral candidosis, an emerging problem, appears most commonly in association with low CD4 counts. Unfortunately, some strains of C albicans show resistance to all of the existing azoles. Furthermore, certain species of Candida—notably, C krusei—are inherently less sensitive to fluconazole. Relapse after treatment of oral candidosis is common. The decision to start prophylactic therapy should be based on frequency of the episodes, likely compliance with the regimen, side-effects of the medications, cost-effectiveness, and possibility of development of resistance. Other oral fungal diseases associated with HIV include histoplasmosis, cryptococcosis, infection12 penicillinosis, and geotrichosis.

Oral hairy leukoplakia Oral hairy leukoplakia (HL) is a white lesion of the tongue which we first saw and investigated in 1981 and published the initial report of its existence among homosexual men in San Francisco in 1984.13 HL occurs in all risk groups and world wide.3,14 It is a little less common in women than in men and is rare in children. In HIV-positive persons, HL heralds more rapid progression to AIDS.3,6,13 HL is also seen in other forms of immunosuppression—eg, among organ or bone-marrow recipients and those receiving long-term steroid therapy.15 A few cases have been reported in immunocompetent individuals.16 The lesion presents as a white patch, often corrugated or even “hairy” in appearance, typically on the lateral margin of the tongue (figure 1). HL can also occur on the buccal mucosa, floor of the mouth, and other parts of the oral mucosa17 but does not affect the vaginal or anal mucosa. The frequency of HL is about 20% in those with otherwise symptom-free HIV infection and increases as the CD4 count falls and the clinical condition deteriorates.3,5,6,18 It is as common among kidney transplant recipients as among HIV-infected people.15 Although the main histological features of HL—surface corrugations, thickening of the prickle-cell layer (acanthosis) with groups or layers of ballooning cells similar to koilocytes, absence of atypia or other features of dysplasia, and lack of inflammatory cell infiltration in the epithelium or adjoining connective tissue13—are highly 730

Figure 1: Hairy leukoplakia on the lateral margin of the tongue

suggestive of the diagnosis they are not pathognomonic since some of them can be seen in clinically similar lesions (pseudo-HL) that are found in non-immunosuppressed patients and lack Epstein-Barr virus (EBV). Furthermore, some of the microscopic appearances associated with HL can be seen in necropsy specimens of clinically normal tongue.19 Thus, evidence of the presence of EBV is required for definitive diagnosis of HL, although presumptive diagnosis can be made on clinical appearance alone.17 The gamma-herpes virus EBV is present in the epithelial cells of HL as huge numbers of herpes virus particles on electron microscopy, as viral antigen detectable by immunocytochemistry, and as fully replicating high copy number EBV-DNA present as the complete genome in linear virion form demonstrable by Southern blotting.20 In-situ hybridisation is suitable for identification of EBV DNA in HL,21 and EBV RNA can be also detected by use of in-situ techniques.22 Multiple strains, recombinants, defective forms, and mutant forms of EBV occur.23 HL represents the only accessible source of replicating EBV in vivo. Neither dysplasia nor carcinoma has been seen in association with HL, but only long-term observation will determine whether HL can transform into carcinoma. There are conflicting reports as to whether the keratin phenotype profile of HL resembles that of benign epithelial hyperplasias and differs from that seen in epithelial premalignant lesions.24 Why does EBV infect the tongue epithelium, producing HL, notably in HIV infection? Langerhans cells are reduced or absent in HL lesions.25 One possibility is that antigen-processing cells in this location are damaged directly or indirectly by HIV infection, permitting EBV entry or reactivation. Intriguing data have been reported from transgenic mice carrying the BNLF-I oncogene of EBV: the mice show epithelial proliferation of the skin and tongue associated with keratin type 6.26 Perhaps induction of this keratin by EBV causes the epithelial hyperplasia of HL. Homology between the BHRF1 gene of EBV, which is expressed in HL, and the cellular gene Bcl-2, which delays apoptosis,22 raises the question of whether the hyperplasia seen in HL is due to a reduced rate of epithelial cell death. Although HL is usually symptomless, complaints about the discomfort and appearance sometimes justify treatment.27 The lesion shows a striking but temporary response to high doses of acyclovir or ganciclovir, and also to podophyllin and to retinoin.

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Other herpes viruses Herpes simplex virus causes both primary and recurrent oral disease. The primary event manifests as fever, lymphadenopathy, gingivitis, and painful oral lesions that start as vesicles and then rupture to form ulcers. These lesions can occur on any mucosal surface. Recurrent herpes simplex affects the lips or the intraoral mucosa. Herpes labialis appears as small vesicles that rupture, ulcerate, and then form a crust. The intraoral lesions are usually confined to the keratinised mucosa and begin as small crops of vesicles on the hard palate or gingiva, occasionally on the dorsal surface of the tongue; these also rupture to produce small painful ulcers. In people with HIV infection, recurrent herpes simplex may occur frequently, in painful outbreaks that can last several weeks. In such cases acyclovir may be useful. Acyclovirresistant herpes simplex may cause serious progressive disease involving oral cavity, lips, and face, but such lesions usually respond to foscarnet.28 Ulcers caused by cytomegalovirus occur in the mouth, usually in individuals with disseminated cytomegalovirus infection and only occasionally as the first sign of infection. Diagnosis is made on histological examination with immunohistochemistry. Ulcers co-infected with cytomegalovirus and herpes simplex virus have been reported.29 Varicella-zoster may present with a prodrome of dental pain, preceding oral and skin vesicles and ulcers following one or more branches of the trigeminal nerve. Treatment with acyclovir should be started promptly. Papillomavirus infection flourishes in the context of immunosuppression, and oral warts are fairly common in HIV infection. An unusual form of flat wart known as focal epithelial hyperplasia is seen and is due to human papillomavirus (HPV) types 12 and 32. The more common cauliflower and spiky warts can be due to various HPV types, including 2, 11, 16, and 18 as well as HPV 7,12 which was not seen in the mouth before HIV infection. Some warts show epithelial atypia30 and these contain new HPV types. Oral warts can be removed surgically with various techniques, but the recurrence rate is high. Malignant transformation has not been seen.

Periodontal disease Some unusual and often severe periodontal infections are seen in individuals with HIV infection. Linear gingival erythema (formerly known as HIV-gingivitis) is a red band at the gingival margin in children or adults. It does not seem to be due to inflammation, is frequently not

Figure 2: Major aphthous ulcer

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Figure 3: Enlarged parotid glands due to HIV salivary gland disease

associated with plaque accumulation, and may not completely resolve with therapy directed towards gingivitis. Rather than a gingivitis, this disorder may represent hyperaemia due to vasoactive cytokines. A more serious lesion, necrotising ulcerative periodontitis (formerly known as HIV-periodonitis), causes pain, spontaneous gingival bleeding, and extensive and rapid destruction of gingiva, periodontal tissues, and toothsupporting bone which may result in exposure and sequestration of bone and loosening of teeth, sometimes leading to exfoliation. The epidemiology and pathogenesis of this lesion remain uncler. Prevalence estimates range from very low in otherwise symptom-free HIV-positive individuals31 to 6–10% in a population with significant HIV-related disease.32 Cigarette smoking seems to be a cofactor in this condition.33 The pathogenesis may involve a loss of helper T-cell activity (on which immunological response to the periodontal flora depends), polymorphonuclear cell defects, and specific microorganisms yet to be determined. The role of microorganisms is questionable since several studies have failed to identify pronounced differences from the bacterial flora found in conventional chronic inflammatory periodontal disease.34 Therapy consists of local measures, with mechanical debridement, root planing, and irrigation with povidone-iodine. This treatment may be combined with the use of systemic antibiotics and home use of chlorhexidine mouth rinses.

Aphthous ulcers Recurrent aphthous ulcers (RAU) may not be more common among people with HIV infection but they are more severe and prolonged.35 In contrast to recurrent intraoral herpes simplex, RAU occur on non-keratinised mucosa such as the buccal and labial mucosa and the lateral margin of the tongue. Minor RAU appear as ulcers 2–5 mm in diameter, covered with pseudomembrane and surrounded by an erythematous halo. Major RAU (figure 2) are large, over 1 cm in diameter; they may persist for months and cause pain, impairment of speech, and difficulty in swallowing. Diagnosis of major aphthae may require biopsy to rule out malignancy and opportunistic infections. Herpetiform RAU are 1–2 mm in diameter and occur in crops. Treatment of RAU involves the use of topical steroids; persistent major aphthae have been shown to heal with the use of thalidomide (100–200 mg/day).36 731

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Salivary gland disease Enlargement of the salivary glands due to infiltration by CD8 lymphocytes is seen in both adult and paediatric HIV infection (figure 3). Some of these glands undergo cystic change, and such benign lymphoepithelial cysts occasionally cause pain. The cause of HIV-related salivary gland disease is unclear, for no aetiological agents have been identified. It could represent a relatively beneficial host CD8 response, diffuse infiltrative lymphocytosis syndrome or DILS37 the lymphocytes may be anti-HIV CD8 cells. Adults and children with salivary gland enlargement seem to experience slower progression of HIV disease.7 No treatment is indicated for the salivary gland enlargement, although large cystic glands are sometimes removed surgically for cosmetic purposes. Radiation therapy has been used to reduce the swelling. Xerostomia may be associated with the salivary gland enlargement but is also a common consequence of medications used by this population. Symptomatic relief may be provided by salivary stimulants such as sugarless chewing gum or sugarless sweets or salivary substitutes. Prevention of dental caries in people with xerostomia is extremely important, and the use of topical fluoride gels and rinses should be encouraged, even in areas where the drinking water supply contains fluoride.

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Kaposi’s sarcoma Oral lesions of Kaposi’s sarcoma (KS) are common in HIV infection and may be the first presentation of this condition. The role of oral transmission of the putative KS herpesvirus (HHV8) has yet to be determined. Oral KS lesions occur most commonly on the palate, although any oral site may be involved. The lesions appear first as small red or purple patches; later they become nodular and ulcerate if traumatised, causing pain. Large lesions may be unsightly and interfere with speaking and eating. Those at the gingival margin may cause the accumulation of plaque, making oral hygiene difficult and leading to secondary infection and pain. The small oral lesions may be treated27 with surgical debulking, intralesional vinblastine, or sclerosing solutions. Larger lesions may require radiation therapy. The differential diagnosis includes bacillary angiomatosis, pyogenic granuloma, and haemangioma. Biopsy is indicated if KS has not been diagnosed already. Drugs such as ketoconazole and zidovudine can cause oral pigmentation, which, although usually brown, should not be confused with the reddish or purple colour of KS lesions.

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Non-Hodgkin lymphoma Non-Hodgkin lymphoma is the other AIDS-associated malignancy that can present in the mouth. The disease may appear as a swelling, sometimes mimicking dental infection, or as single or multiple ulcers. Biopsy is necessary to distinguish the lesion from other causes of prolonged oral ulcers, such as major RAU and opportunistic infections. Multifocal ulcerative lymphoma occurring as ulcers on several mucosal surfaces has been described, as has oral lymphoma which disappeared and then reappeared.38

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We thank Evangeline Leash for expert editorial assistance. This work is supported by NIH PO1DE07946.

References 1 Greenspan JS, Greenspan D, eds. Oral manifestations of HIV

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infection: proceedings of the 2nd international workshop on the oral manifestations of HIV infection, Jan 31–Feb 3, 1993. Carol Stream, III: Quintessence Publishing, 1995. Tindall B, Carr A, Cooper DA. Primary HIV infection: clinical, immunologic, and serologic aspects. In: Sande MA, Volberding PA, eds. The medical management of AIDS. Philadelphia: WB Saunders, 1995: 105–29. Glick M, Muzyka BC, Lurie D, Salkin LM. Oral manifestations associated with HIV-related disease as markers for immune suppression and AIDS. Oral Surg Oral Med Oral Pathol 1994; 77: 344–49. Dodd CL, Greenspan D, Katz MH, Westenhouse JL, Feigal DW, Greenspan JS. Oral candidiasis in HIV infection: pseudomembranous and erythematous candidiasis show similar rates of progression to AIDS. AIDS 1991; 5: 1339–43. Feigel DW, Katz MH, Greenspan D, et al. The prevalence of oral lesions in HIV-infected homosexual and bisexual men: three San Francisco epidemiological cohorts. AIDS 1991; 5: 519–25. Lifson AR, Hilton JF, Westenhouse JL, et al. Time from HIV seroconversion to oral candidiasis or hairy leukoplakia among homosexual and bisexual men enrolled in three prospective cohorts. AIDS 1994; 8: 73–79. Katz MH, Mastrucci MT, Leggott PJ, Westenhouse J, Greenspan JS, Scott GB. Prognostic significance of oral lesions in children with perinatally acquired human immunodeficiency virus infection. Am J Dis Child 1993; 147: 45–48. Agabian N, Miyasaki SH, Kohler G, White TC. Candidiasis and HIV infection: virulence as an adaptive response. In: Greenspan JS, Greenspan D, eds. Oral manifestations of HIV infection: proceedings of the 2nd international workshop on the oral manifestations of HIV infection, Jan 31–Feb 3, 1993. Carol Stream, ILL: Quintessence Publishing, 1995: 85–92. Miyasaki SH, Hicks JB, Greenspan D, et al. The identification and tracking of Candida albicans isolates from oral lesions in HIVseropositive individuals. J Acquir Immune Defic Syndr 1992; 5: 1039–42. Powderly WG, Robinson K, Keath EJ. Molecular epidemiology of recurrent oral candidiasis in human immunodeficiency virus-positive patients: evidence for two patterns of recurrence. J Infect Dis 1993; 168: 463–66. Greenspan D. Treatment of oral candidiasis in HIV infection. Oral Surg Oral Med Oral Pathol 1994; 78: 211–15. Greenspan D, Greenspan JS, Pindborg JJ, Schiodt M. AIDS and the mouth. Copenhagen: Munksgaard, 1990. Greenspan D, Greenspan JS, Conant M, Petersen V, Silverman S Jr, De Souza Y. Oral “hairy” leucoplakia in male homosexuals: evidence of association with both papillomavirus and a herpes-group virus. Lancet 1984; ii: 831–34. Shiboski CH, Hilton JF, Greenspan D, et al. HIV-related oral manifestations in two cohorts of women in San Francisco. J Acquir Immune Defic Syndr 1994; 7: 964–71. King GN, Healy CM, Glover MT, et al. Prevalence and risk factors associated with leukoplakia, hairy leukoplakia, erythematous candidiasis, and gingival hyperplasia in renal transplant recipients. Oral Surg Oral Med Oral Pathol 1994; 78: 18–26. Felix DH, Watret K, Wray D, Southam JC. Hairy leukoplakia in an HIV-negative, nonimmunosuppressed patient. Oral Surg Oral Med Oral Pathol 1992; 74: 563–66. EC-Clearinghouse on Oral Problems Related to HIV Infection and WHO Collaborating Centre on the Oral Manifestations of the Immunodeficiency Virus. Classification and diagnostic criteria for oral lesions in HIV infection. J Oral Pathol Med 1993; 22: 289–91. Aragues M, Sanchez Perez J, Fraga J, Burgos E, Noguerado A, Garcia Diez A. Hairy leucoplakia: a clinical, histopathological and ultrastructural study in 33 patients. Clin Exp Dermatol 1990; 15: 335–39. Andersen L, Philipsen HP, Reichart PA. Macro- and microanatomy of the lateral border of the tongue with special reference to oral hairy leukoplakia. J Oral Pathol Med 1990; 19: 77–80. Greenspan JS, Greenspan D, Lennette ET, et al. Replication of Epstein-Barr virus within the epithelial cells of “hairy” leukoplakia, an AIDS-associated lesion. N Engl J Med 1985; 313: 1564–71. Loning T, Henke R-P, Reichart P, Becker J. In situ hybridization to detect Epstein-Barr virus DNA in oral tissues of HIV-infected patients. Virchows Arch [A] 1987; 412: 127–33. Young LS, Niedobitek G. Epstein-Barr virus and hairy leukoplakia: implications for virus persistence and replication. In: Greenspan JS, Greenspan D, eds. Oral manifestations of HIV infection: proceedings of the 2nd international workshop on the oral manifestations of HIV infection, Jan 31–Feb 3, 1993. Carol Stream, ILL: Quintessence Publishing, 1995: 166–74. Raab-Traub N, Walling DM. Epstein-Barr virus strain variation and expression of oral hairy leukoplakia. In: Greenspan JS, Greenspan D, eds. Oral manifestations of HIV infection: proceedings of the 2nd

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Pathol 1994; 21: 217–23. 31 Winkler JR, Herrera C, Westenhouse J, et al. Periodontal disease in HIV-infected and uninfected homosexual and bisexual men. AIDS 1992; 6: 1041–43. 32 Glick M, Muzyka BC, Salkin LM, Lurie D. Necrotizing ulcerative periodontitis: a marker for immune deterioration and a predictor for the diagnosis of AIDS. J Periodontol 1994; 65: 393–97. 33 Swango PA, Kleinman DV, Konzelman JL. HIV and periodontal health: a study of military personnel with HIV. J Am Dent Assoc 1991; 122: 49–54. 34 Zambon JJ, Reynolds H, Smutko J, et al. Are unique bacterial pathogens involved in HIV-associated periodontal diseases? In: Greenspan JS, Greenspan D, eds. Oral manifestations of HIV infection: proceedings of the 2nd international workshop on the oral manifestations of HIV infection, Jan 31–Feb 3, 1993. Carol Stream, ILL: Quintessence Publishing, 1995: 257–62. 35 MacPhail LA, Greenspan D, Greenspan JS. Recurrent aphthous ulcers in association with HIV infection: diagnosis and treatment. Oral Surg Oral Med Oral Pathol 1992; 73: 283–88. 36 Paterson DL, Georghiou PR, Allworth AM, Kemp RJ. Thalidomide as treatment of refractory aphthous ulceration related to human immunodeficiency virus infection. Clin Infect Dis 1995; 20: 250–54. 37 Itescu S, Wichester R. Diffuse infiltrative lymphocytosis syndrome: a disorder occurring in human immunodeficiency virus-1 infection that may present as a sicca syndrome. Rheum Dis Clin North Am 1990; 118: 683–97. 38 Dodd CL, Greenspan D, Schiodt M, et al. Unusual oral presentation of non-Hodgkin’s lymphoma in association with HIV infection. Oral Surg Oral Med Oral Pathol 1992; 73: 603–08.

Medicine and art

Pen and ink drawing by a heroin addict

Joyce Laing

This image (ink on paper, 41 ⫻ 28 cm) was drawn by a heroin addict during a session of art therapy in 1978. The symbolism is of crucifixion, with a head on a giant foot intermingled with visual references to user paraphernalia (needles and candles). The drawing, which is in a collection owned by art therapist Joyce Laing, can be seen at a two-part thematic exhibition called Inner Necessity, which explores the history of art therapy and Art Extraordinary in Scotland (Art Extraordinary is the name of the Scottish collection of outsider art). On show will be paintings, drawing, sculpture, and ceramics from the Extraordinary collection as well as works related to the clinical application of art therapy, from the late 1940s with tuberculosis patients to current practice and training of art therapists at the Edinburgh School of Art Therapy in the University Settlement. The exhibition, at the Talbot Rice Gallery, University of Edinburgh, UK, runs from Sept 28 to Nov 2, 1996, and ends with an international conference to be held at the University (Oct 30–Nov 2), in which the practical experience of art therapy will be highlighted.

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