Chlorhexidine mouthwash-induced fixed drug eruption Case report and review of the literature Behjat K. H. Moghadam, DDS, DSCD,~ Connie L. Drisko, DDS,b and Ronald E. Gier, DMD, iUSD,c Kansas City, MO. UNIVERSITY OF MISSOURI, KANSAS CITY Various adverse reactions including anaphylactic shock have already been reported after the topical application of chlorhexidine. This article reports for the first time a hypersensitivity reaction in the form of fixed drug eruption after the use of a mouthwash containing chlorhexidine. This report should bring an increased awareness of the possibility of systemic hypersensitivity reaction to chlorhexidine in a previously sensitized person. The report also will add fixed drug eruption to the list of skin hypersensitivity reactions caused by chlorhexidine. (ORAL SURC ORAL MED ORAL PATHOL 1991;71:431-4)
T
he skin and mucosal surfaces provide a route for the transfer of solutes from the host tissuesto the surface and also in the opposite direction. When a material comes into contact with oral mucosa, small antigenic molecules can pass through the epithelial barrier. At least three mechanisms are involved: diffusion, carrier-facilitated transport, and pinocytosis.’ Penetrated antigens can react with antibodies and produce an immune hypersensitivity reaction. Such a reaction may appear as a benign contact hypersensitivity reaction or may manifest as a life-threatening episode such as an anaphylactic shock. Both conditions may occur as a result of medical or dental treatments. According to Malamed, 15% of the U.S. population have allergic reactions severe enough to require medical management. The atopic patient (a person with a genetic predisposition to allergy) represents a potentially serious risk when exposedto a variety of commonly used drugs. Some agents that can cause hypersensitivity reactions are related to the field of dentistry. The available data suggest that components of local anesthetics,3dental materials,4-9 toothpastes,lO and topical fluoride” can cause a hypersensitivity reaction in a susceptible host.
aAssistant Professor, Department of Oral Diagnosis and Radiology. bAssociate Professor, Department of Periodontics. ‘Professor, Department of Oral Diagnosis and Radiology. 7/13/26016
Chlorhexidine mouthrinse was first introduced by Liie12 in 1969. The agent has since been approved for sale in the United States by the Food and Drug Administration and approved by the American Dental Association Council on Dental Therapeutics.13 Reported oral complications after rinsing with chlorhexidine mouthwash include altered taste sensation,14 superficial desquamation of oral mucosa,ls brownish discoloration of the tongue or teeth,‘6-24and increased calculus formation.25 In addition, some adverse reactions have been reported after the use of the agent in other organs. These reactions include (1) ototoxicity and deafness on contact with the middle ear,26 (2) conjunctivitis associated with the use of soft contact lens solution 27,2* and (3) colitis after a cleanser enema.29 Two other major side effects are anaphylactic shock and cutaneous eruptions. In general, topical application of agents rarely inducesanaphylactic reactions, However, various symptoms of immediate hypersensitivity including anaphylactic reactions have been reported after topical treatment with chlorhexidine. Skin reactions such as contact dermatitis, contact urticaria, and photosensitive dermatitis also have been reported after the use of chlorhexidine.30-37 Drug-induced cutaneous eruptions could be caused by immediate and delayed types of hypersensitivity. IgE-mediated histamine releaseis probably responsible for the urticarial lesions.38-41 Clinically, the reaction is characterized by palpable purpura and erythematous patches of urticaria. In rare casesthe skin re431
432
Fig.
Moghadam, Drisko, and Gier
1. Arrows
outline erythematous patch of FDE on
right hand.
actions may manifest in the form of fixed drug eruption (FDE) . The concept of FDE was first introduced by Brocq4* in 1894. According to a survey done in Finland, the incidence of FDE accounted for 10% of 464 casesof skin reactions.43 FDE consists of isolated lesions recurring in the samesite each time the specific agent is given. Thus cause and effect are hardly ever in doubt. The most common type of FDE consists of slightly elevated inflammatory patches with sharply defined borders, which may be macular, eczematous, or even bullous. Theseeruptions may occur anywhere, including mucous membranes.44-5’ The most commonly useddrugs that have been implicated as a cause of FDE include salicylates, barbiturates, phenolphthalein, phenylbutazone, penicillin, and sulfonamides.44-52 To our knowledge an FDE to chlorhexidine has not been reported. This case may be the first to add the FDE to the list of skin reactions caused by chlorhexidine. CASEREPORT
A 46-year-old white woman was referred to the School of Dentistry, University of Missouri, Kansas City, for periodontal treatment. Routine medical and dental diagnostic procedures were performed. Pertinent medical history revealed numerous allergic reactions, in the form of FDE, to barbiturates and salicylate compounds. The reported eruptions had been observed 2 to 3 hours after the consumption of aspirin or barbiturates and primarily involved the palms of the hands and solesof the feet. The FDEs were severe and had required intravenous injection of calcium compounds and cortisone during a 2- to 3-day period. The periodontal examination revealed relatively high levels of supragingival and subgingival calculus with generalized pocket depths of 3 to 5 mm and up to 6 to 7 mm in somelocalized areas.Periodontal therapy included oral hygiene instructions and an initial grossdebridement followed by four sessionsof root planing with the patient under local anesthesia.Subgingival irrigation with 0.12% chlorhexidine
2. Arrows point to areasof erythematous patches01 FDE on left hand.
Fig.
(Peridex) followed each scaling and root planing procedure. Pocket elimination surgery was performed in four posterior segmentsbefore restorative procedures. Routine postsurgical therapy was performed, and maintenance treatment was scheduled at 3-month intervals. Treatment with Peridex mouthwash was started 1 week after periodontal surgery, which was 4 months after the last root planing appointment. The patient was instructed to use the rinse according to the manufacturer’s directions. The first time she rinsed was at bedtime (I 0:30 PM), and by approximately 1 AM shehad pruritus and erythematous rashes on the palms of the hands and solesof the feet. Becausethe reaction was mild, the patient ignored the symptomsand did not correlate the incident to the mouthwash regimen. The next night the procedure was repeated and the reaction became much more severe(Figs. 1 and 2). The chlorhexidine mouthwash was suspectedas the etiologic agent and was discontinued. The reaction persisted, and on day 3, 50 mg diphenhydramine (Benadryl) was given intramuscularly, followed by 50 mg diphenhydramine (Benadryl) orally three times a day. By day 6 the itching subsided; however, it took 2 more days for the skin eruptions to subside. The patient reported no change in diet, nor had she started any new medication. It was tentatively determined that the FDE was the result of a reaction to the Peridex mouthwash. Becausethe patient is in the field of dentistry, she volunteered to participate further in the studies related to the incident. Several months later, she agreed once again to use the mouthwash to determine whether it was the precipitating agent of the previous FDE. Emergency personnel and drugs were made readily available if needed.This time she was instructed to rinse with % ounce of Peridex mouthwash for only 5 to 10 secondsand to rinse immediately with water. Within 2 hours severeitching began and the previously described skin lesions erupted on the hands and feet. She began oral diphenhydramine, and the symptoms resolved in 4 days. After this reaction, it was still unknown whether the patient was sensitive to the active ingredient (chlorhexidine) or to someother component in the mouthwash formulation. On request, Procter & Gamble Co. supplied a placebo mouthwash that had all the ingredients of Peridex mouthwash except the chlorhexidine. Approximately 2 months
Chlorhexidine hypersensitivity
Volume 7 1 Number 4
after the secondFDE reaction, the patient used the placebo mouthrinse in the samemanner as before but was not aware of the change in the formulation. She reported only a very mild transient itching of the palms and soles after the use of placebo rinse, and skin lesions or residual reactions failed to develop. It was concluded that she was indeed hypersensitive to the chlorhexidine rather than to the other ingredients in the mouthwash formulation. DISCUSSION
In view of the wide useof chlorhexidine mouthrinse, dentists should be aware of the potential adverse reactions induced by chlorhexidine. Eight casesof anaphylactic reactions are reported after the topical application of chlorhexidine in the English-language literature. Six caseswere reported from Japan,53one from Sweden,s4and one from Australia.55 All those patients later tested positive for chlorhexidineinduced hypersensitivity reaction by means of intradermal, scratch, and epicutaneous tests.53-55 According to Ohtoshi et al.,56 more than 30 cases of anaphylactic shock after the topical application of chlorhexidine have been registered in Japan between 1974 and 1984. Sera obtained and examined from sevenof the casesshowed that a specific IgE antibody against chlorhexidine was a mediator of the reaction. Symptoms of anaphylactic reactions were reported as a fall in blood pressure, bronchospasm, dyspnea, cyanosis, and cough. Abdominal pain, numbness, generalized urticaria, and flushing have also been indicated. Time of the onset of symptoms varied from 5 to 40 minutes. The concentrations of chlorhexidine were reported as O-02%,0.05%, 0.2%, OS%, and 1%. The agent was used for disinfecting the skin, mucous membranes (vagina, urinary bladder), and wounds before surgery or other medical procedures. After the increasing reports on anaphylactic reactions, caution and restriction were suggestedwhen the drug was used on mucous membranes and damaged skin.56
Studies on the retention of carbon 16labeled chlorhexidine mouthrinse in the human oral cavity showed that up to 8% of the compound was swallowed by the adults and that 30% was retained in the mouth. The recovery of the radiolabeled chlorhexidine mouthrinse in the liver or kidneys indicated that the chemical penetrated the intact mucosal barrier of the oral cavity or intestinal tract.57,s8 Penetration of chlorhexidine-protein complexes through the skin or mucous membranes may cause sensitization in a susceptible person. Indeed, daily exposure increasesthe risk of severeallergic reactions if the agent is reapplied in a sensitive patient. The incidence of skin reactions to a drug provides a good indication of the risk of allergic drug reaction. In some casesminor symptoms of immediate hypersensitivity not mentioned by the patient may give rise
433
to more serious reaction on reapplication of the agent. The minor symptoms may appear as tingling, itching, and urticaria. Special attention should be focused on atopic patients and in those with a history of multiple drug reactions. Finally, more care should be considered in those cases with compromised oral mucosa. The damaged mucosa may allow the passage of excessive amounts of the antigen through the oral mucosa, which may potentiate life-threatening situations. We thank Ms. Martha Yager for her generous help in typing the manuscript and Mr. David A. Coats for preparing the illustrations. REFERENCES
1. Dolby AE, ed. Oral mucosa in health and disease. London: Blackwell, 1975:122-4. 2. Malamed SF, ed. Handbook of medical emergencies in the dental office. 3rd ed. St. Louis: CV Mosby, 1987:302. 3. Alderete JA, JohnsonDA. Allergy to local anesthetics.JAMA 1969;207:356-7. 4. Brendlinger DL, Tarsitano JJ. Generalized dermatitis due to sensitivity to a chrome cobalt removable partial denture. J Am Dent Assoc 1970;81:392-4. 5. Davenport JC. An adverse reaction to a silicone rubber soft lining material: report of a case. Br Dent J 1970;128:545-6. 6. Elgart ML, Higdon RS. Allergic contact dermatitis to gold. Arch Dermatol 1971;103:649-53. 7. Nealy ET, de1Rio CE. Stomatitis venenata: reaction of a patient to acrylic resin. J Prosthet Dent 1969;21:480-4. 8. Strain JC. Reactions associated with acrylic denture base resins. J Prosthet Dent 1967;18:465-8. 9. Juhlin L, Ohman S. Allergic reaction to mercury in red tattoos and in mercury adjacent to amalgam fillings. Acta Dermatol 1968;48:103-5. 10. Kirton V, Wilkerson DS. Contact sensitivity to toothpaste. Br Med J 1973;2:115-6. 11. Shea JJ, Gillespie SM, Waldbott GL. Allergy to fluoride. Ann Allergy 1967;25:388-91. 12. L6e H. Present day status and direction for future research on the etiology and prevention of periodontal diseases.J Periodontol 1969;40:678-82. 13. Council on Dental Therapeutics. Council on Dental Therapeutics accepts Peridex. J Am Dent Assoc 1988;117:516-7. 14. Flotra L, Gjermo G, Rolla G, Waerbang J. Side effects of chlorhexidine mouth washes. Stand J Dent Res 1971;79: 119-25. 15. Skoglund LA, Holst E. Desquamative mucosal reactions due to chlorhexidine gluconate. Int J Oral Surg 1982;11:380-2. 16. Eriksen HM, Gjermo P. Incidence of stained tooth surfaces in students using chlorhexidine-containing dentifrices. Stand J Dent Res 1973;81:533-7. 17. Eriksen HM, Nordb H, Kantanen H, Ellingsen JE. Chemical plaque control and extrinsic discoloration: a review of possible mechanisms. J Clin Periodontol 1985;12:345-50. 18. Prayitno S, Addy M. An in vitro study of factors affecting the development of staining associated with the use of chlorhexidine. J Periodont Res 1979;14:397-402. 19. Addy M, Prayitno SW. Light microscopic and color television image analysis of the development of staining on chlorhexidine-treated surfaces. J Periodontol 1980:51:39-43. 20. JensenJE. Binding of dyes to chlorhexidine-treated hydroxyapatite. Stand J Dent Res 1977;85:334-40. 21. Addy M, Jenkins PM. Chlorhexidine staining: in vitro study of beverages as aetiological factors. IRCS Med Sci Biomed Technol (Dent Oral Biol Sot Occup Med) 1977;5:393. 22. Addy M, Moran J. The formation of stain on acrylic surfaces by the interaction of cationic antiseptic mouthwashesand tea. J Biomed Mater Res 1984;18:631-41.
434
Moghadam, Drisko, and Gier
23. Addy M, Prayitno S, Taylor L, Cadogan S. An in vitro study of the role of dietary factors in the aetiology of tooth staining associated with the use of chlorhexidine. J Periodont Res 1979;14:403-10. 24 Prayitno S, Taylor L, Cadogan S, Addy M. An in vitro study of dietary factors in the aetiology of tooth staining associated with the use of chlorhexidine. J Periodont Res 1979;14:411-7. 25. Lee H, Mandell M, Derry A, Schiott CR. The effect of mouthrinses and topical application of chlorhexidine on calculus formation in man. J Periodont Res 1971;6:312-4. 26. Bicknell PG. Sensorineural deafnessfollowing myringoplasty operations. J Laryngol Otol 1971;85:957-61. 21. Van Ketel WG, Melzer-van Riemsdijk FA. Conjunctivitis due to soft lens solution. Contact Dermatitis 1980;6:321-4. 28. Mondino BJ, Salamon SM, Zaidman GW. Allergic and toxic reactions of soft contact lens wearers. Surv Ophthalmol 1982;26:337-44. 29. Hardin RD, Tedesco FJ. Colitis after Hibiclens enema. J Clin Gastroenterol 1986;8:572-5. 30. Roberts DL, Summerly R, Byrne JP. Contact dermatitis due to the constituents of Hibiscrub. Contact Dermatitis 1981; 71326-8. 31. Lasthein Andersen B, Brandrup F. Contact dermatitis from chlorhexidine. Contact Dermatitis 1985;13:307-9. 32. Bergqvist-Karlsson A. Delayed and immediate-type hypersensitivity to chlorhexidine. Contact Dermatitis 1988;18:84-8. 33. Fisher AA. Contact urticaria from chlorhexidine. Cutis 1989; 43:17-g. 34. OsmundsenPE. Contact dermatitis to chlorhexidine. Contact Dermatitis 1982;8:81-3. 35. Bechgaard E, Ploug E, Hjorth N. Contact sensitivity to chlorhexidine? Contact Dermatitis 1985;13:53-5. 36. Wahlberg JE, Wennersten G. Hypersensitivity and photosensitivity to chlorhexidine. Dermatologica 1971;143:376-9. 37. Nishioka K, Doi T, Katayama I. Histamine release in contact urticaria. Contact Dermatitis 1984;11:191. 38. Park BK, Coleman JW. The immunological basis of adverse drug reactions: a report on a symposium held in Liverpool on 6th April 1988. Br J Clin Pharmacol 1988;26:491-5. 39. Van Arsdel PP Jr. Drug reactions: allergy and near-allergy. Ann Allergy 1986;57:305-11. 40. Witte KW, West DP. Immunology of adverse drug reactions. Pharmacotherapy 1982;2:54-65. 41. Anderson JA, Adkinson NF Jr. Allergic reactions to drugs and biologic agents. JAMA 1987;258:2891-9. 42. Brocq L. Eruption erythemato-pigment&e fix due a l’antipyrine. Ann Derma Syph 1894;3:308-13. 43. Kuokkanen K. Drug eruptions: a seriesof 464 casesin the Department of Dermatology, University of Turku, Finland, during 1966-70. Acta Allergol 1972;27:407-38.
ORAL SURGORAL MED ORAL PATHOI. April 1991 44. DomonkesAN, ed. Andrews’ diseasesof theskin: clinical dermatology. 6th ed. Philadelphia: WB Saunders, 1971:109-20. 45. Stritzler C, Kopf AW. Fixed drug eruption caused by 8-chlorotheophyllin in Dramamine with clinical and histological studies. J Invest Dermatol 1960;34:319-30. 46. Van Arsdel PP Jr. Allergy and -adversedrug reactions. J Am Acad Dermatol 1982;6:833-45. 47. Lever WF, Schaumburg-Lever G, eds. Histopathology of the skin. 6th ed. Philadelphia: JB Lippincott, 1983:259-70. 48. Bellanti JA. Immunology Il. Philadelphia: WB Saunders, 1978~527-36. 49. Knowles FC, Decker HB, Kandle RP. Phenolphthalein dermatitis: an experimental study including reproduction of the eruption in skin transplants. Arch Dermatol Syph 1936;33: 227-31. 50. Wise F, Sulzberger MB. Drug eruptions. 1. Fixed phenolphthalein eruptions. Arch Dermatol Syph 1933;27:549-67. 51. Wyatt E, Greaves M, Sondergaard J. Fixed drug eruption (phenolphthalein): evidence for a blood-borne mediator. Arch Dermatol 1972;106:671-3. 52. Gimenez-Camarasa JM, Garcia-Calderon P, De Moragas JM. Lymphocyte transformation test in fixed drug eruption. N Engl J Med 1975;292:819-21. 53. Okano M, Nomura M, Hata S, et al. Anaphylactic symptoms due to chlorhexidine gluconate. Arch Dermatol 1989;125: 50-2. 54. Bergqvist-Karlsson A. Delayed and immediate-type hypersensitivity to chlorhexidine. Contact Dermatitis 1988;18:84-8. 55. Cheung J, O’Leary JJ. Allergic reaction to chlorhexidine in an anesthesizedpatient. Anaesth Intensive Care 1985;13:429-30. 56. Ohtoshi T, Yamauchi N, Tadokora K, et al. IgE antibodymediated shock reaction caused by topical application of chlorhexidine. Clin Allergy 1986;16:155-61. 57. Bonesvoll P, Lokken P, Rolla G. The retention of 14Cchlorhexidine in the human oral cavity after mouth rinses.Proc Stand Div IADR, 1972: Abstract 36. 58. Winrow MJ. Metabolic studies with radiolabelled chlorhexidine in animals and man. J Periodont Res 1973;8(suppl 12):45-g. Reprint requests to:
Behjat K. H. Moghadam, DDS, DScD Department of Oral Diagnosis School of Dentistry Universitv of Missouri. Kansas Citv 650 E. 25th St. Kansas City, MO 64108
T
he skin and mucosal surfaces provide a route for the transfer of solutes from the host tissuesto the surface and also in the opposite direction. When a material comes into contact with oral mucosa, small antigenic molecules can pass through the epithelial barrier. At least three mechanisms are involved: diffusion, carrier-facilitated transport, and pinocytosis.’ Penetrated antigens can react with antibodies and produce an immune hypersensitivity reaction. Such a reaction may appear as a benign contact hypersensitivity reaction or may manifest as a life-threatening episode such as an anaphylactic shock. Both conditions may occur as a result of medical or dental treatments. According to Malamed, 15% of the U.S. population have allergic reactions severe enough to require medical management. The atopic patient (a person with a genetic predisposition to allergy) represents a potentially serious risk when exposedto a variety of commonly used drugs. Some agents that can cause hypersensitivity reactions are related to the field of dentistry. The available data suggest that components of local anesthetics,3dental materials,4-9 toothpastes,lO and topical fluoride” can cause a hypersensitivity reaction in a susceptible host.
aAssistant Professor, Department of Oral Diagnosis and Radiology. bAssociate Professor, Department of Periodontics. ‘Professor, Department of Oral Diagnosis and Radiology. 7/13/26016
Chlorhexidine mouthrinse was first introduced by Liie12 in 1969. The agent has since been approved for sale in the United States by the Food and Drug Administration and approved by the American Dental Association Council on Dental Therapeutics.13 Reported oral complications after rinsing with chlorhexidine mouthwash include altered taste sensation,14 superficial desquamation of oral mucosa,ls brownish discoloration of the tongue or teeth,‘6-24and increased calculus formation.25 In addition, some adverse reactions have been reported after the use of the agent in other organs. These reactions include (1) ototoxicity and deafness on contact with the middle ear,26 (2) conjunctivitis associated with the use of soft contact lens solution 27,2* and (3) colitis after a cleanser enema.29 Two other major side effects are anaphylactic shock and cutaneous eruptions. In general, topical application of agents rarely inducesanaphylactic reactions, However, various symptoms of immediate hypersensitivity including anaphylactic reactions have been reported after topical treatment with chlorhexidine. Skin reactions such as contact dermatitis, contact urticaria, and photosensitive dermatitis also have been reported after the use of chlorhexidine.30-37 Drug-induced cutaneous eruptions could be caused by immediate and delayed types of hypersensitivity. IgE-mediated histamine releaseis probably responsible for the urticarial lesions.38-41 Clinically, the reaction is characterized by palpable purpura and erythematous patches of urticaria. In rare casesthe skin re431
432
Fig.
Moghadam, Drisko, and Gier
1. Arrows
outline erythematous patch of FDE on
right hand.
actions may manifest in the form of fixed drug eruption (FDE) . The concept of FDE was first introduced by Brocq4* in 1894. According to a survey done in Finland, the incidence of FDE accounted for 10% of 464 casesof skin reactions.43 FDE consists of isolated lesions recurring in the samesite each time the specific agent is given. Thus cause and effect are hardly ever in doubt. The most common type of FDE consists of slightly elevated inflammatory patches with sharply defined borders, which may be macular, eczematous, or even bullous. Theseeruptions may occur anywhere, including mucous membranes.44-5’ The most commonly useddrugs that have been implicated as a cause of FDE include salicylates, barbiturates, phenolphthalein, phenylbutazone, penicillin, and sulfonamides.44-52 To our knowledge an FDE to chlorhexidine has not been reported. This case may be the first to add the FDE to the list of skin reactions caused by chlorhexidine. CASEREPORT
A 46-year-old white woman was referred to the School of Dentistry, University of Missouri, Kansas City, for periodontal treatment. Routine medical and dental diagnostic procedures were performed. Pertinent medical history revealed numerous allergic reactions, in the form of FDE, to barbiturates and salicylate compounds. The reported eruptions had been observed 2 to 3 hours after the consumption of aspirin or barbiturates and primarily involved the palms of the hands and solesof the feet. The FDEs were severe and had required intravenous injection of calcium compounds and cortisone during a 2- to 3-day period. The periodontal examination revealed relatively high levels of supragingival and subgingival calculus with generalized pocket depths of 3 to 5 mm and up to 6 to 7 mm in somelocalized areas.Periodontal therapy included oral hygiene instructions and an initial grossdebridement followed by four sessionsof root planing with the patient under local anesthesia.Subgingival irrigation with 0.12% chlorhexidine
2. Arrows point to areasof erythematous patches01 FDE on left hand.
Fig.
(Peridex) followed each scaling and root planing procedure. Pocket elimination surgery was performed in four posterior segmentsbefore restorative procedures. Routine postsurgical therapy was performed, and maintenance treatment was scheduled at 3-month intervals. Treatment with Peridex mouthwash was started 1 week after periodontal surgery, which was 4 months after the last root planing appointment. The patient was instructed to use the rinse according to the manufacturer’s directions. The first time she rinsed was at bedtime (I 0:30 PM), and by approximately 1 AM shehad pruritus and erythematous rashes on the palms of the hands and solesof the feet. Becausethe reaction was mild, the patient ignored the symptomsand did not correlate the incident to the mouthwash regimen. The next night the procedure was repeated and the reaction became much more severe(Figs. 1 and 2). The chlorhexidine mouthwash was suspectedas the etiologic agent and was discontinued. The reaction persisted, and on day 3, 50 mg diphenhydramine (Benadryl) was given intramuscularly, followed by 50 mg diphenhydramine (Benadryl) orally three times a day. By day 6 the itching subsided; however, it took 2 more days for the skin eruptions to subside. The patient reported no change in diet, nor had she started any new medication. It was tentatively determined that the FDE was the result of a reaction to the Peridex mouthwash. Becausethe patient is in the field of dentistry, she volunteered to participate further in the studies related to the incident. Several months later, she agreed once again to use the mouthwash to determine whether it was the precipitating agent of the previous FDE. Emergency personnel and drugs were made readily available if needed.This time she was instructed to rinse with % ounce of Peridex mouthwash for only 5 to 10 secondsand to rinse immediately with water. Within 2 hours severeitching began and the previously described skin lesions erupted on the hands and feet. She began oral diphenhydramine, and the symptoms resolved in 4 days. After this reaction, it was still unknown whether the patient was sensitive to the active ingredient (chlorhexidine) or to someother component in the mouthwash formulation. On request, Procter & Gamble Co. supplied a placebo mouthwash that had all the ingredients of Peridex mouthwash except the chlorhexidine. Approximately 2 months
Chlorhexidine hypersensitivity
Volume 7 1 Number 4
after the secondFDE reaction, the patient used the placebo mouthrinse in the samemanner as before but was not aware of the change in the formulation. She reported only a very mild transient itching of the palms and soles after the use of placebo rinse, and skin lesions or residual reactions failed to develop. It was concluded that she was indeed hypersensitive to the chlorhexidine rather than to the other ingredients in the mouthwash formulation. DISCUSSION
In view of the wide useof chlorhexidine mouthrinse, dentists should be aware of the potential adverse reactions induced by chlorhexidine. Eight casesof anaphylactic reactions are reported after the topical application of chlorhexidine in the English-language literature. Six caseswere reported from Japan,53one from Sweden,s4and one from Australia.55 All those patients later tested positive for chlorhexidineinduced hypersensitivity reaction by means of intradermal, scratch, and epicutaneous tests.53-55 According to Ohtoshi et al.,56 more than 30 cases of anaphylactic shock after the topical application of chlorhexidine have been registered in Japan between 1974 and 1984. Sera obtained and examined from sevenof the casesshowed that a specific IgE antibody against chlorhexidine was a mediator of the reaction. Symptoms of anaphylactic reactions were reported as a fall in blood pressure, bronchospasm, dyspnea, cyanosis, and cough. Abdominal pain, numbness, generalized urticaria, and flushing have also been indicated. Time of the onset of symptoms varied from 5 to 40 minutes. The concentrations of chlorhexidine were reported as O-02%,0.05%, 0.2%, OS%, and 1%. The agent was used for disinfecting the skin, mucous membranes (vagina, urinary bladder), and wounds before surgery or other medical procedures. After the increasing reports on anaphylactic reactions, caution and restriction were suggestedwhen the drug was used on mucous membranes and damaged skin.56
Studies on the retention of carbon 16labeled chlorhexidine mouthrinse in the human oral cavity showed that up to 8% of the compound was swallowed by the adults and that 30% was retained in the mouth. The recovery of the radiolabeled chlorhexidine mouthrinse in the liver or kidneys indicated that the chemical penetrated the intact mucosal barrier of the oral cavity or intestinal tract.57,s8 Penetration of chlorhexidine-protein complexes through the skin or mucous membranes may cause sensitization in a susceptible person. Indeed, daily exposure increasesthe risk of severeallergic reactions if the agent is reapplied in a sensitive patient. The incidence of skin reactions to a drug provides a good indication of the risk of allergic drug reaction. In some casesminor symptoms of immediate hypersensitivity not mentioned by the patient may give rise
433
to more serious reaction on reapplication of the agent. The minor symptoms may appear as tingling, itching, and urticaria. Special attention should be focused on atopic patients and in those with a history of multiple drug reactions. Finally, more care should be considered in those cases with compromised oral mucosa. The damaged mucosa may allow the passage of excessive amounts of the antigen through the oral mucosa, which may potentiate life-threatening situations. We thank Ms. Martha Yager for her generous help in typing the manuscript and Mr. David A. Coats for preparing the illustrations. REFERENCES
1. Dolby AE, ed. Oral mucosa in health and disease. London: Blackwell, 1975:122-4. 2. Malamed SF, ed. Handbook of medical emergencies in the dental office. 3rd ed. St. Louis: CV Mosby, 1987:302. 3. Alderete JA, JohnsonDA. Allergy to local anesthetics.JAMA 1969;207:356-7. 4. Brendlinger DL, Tarsitano JJ. Generalized dermatitis due to sensitivity to a chrome cobalt removable partial denture. J Am Dent Assoc 1970;81:392-4. 5. Davenport JC. An adverse reaction to a silicone rubber soft lining material: report of a case. Br Dent J 1970;128:545-6. 6. Elgart ML, Higdon RS. Allergic contact dermatitis to gold. Arch Dermatol 1971;103:649-53. 7. Nealy ET, de1Rio CE. Stomatitis venenata: reaction of a patient to acrylic resin. J Prosthet Dent 1969;21:480-4. 8. Strain JC. Reactions associated with acrylic denture base resins. J Prosthet Dent 1967;18:465-8. 9. Juhlin L, Ohman S. Allergic reaction to mercury in red tattoos and in mercury adjacent to amalgam fillings. Acta Dermatol 1968;48:103-5. 10. Kirton V, Wilkerson DS. Contact sensitivity to toothpaste. Br Med J 1973;2:115-6. 11. Shea JJ, Gillespie SM, Waldbott GL. Allergy to fluoride. Ann Allergy 1967;25:388-91. 12. L6e H. Present day status and direction for future research on the etiology and prevention of periodontal diseases.J Periodontol 1969;40:678-82. 13. Council on Dental Therapeutics. Council on Dental Therapeutics accepts Peridex. J Am Dent Assoc 1988;117:516-7. 14. Flotra L, Gjermo G, Rolla G, Waerbang J. Side effects of chlorhexidine mouth washes. Stand J Dent Res 1971;79: 119-25. 15. Skoglund LA, Holst E. Desquamative mucosal reactions due to chlorhexidine gluconate. Int J Oral Surg 1982;11:380-2. 16. Eriksen HM, Gjermo P. Incidence of stained tooth surfaces in students using chlorhexidine-containing dentifrices. Stand J Dent Res 1973;81:533-7. 17. Eriksen HM, Nordb H, Kantanen H, Ellingsen JE. Chemical plaque control and extrinsic discoloration: a review of possible mechanisms. J Clin Periodontol 1985;12:345-50. 18. Prayitno S, Addy M. An in vitro study of factors affecting the development of staining associated with the use of chlorhexidine. J Periodont Res 1979;14:397-402. 19. Addy M, Prayitno SW. Light microscopic and color television image analysis of the development of staining on chlorhexidine-treated surfaces. J Periodontol 1980:51:39-43. 20. JensenJE. Binding of dyes to chlorhexidine-treated hydroxyapatite. Stand J Dent Res 1977;85:334-40. 21. Addy M, Jenkins PM. Chlorhexidine staining: in vitro study of beverages as aetiological factors. IRCS Med Sci Biomed Technol (Dent Oral Biol Sot Occup Med) 1977;5:393. 22. Addy M, Moran J. The formation of stain on acrylic surfaces by the interaction of cationic antiseptic mouthwashesand tea. J Biomed Mater Res 1984;18:631-41.
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Behjat K. H. Moghadam, DDS, DScD Department of Oral Diagnosis School of Dentistry Universitv of Missouri. Kansas Citv 650 E. 25th St. Kansas City, MO 64108
