atrogenic Peter A. Reichart, Prof. Dr. Med. Dent., Berlin, Germany FREIE
UNIVERSIT.&T
BERLIN
Ulcerative lesions of oropharyngeal mucous membranes are less commonly seen than other lesions in HIV infection and may be associated with mycotic, bacteriai, and viral infection, as well as neoplasia. Differential diagnosis may be difficult because of the clinical similarity of ulcerations that can represent various causes. The term “atypical ulceration” has been suggested because it may be impossible to differentiate some of the oral ulcerations from each other. latrogenic ulceration is seen occasionally, as the consequence of chemotherapy or irradiation. (ORAL SURC
ORAL MED ORAL PATHOL
1992;73:212-4)
wide variety of oral ulcerations are observed during the course of HIV infection and AIDS. Oral ulceration may be associated with fungal infections (e.g., histoplasmosis, cryptococcosis, zygomycosis), bacterial infections (e.g., necrotizing gingivitis, Enterobacteriaceae infection), viral infections (e.g., herpes simplex virus, cytomegalovirus, varicellazoster virus), and neoplasia (e.g., Kaposi’s sarcoma [KS], non-Hodgkin’s lymphoma). In addition to these specific oral ulcerative diseases, Pindborg’s classification’ of HIV-associated oral lesions mentioned recurrent aphthous ulcers and progressive necrotizing ulcers under the heading of “unknown cause.” These ulcerations are less commonly associated with HIV infection and are characterized by unusual clinical appearance and size, persistence, pain, progression, and therapy resistance. In a recent revision on the classification of HIV-associated oral lesions as agreed on at a meeting of the European Economic Community Clearinghouse on oral problems related to HIV infection in August 1990, it was suggested that these ulcerations be referred to as atypical because of their unusual appearance and behavior. HIV-infected patients, particularly those with the full-blown syndrome, receive polychemotherapy, often as a prophylactic measure to prevent or treat systemic infection or neoplasia. As a result of these therapy regimens, drug-induced oral lesions including ulceration have been described. In addition, side effects of oral irradiation of HIV-associated neoplasia have T/12/31458 212
been observed. It is the purpose of this article to review atypical ulceration (recurrent aphthous ulcers, progressive necrotizing ulcers) and some of the rare bacterial infections touted to be associated with Enterobacteriaceae. In addition, this article focuses on problems related to drug-induced lesions in HIVinfected patients. POSSIBLE ASSOCIATION ENTEROBACTERIACEAE ULCERATION
OF WITH ORAL
Only a few cases of oral ulceration associated with Enterobacteriaceae have been reported. Superficial ulceration of the lingual epithelium, supposedly associated with Klebsiella pneumoniae, was described in a single case.2 Enterobacter cloacae was demonstrated in a mucosal ulcer with osteitis2 and Escherichia coli was cultured from a lingual ulcer in a patient with acquired immunodeficiency syndrome.3 This small number of reported cases does not substantiate a causative role for Enterobacteriaceae because they may easily have been secondarily infected. A recent retrospective study on the presence of oral Enterobacteriaceae in HIV-infected patients revealed that the organisms may be cultured from the oral mucosal membranes; however, no specific oral lesions with positive cultural findings for Enterobacteriaceae were noted.4 A prospective study on the presence of Enterobacteriaceae on oral mucous membranes in HIV-infected patients failed to show a correlation between oral lesions and the presence of such bacteria. In this study, however, it was shown that with im-
Oral ulceration in HIV infection
Volume 73 Number 2
proved culturing techniques, Enterobacteriaceae could be found in 21% of the cases (SchmidtWesthausen A, unpublished data). Clarification of the etiology of oral ulceration is obfuscated by the possibility of secondary infection. Any break of the oral mucosa in HIV-infected patients may serve as an entry route by mycotic, bacterial, or viral secondary invaders. ATYPIICAL
ULCERATION
Atypical ulceration, including recurrent aphthous ulcers or progressive necrotizing ulcers, is occasionally found in HIV infection. Oral aphthae were observed in 8% of 375 homosexual men.5 Atypical or aphthous-like ulcers are often of the major type, resulting in serious morbidity as a result of pain and dysphagia.6 This unusual type of ulceration may arise during the acute stage of HIV seroconversion.2> 5,7 Biopsies show nonspecific inflammation, usually without underlying recognizable virus or mycotic infection.6 In 1989 Pindborg’ pointed to the problem that recurrent aphthous ulcers are commonly encountered in most populations and that it is therefore difficult to state whether the prevalence of these ulcers is higher in HIV-infected patients than in the normal population. The patho’genesis and etiology of atypical ulceration are not clear. The fact that this t.ype of ulceration may be secondarily infected by opportunistic organisms adds to the problem of diagnosis. Because of the present difficulties in determining the pathogenesis and etiology of these ulcerations, it was proposed to ap-ply the term “atypical ulcerations.” IATROGENIC
DISEASE
Drug reactions caused by chemotherapy and other therapeutic regimens may be observed during HIV infection, Several of these reactions are associated with ulceration. Oral ulcers have been described consequent to the use of foscarnetX and interferon.9 The cytidine analogue 2.’ ,3 ‘-dideoxycytidine also results in ulcers in almost 60% of patients. These ulcers may resolve when the drug is withdrawn; they do not develop in patients given low-dose therapy.‘O As a consequence of polychemotherapy, toxic epidermolysis has been described,” usually with a fatal outcome within a few days. Less severe cases resembling Stevens-Johnson syndrome or erythema multiforme have lbeen observed (personal observation). Particularly after intraoral but also extraoral irradiation of oral KS or non-Hodgkin’s lymphoma, palatal perforation or severe ulceration may occur (personal observation). In addition, mucositis may be a complication of oral irradiation for HIV-associated neoplasia. Intralesional therapy of KS lesions with vinblas-
213
tine or vincristine may result in ulceration of the respective oral neoplasia. Agranulocytosis caused by zidovudine with resulting oral ulceration has also been observed (Langford A, personal communication). Oral hyperpigmentation may be observed as a consequence of clofazimine and ketokonazole*2 (also see article by Ficarra, pp. 20 1- 11). Another side effect is the metallic taste reported by patients treated with dithiocarb.13 DISCUSSION
Oral ulcers in HIV-infected patients appear to have a complex etiology and pathogenesis. Principally, different mechanisms may be operative in the etiology of oral ulcers: (1) directly or indirectly antibody-mediated mechanism, (2) T cell-mediated mechanism, (3) antibody-dependent cellular cytotoxicity, (4) natural killer (NK) cell-mediated mechanism, or (5) specific or nonspecific immune complex-mediated mechanism. Antibody-mediated damage may be direct through Type II cytotoxic reactions or indirect through antibody-dependent cellular cytotoxic mechanisms. However, damage may also occur as a result of an inflammatory reaction associated with the activation of complement. This immune complex-mediated damage may be specifically related to the inducing antigen or may be nonspecific with activation of the alternate pathway of complement. Cellular mechanisms include direct cytotoxicity from T cells and indirect cell-mediated damage from NK cells that have been activated by specific T cells. It is possible that when these NK cells are activated by specific T cells, interferon, or interleukin-2, they may have a direct toxic effect on epithelial cells. The mechanisms can be activated by a variety of antigens and factors, including (1) antigens from local microbial flora or food, (2) accumulation of circulating antigens, (3) B-cell mitogens from microorganisms and food, (4) mitogenic complement split products, (5) blastogenic factors from locally activated T or B cells, (6) stimulatory factors from macrophages and neutrophils, (7) altered autologous IgG immune complexes, and (8) endogenous tissue antigens cross-reacting with microbial components. The oral mucosa is constantly in contact with various antigens, and any deficiency in the surface mucosal system may result in increased antigen access. Trauma or inflammation may also result in increased penetration. It seems that the pathogenesis of oral ulceration may be related to the fact that those tissue antigens cross-react with microbial components resulting in stimulation of a normal immune response and subsequent host damage. If the antigen is not
2 14
Reichart
ORAL SURG ORAL MLD
ORAL PATHOL
February 1992
cleared from the mucosal site or if further antigen gains access, locally activated T and B ceils may release various blastogenic factors and lymphostimulatory factors from associated macrophages and neutrophils, which can result in localized inflammatory action, causing damage to the host as a by-product of an attempt to clear the antigen from the area. CONCLUSION
To clarify the pathogenesis and etiology of oral ulceration in HIV-infected patients, epidemiologic studies with distinct criteria for diagnosis are needed. In addition, basic research of tissue damage related to immune complexes and autoantibody phenomena must be initiated. The phenomenon of secondary infection with mycotic, bacterial, or viral agents must be kept in mind so as not to confuse causative mechanisms with secondary events. Closely related to the study of oral ulcers are those of wound repair and healing. As such, oral ulceration in HIV disease will remain a challenge for the future, and, it is hoped, will allow more insight into the mechanisms of tissue destruction and repair. REFERENCES 1. Pindborg JJ. Classification of oral lesions associated with HIV infection. ORAL SURF ORAL MED ORAL PATHOL 1959;67: 292-5. 2. Greenspan D, Greenspan J, Pindborg JJ, Schigdt M. AIDS and the dental team. Copenhagen: Munksgaard, 1986. 3. Silverman S Jr. AIDS update: oral findings, diagnosis, and precautions. J Am Dent Assoc 1987;115:559-63.
4. Schmidt-Westhausen A. Fehrenbach FJ, Reichart PA. Oral Enterobacteriaceae in patients with HIV infection. J Oral Path01 Med 1990; 19:229-3 1. 5. Silverman S Jr, Migliorati CA, Lozada-Nur F, Greenspan D, Conant M. Oral findings in peop!e with or at high risk for AIDS: a study of 375 homosexual males. J Am Dent Assoc 1986;112:187-92. 6. Bach MC, Howell DA, Valenti AJ, Smith TJ, Winslow DI. Aphthous ulceration of the gastrointestinal tract in patients with the acquired immunodehciency syndrome (AIDS). Ann Intern Med 1990; 112:465-7. I. Silverman S. Color atlas of oral manifestations of AIDS. Toronto: BC Decker, 1989. 8. Gilquin J, Weiss L, Kazatchkine MD. Genital and oral erosions induced by foscarnet. Lancet 1990;335:287. 9. Penneys NS, Hick B. Unusual cutaneous lesions associated with acquired immunodeficiency syndrome. J Am Acad Dermatol 1985;13:845-52. 10. McNeeley MC, Yarchoan R, Broder S, Lawley TJ. Dermatologic complications associated with administration of 2’,3’dideoxycytidine in patients with human immunodeficiency virus infection. J Am Acad Dermatol 1989;21:12!3-7. Ii. Reichart P, Gelderblom HR, Becker J, Kuntz A. AIDS and the oral cavity: the HIV-infection-virology, etiology, origin, immunology, precautions and clinical observations in 110 patients. Int J Oral Maxillofac Surg 1987; 16: 129-53. 12. Langford A, Pohle HD, Gelderblom H, Zhang X, Reichart PA. Oral hyperpigmentation in HIV-infected patients. ORAL SURG ORAL MED ORAL PATHOL
1989: l&47
l-4.
13. Reisinger EC, Kern P, Ernst M, Bock P; Flad I-ID, Dietricb M. lnhibition of HIV progression by dithiocarb. Lancet 1990; 3351679-82. Reprint requests. Prof. Dr. Peter A. Reichart Department of Oral Surgery (North) Freie Universitat Berlin Fiihrer Str. 15 D-1000 Berlin 65, Germany
UNIVERSIT.&T
BERLIN
Ulcerative lesions of oropharyngeal mucous membranes are less commonly seen than other lesions in HIV infection and may be associated with mycotic, bacteriai, and viral infection, as well as neoplasia. Differential diagnosis may be difficult because of the clinical similarity of ulcerations that can represent various causes. The term “atypical ulceration” has been suggested because it may be impossible to differentiate some of the oral ulcerations from each other. latrogenic ulceration is seen occasionally, as the consequence of chemotherapy or irradiation. (ORAL SURC
ORAL MED ORAL PATHOL
1992;73:212-4)
wide variety of oral ulcerations are observed during the course of HIV infection and AIDS. Oral ulceration may be associated with fungal infections (e.g., histoplasmosis, cryptococcosis, zygomycosis), bacterial infections (e.g., necrotizing gingivitis, Enterobacteriaceae infection), viral infections (e.g., herpes simplex virus, cytomegalovirus, varicellazoster virus), and neoplasia (e.g., Kaposi’s sarcoma [KS], non-Hodgkin’s lymphoma). In addition to these specific oral ulcerative diseases, Pindborg’s classification’ of HIV-associated oral lesions mentioned recurrent aphthous ulcers and progressive necrotizing ulcers under the heading of “unknown cause.” These ulcerations are less commonly associated with HIV infection and are characterized by unusual clinical appearance and size, persistence, pain, progression, and therapy resistance. In a recent revision on the classification of HIV-associated oral lesions as agreed on at a meeting of the European Economic Community Clearinghouse on oral problems related to HIV infection in August 1990, it was suggested that these ulcerations be referred to as atypical because of their unusual appearance and behavior. HIV-infected patients, particularly those with the full-blown syndrome, receive polychemotherapy, often as a prophylactic measure to prevent or treat systemic infection or neoplasia. As a result of these therapy regimens, drug-induced oral lesions including ulceration have been described. In addition, side effects of oral irradiation of HIV-associated neoplasia have T/12/31458 212
been observed. It is the purpose of this article to review atypical ulceration (recurrent aphthous ulcers, progressive necrotizing ulcers) and some of the rare bacterial infections touted to be associated with Enterobacteriaceae. In addition, this article focuses on problems related to drug-induced lesions in HIVinfected patients. POSSIBLE ASSOCIATION ENTEROBACTERIACEAE ULCERATION
OF WITH ORAL
Only a few cases of oral ulceration associated with Enterobacteriaceae have been reported. Superficial ulceration of the lingual epithelium, supposedly associated with Klebsiella pneumoniae, was described in a single case.2 Enterobacter cloacae was demonstrated in a mucosal ulcer with osteitis2 and Escherichia coli was cultured from a lingual ulcer in a patient with acquired immunodeficiency syndrome.3 This small number of reported cases does not substantiate a causative role for Enterobacteriaceae because they may easily have been secondarily infected. A recent retrospective study on the presence of oral Enterobacteriaceae in HIV-infected patients revealed that the organisms may be cultured from the oral mucosal membranes; however, no specific oral lesions with positive cultural findings for Enterobacteriaceae were noted.4 A prospective study on the presence of Enterobacteriaceae on oral mucous membranes in HIV-infected patients failed to show a correlation between oral lesions and the presence of such bacteria. In this study, however, it was shown that with im-
Oral ulceration in HIV infection
Volume 73 Number 2
proved culturing techniques, Enterobacteriaceae could be found in 21% of the cases (SchmidtWesthausen A, unpublished data). Clarification of the etiology of oral ulceration is obfuscated by the possibility of secondary infection. Any break of the oral mucosa in HIV-infected patients may serve as an entry route by mycotic, bacterial, or viral secondary invaders. ATYPIICAL
ULCERATION
Atypical ulceration, including recurrent aphthous ulcers or progressive necrotizing ulcers, is occasionally found in HIV infection. Oral aphthae were observed in 8% of 375 homosexual men.5 Atypical or aphthous-like ulcers are often of the major type, resulting in serious morbidity as a result of pain and dysphagia.6 This unusual type of ulceration may arise during the acute stage of HIV seroconversion.2> 5,7 Biopsies show nonspecific inflammation, usually without underlying recognizable virus or mycotic infection.6 In 1989 Pindborg’ pointed to the problem that recurrent aphthous ulcers are commonly encountered in most populations and that it is therefore difficult to state whether the prevalence of these ulcers is higher in HIV-infected patients than in the normal population. The patho’genesis and etiology of atypical ulceration are not clear. The fact that this t.ype of ulceration may be secondarily infected by opportunistic organisms adds to the problem of diagnosis. Because of the present difficulties in determining the pathogenesis and etiology of these ulcerations, it was proposed to ap-ply the term “atypical ulcerations.” IATROGENIC
DISEASE
Drug reactions caused by chemotherapy and other therapeutic regimens may be observed during HIV infection, Several of these reactions are associated with ulceration. Oral ulcers have been described consequent to the use of foscarnetX and interferon.9 The cytidine analogue 2.’ ,3 ‘-dideoxycytidine also results in ulcers in almost 60% of patients. These ulcers may resolve when the drug is withdrawn; they do not develop in patients given low-dose therapy.‘O As a consequence of polychemotherapy, toxic epidermolysis has been described,” usually with a fatal outcome within a few days. Less severe cases resembling Stevens-Johnson syndrome or erythema multiforme have lbeen observed (personal observation). Particularly after intraoral but also extraoral irradiation of oral KS or non-Hodgkin’s lymphoma, palatal perforation or severe ulceration may occur (personal observation). In addition, mucositis may be a complication of oral irradiation for HIV-associated neoplasia. Intralesional therapy of KS lesions with vinblas-
213
tine or vincristine may result in ulceration of the respective oral neoplasia. Agranulocytosis caused by zidovudine with resulting oral ulceration has also been observed (Langford A, personal communication). Oral hyperpigmentation may be observed as a consequence of clofazimine and ketokonazole*2 (also see article by Ficarra, pp. 20 1- 11). Another side effect is the metallic taste reported by patients treated with dithiocarb.13 DISCUSSION
Oral ulcers in HIV-infected patients appear to have a complex etiology and pathogenesis. Principally, different mechanisms may be operative in the etiology of oral ulcers: (1) directly or indirectly antibody-mediated mechanism, (2) T cell-mediated mechanism, (3) antibody-dependent cellular cytotoxicity, (4) natural killer (NK) cell-mediated mechanism, or (5) specific or nonspecific immune complex-mediated mechanism. Antibody-mediated damage may be direct through Type II cytotoxic reactions or indirect through antibody-dependent cellular cytotoxic mechanisms. However, damage may also occur as a result of an inflammatory reaction associated with the activation of complement. This immune complex-mediated damage may be specifically related to the inducing antigen or may be nonspecific with activation of the alternate pathway of complement. Cellular mechanisms include direct cytotoxicity from T cells and indirect cell-mediated damage from NK cells that have been activated by specific T cells. It is possible that when these NK cells are activated by specific T cells, interferon, or interleukin-2, they may have a direct toxic effect on epithelial cells. The mechanisms can be activated by a variety of antigens and factors, including (1) antigens from local microbial flora or food, (2) accumulation of circulating antigens, (3) B-cell mitogens from microorganisms and food, (4) mitogenic complement split products, (5) blastogenic factors from locally activated T or B cells, (6) stimulatory factors from macrophages and neutrophils, (7) altered autologous IgG immune complexes, and (8) endogenous tissue antigens cross-reacting with microbial components. The oral mucosa is constantly in contact with various antigens, and any deficiency in the surface mucosal system may result in increased antigen access. Trauma or inflammation may also result in increased penetration. It seems that the pathogenesis of oral ulceration may be related to the fact that those tissue antigens cross-react with microbial components resulting in stimulation of a normal immune response and subsequent host damage. If the antigen is not
2 14
Reichart
ORAL SURG ORAL MLD
ORAL PATHOL
February 1992
cleared from the mucosal site or if further antigen gains access, locally activated T and B ceils may release various blastogenic factors and lymphostimulatory factors from associated macrophages and neutrophils, which can result in localized inflammatory action, causing damage to the host as a by-product of an attempt to clear the antigen from the area. CONCLUSION
To clarify the pathogenesis and etiology of oral ulceration in HIV-infected patients, epidemiologic studies with distinct criteria for diagnosis are needed. In addition, basic research of tissue damage related to immune complexes and autoantibody phenomena must be initiated. The phenomenon of secondary infection with mycotic, bacterial, or viral agents must be kept in mind so as not to confuse causative mechanisms with secondary events. Closely related to the study of oral ulcers are those of wound repair and healing. As such, oral ulceration in HIV disease will remain a challenge for the future, and, it is hoped, will allow more insight into the mechanisms of tissue destruction and repair. REFERENCES 1. Pindborg JJ. Classification of oral lesions associated with HIV infection. ORAL SURF ORAL MED ORAL PATHOL 1959;67: 292-5. 2. Greenspan D, Greenspan J, Pindborg JJ, Schigdt M. AIDS and the dental team. Copenhagen: Munksgaard, 1986. 3. Silverman S Jr. AIDS update: oral findings, diagnosis, and precautions. J Am Dent Assoc 1987;115:559-63.
4. Schmidt-Westhausen A. Fehrenbach FJ, Reichart PA. Oral Enterobacteriaceae in patients with HIV infection. J Oral Path01 Med 1990; 19:229-3 1. 5. Silverman S Jr, Migliorati CA, Lozada-Nur F, Greenspan D, Conant M. Oral findings in peop!e with or at high risk for AIDS: a study of 375 homosexual males. J Am Dent Assoc 1986;112:187-92. 6. Bach MC, Howell DA, Valenti AJ, Smith TJ, Winslow DI. Aphthous ulceration of the gastrointestinal tract in patients with the acquired immunodehciency syndrome (AIDS). Ann Intern Med 1990; 112:465-7. I. Silverman S. Color atlas of oral manifestations of AIDS. Toronto: BC Decker, 1989. 8. Gilquin J, Weiss L, Kazatchkine MD. Genital and oral erosions induced by foscarnet. Lancet 1990;335:287. 9. Penneys NS, Hick B. Unusual cutaneous lesions associated with acquired immunodeficiency syndrome. J Am Acad Dermatol 1985;13:845-52. 10. McNeeley MC, Yarchoan R, Broder S, Lawley TJ. Dermatologic complications associated with administration of 2’,3’dideoxycytidine in patients with human immunodeficiency virus infection. J Am Acad Dermatol 1989;21:12!3-7. Ii. Reichart P, Gelderblom HR, Becker J, Kuntz A. AIDS and the oral cavity: the HIV-infection-virology, etiology, origin, immunology, precautions and clinical observations in 110 patients. Int J Oral Maxillofac Surg 1987; 16: 129-53. 12. Langford A, Pohle HD, Gelderblom H, Zhang X, Reichart PA. Oral hyperpigmentation in HIV-infected patients. ORAL SURG ORAL MED ORAL PATHOL
1989: l&47
l-4.
13. Reisinger EC, Kern P, Ernst M, Bock P; Flad I-ID, Dietricb M. lnhibition of HIV progression by dithiocarb. Lancet 1990; 3351679-82. Reprint requests. Prof. Dr. Peter A. Reichart Department of Oral Surgery (North) Freie Universitat Berlin Fiihrer Str. 15 D-1000 Berlin 65, Germany
