Chlorhexidine and Hypersensitivity Reactions in Dentistry

Home , Type IV hypersensitivity

Chlorhexidine and IN BRIEF • Describes the history of chlorhexidine use in medicine and dentistry. PRACTICE hypersensitivity reactions • Highlights the spectrum of reported hypersensitivity reactions to chlorhexidine. • Reports two cases of death due to in dentistry anaphylaxis following the use of chlorhexidine in post-extraction tooth M. N. Pemberton1 and J. Gibson2 socket care.

VERIFIABLE CPD PAPER

Immunological reactions to chlorhexidine, including allergy (Type I hypersensitivity) and allergic contact dermatitis/stoma‑ titis (Type IV hypersensitivity), have been recognised for many years. This potential safety issue, however, is not well known within dentistry. The purpose of this paper is to alert dentists and dental care professionals to the potential of chlorhex‑ idine in causing hypersensitivity reactions and to consider this possibility if unexplained hypersensitivity reactions occur.

INTRODUCTION skin creams and disinfectants used to pre- Table 1 Mild allergy – signs, symptoms and management13 In the 1970s, seminal studies on the value pare the skin for surgical procedures. In the of chlorhexidine mouthwash in the control early 1990s, chlorhexidine also began to be Key symptoms and signs of mild allergy of plaque and gingivitis were undertaken.1,2 incorporated into the composition of medi- Urticaria and rash, particularly of chest, Following these studies, 0.1‑0.2% chlorhex- cal devices including intravenous catheters, hands and feet idine mouthwash has become a frequently topical antimicrobial skin dressings and Rhinitis, conjunctivitis 4 recommended or prescribed treatment in implanted antimicrobial surgical mesh. No difficulty breathing the management of gingivitis. Studies have From use in all of these medical applica- Key management principles of mild allergy shown its benefit over other potentially use- tions, it has become apparent that chlo- ful plaque inhibiting agents and indicated rhexidine has the potential to produce Assess the patient specific situations in which chlorhexidine hypersensitivity reactions. Hypersensitivity Give oral antihistamine (for example, chlorphena‑ is of particular benefit.3 As well as being reactions are generally known to occur in mine 4 mg tablet or loratadine 10 mg tablet in adults. Refer to BNF or BNFC available in a mouthwash form, chlorhex- four main forms, I–IV, with Type I (imme- for child doses) idine is also available in other vehicles for diate and mediated chiefly by immuno- Reassess the patient. If severe reaction use in oral healthcare including toothpastes, globulin E) and Type IV (delayed and developing, treat as for anaphylaxis sprays and gels. Common side effects, such mediated by the cells of the immune sys- Refer patient to their general medical practitioner as staining of teeth are well recognised; tem) being the reactions of greatest con- however, rarer, but potentially more severe cern in the orofacial region. side effects including hypersensitivity, are The Type IV hypersensitivity reaction manage mild Type 1 hypersensitivity (aller- less well known. of contact dermatitis to chlorhexidine has gic) reactions and anaphylaxis are given in been reported in both adults and children Tables 1 and 2.12,13 The true prevalence of CHLORHEXIDINE HYPERSENSITIVITY with confirmation by patch testing in many these reactions remains unknown. In the AND MEDICAL PRODUCTS cases.5–7 This delayed type of hypersensi- medical literature, reactions have mainly For many years, chlorhexidine-containing tivity has most frequently followed the been recorded in case reports with these products have also been used in other areas use of chlorhexidine-containing topical cases falling into three broad categories.14 of medicine because of chlorhexidine’s medicinal creams used to treat inflamed Type I hypersensitivity reactions have beneficial effects as a topical antimicrobial skin. It has also followed the use of cos- been reported when chlorhexidine has agent. These products include antiseptic metic products containing chlorhexidine. been applied to damaged skin surfaces.8,10,14 Type I hypersensitivity reactions These instances include wounds and burns 1*Consultant in Oral Medicine and Honorary Lecturer, have been reported especially where or when the skin was cut in surgical pro- University Dental Hospital of Manchester and School of Dentistry, Higher Cambridge Street, Manchester, M15 chlorhexidine has been used topically, cedures and a chlorhexidine containing 6FH; 2Consultant and Honorary Senior Lecturer in Oral intra-urethrally, and with chlorhexidine- product had been used in the prepara- Medicine, Department of Oral Medicine, Dundee Dental Hospital & School, Dundee, DD1 4HN impregnated catheters. Incidents of this tion of the skin. Anaphylactic reactions *Correspondence to: Michael Pemberton immediate allergic type of hypersensitiv- have been reported. There have also been Email: [email protected] ity have been reported from all over the a few cases in which chlorhexidine use on Refereed Paper world, with the reactions reported ranging unbroken skin has also led to immediate Accepted 10 October 2012 14 DOI: 10.1038/sj.bdj.2012.1086 from localised urticaria to life-threatening type hypersensitivity reactions. These ©British Dental Journal 2012; 213: 547-550 anaphylactic shock.8–11 Details of how to include when chlorhexidine has been

applied to pre-existing hand dermatitis, early 1970s, many studies were carried Table 2 Anaphylaxis – signs, symptoms acne or to erythematous skin. out looking at the utility of chlorhex- and management12,13 Type I hypersensitivity reactions, includ- idine mouthwash as part of dental care. Key symptoms and signs of anaphylaxis ing anaphylaxis, have been reported when Radiolabelling of chlorhexidine was used may include chlorhexidine has been applied to mucous to identify the retention and distribu- Facial flushing, swelling and paraesthesia membranes.11,14–16 In the majority of cases, tion of 10 ml of a chlorhexidine 0.2% Generalised urticaria or itching these have been associated with chlo- mouthwash used in healthy volunteers. It rhexidine-containing gels and lubricants was found that an average of 4% of the Wheezing, stridor or difficulty breathing inserted into the urethra before catheteri- compound was swallowed by the adults Abdominal pain sation or cystoscopy. Other cases have been studied and an average of 30% retained Sense of impending doom reported following chlorhexidine lubricant in the mouth.19 There was a rapid fall in applied intra-vaginally before gynaeco- the chlorhexidine concentration found Rapid, weak or impalpable pulse logical examination and chlorhexidine- in the mouth over the first few hours, Falling blood pressure containing ophthalmic wash solution. but with some activity still present after Type I hypersensitivity reactions have 24 hours. While chlorhexidine appeared Key management principles of anaphylaxis been reported when chlorhexidine has to be a poorly absorbed drug, radiola- Assess the patient using an ABCDE approach been impregnated into central venous belled chlorhexidine was detected in the Call ambulance catheters.14,17,18 In 1996, such catheters kidney and liver in animal studies, indi- 20 Secure the airway and give 100% oxygen were introduced into practice and within cating some absorption had occurred. In (10‑15 litres per minute flow rate) the next few years, there were reports of 1971, a study looked at the side effects of Lay patient flat and raise legs to support patients experiencing anaphylactic-like chlorhexidine mouthwashes in a group of blood pressure 21 adverse effects. Reports came from sev- 50 soldiers over a period of four months. Administer 0.5 ml of 1:1000 adrenaline eral countries, but the majority were from The study found some cases where chlo- (adrenaline) in adults via intramuscular Japan. It is not clear why the majority of rhexidine mouthwash caused irritation injection and repeat at 5 minute intervals if needed. (For children, child 6‑12 years give these reactions occurred in the Japanese and damage to the oral mucosa with 0.3 ml of 1:1000 adrenaline, child less than population. Possible explanations include resultant chemically-induced trauma. The 6 years give 0.15 ml of 1:1000 adrenaline) a genetic predisposition or an increased frequency of this side effect appeared to Monitor patient and if cardiac arrest occurs, start exposure to chlorhexidine-containing increase with increasing chlorhexidine basic life support immediately products resulting in heightened sensitiv- concentration. ity. The catheter was subsequently with- In the early 1970s, no cases of sensitisa- shortly after an upper lip injury was dis- drawn from use in Japan, and the United tion to chlorhexidine used in the mouth infected with 0.05% chlorhexidine gluco- States Food and Drug Administration had yet been observed.21 Since then, immu- nate.16 The patient subsequently showed a issued an alert concerning potential hyper- nological reactions to chlorhexidine when positive response to an intra-dermal test. sensitivity reactions to chlorhexidine- used in the mouth have been infrequently Recently we have become aware of impregnated medical devices.4,17 The alert documented in the medical and dental liter- two cases of anaphylaxis in the UK, recommended that if a patient exhibited ature. Allergic contact stomatitis (Type IV thought to be triggered by chlorhexidine an unexplained hypersensitivity reaction, hypersensitivity) has been reported follow- products used in dental practice – both then steps should be taken to determine ing the use of chlorhexidine-containing of which resulted in fatalities. Both cases whether chlorhexidine was used or not. mouthwash with the hypersensitivity appear to have involved the use of chlo- Confirmation of Type I hypersensitiv- confirmed by patch testing.7 However, in rhexidine in the treatment of tooth sockets ity reactions to substances is usually other reports of possible hypersensitivity after dental extraction. It is unclear how undertaken by skin prick testing or iden- relating to chlorhexidine-containing prod- much the application of chlorhexidine to tification of specific IgE antibodies in the ucts used in the mouth, it is sometimes an ‘open wound’ influenced the nature blood. In many of the reported cases of unclear as to which type of immunologi- and severity of the allergic reactions that chlorhexidine allergy, positive reactions on cal response is actually occurring.22 Rarely ensued, but it is likely to have increased skin prick testing with weak concentra- Type I allergy has been reported follow- the amount of chlorhexidine absorbed into tions of chlorhexidine have been found.8 ing use of chlorhexidine in the mouth, the blood stream compared to a topical Chlorhexidine specific IgE antibodies have or on the lips. In one case, confirmed by application on intact oral mucosa. been identified in the serum of affected positive skin prick testing, anaphylactic patients, which lends further evidence that symptoms occurred following treatment Case one a true Type I hypersensitivity reaction has with antiseptic dental gel containing 1% The death of a 63-year-old male patient occurred in these individuals.8 chlorhexidine gluconate.23 In another case following dental treatment in Penrith, UK, confirmed by skin prick testing, urticarial was considered at a coroner’s inquest in CHLORHEXIDINE HYPERSENSITIVITY skin lesions followed the use chlorhexidine February 2011, the death having taken AND DENTAL PRODUCTS gluconate-containing mouthwash.24 In a place in October 2009.25 The coroner Chlorhexidine is most commonly used further case, generalised urticaria, flush- returned a verdict of accidental death due in dentistry as a mouthwash. In the ing, cough and general fatigue followed to an allergic reaction. The inquest heard

expert evidence that there was a 95% cer- workers were found to have the second the potential to cause serious adverse reac- tainty that the allergic reaction had been highest risk of developing latex allergy. tions. We hope that this paper also serves to chlorhexidine. The patient had a res- Following the ban on the use of powdered as a reminder to practitioners of this very piratory arrest and died in hospital with- latex gloves, the incidence of latex allergy rare, but important risk. The circumstances out regaining consciousness, despite the in all groups, including healthcare work- of the recent fatalities in a UK dental set- dental practice staff offering the patient ers, has fallen markedly.30 ting where chlorhexidine appears to have the best possible treatment for his ana- Several studies have attempted to look been used in the management of patients phylaxis, including the administration of at the incidence of chlorhexidine hyper- after the extraction of teeth may suggest adrenaline by injection, as reported at the sensitivity susceptibility among health- that, like other situations in medicine inquest. Chlorhexidine had been used to care workers. In 2003, Danish healthcare and surgery described previously, ‘open irrigate a tooth socket and other causes for workers were investigated with skin prick wounds’ may increase the likelihood of the anaphylaxis were effectively excluded. testing (for Type I hypersensitivity), patch allergic reactions occurring.

testing (for Type IV hypersensitivity) and 1. Löe H, Schiott C R. The effect of mouthrinses and Case two by questionnaires.31 There were no posi- topical applications of chlorhexidine on the devel‑ opment of dental plaque and gingivitis in man. The death of a 30-year-old female patient tive tests in 104 participants tested and J Periodontal Res 1970; 5: 79–83. following dental treatment in Brighton, no histories of suspected hypersensitivity 2. Löe H, Schiott C R, Karring G, Karring T. Two years oral use of chlorhexidine in man. I. General design UK, was considered at a coroner’s inquest reactions to chlorhexidine. More recently, and clinical effects. J Periodontal Res 1976; in September 2011, the death having taken in 2009, British healthcare workers in a 11: 135–144. 26,27 3. Addy M, Moran J M. Clinical indications for the place in February 2011. The coroner district general hospital who thought they use of chemical adjuncts to plaque control: returned a verdict of death by medical might be allergic to chlorhexidine were chlorhexidine formulations. Periodontol 2000 1997; 15: 52–54. misadventure, with the death being due investigated by skin prick testing and 4. Food and Drug Administration. FDA public health to anaphylaxis, most likely to a dental identification of positive specific IgE to notice: potential hypersensitivity reactions to 32 chlorhexidine-impregnated medical devices. mouthwash containing chlorhexidine. chlorhexidine. Four cases were positive Washington: Food and Drug Administration, Centre Once again, the mouthwash had been used on testing. These were the first reports for Devices and Radiological Health, 1998. 5. Goon A T, White I R, Rycroft R J, McFadden J P. in the clinical situation of treating a socket of confirmed occupational IgE mediated Allergic contact dermatitis from chlorhexidine. days after a tooth had been extracted. chlorhexidine allergy in healthcare work- Dermatitis 2004; 15: 45–47. 6. Le Corre Y, Barbarot S, Frot A S, Milpied B. Allergic The coroner reported that, ‘the failure to ers. In all four cases there was a history contact dermatitis to chlorhexidine in a very young diagnose anaphylactic shock was regret- of itching and urticaria of the skin after child. Paediatr Dermatol 2010; 27: 485–487. 7. Liippo J, Kousa P, Lammintausta K. The relevance of table but understandable in the light of the using chlorhexidine-containing handwash. chlorhexidine contact allergy. Contact Dermatitis extraordinary speed of the illness.’ Two of the cases were also found to be 2011; 64: 229–234. 8. Ohtoshi T, Yamauchi N, Tadokoro K et al. IgE allergic to latex as well. None had had a antibody-mediated shock reaction caused by topi‑ CHLORHEXIDINE HYPERSENSITIVITY more serious anaphylactic reaction. Where cal application of chlorhexidine. Clin Allergy 1986; AND HEALTHCARE WORKERS 16: 155–161. identified, chlorhexidine hypersensitive 9. Ramselaar C G, Craenen A, Bijleveld R T. Severe The use of chlorhexidine within medi- healthcare workers should use non-chlo- allergic reaction to an intraurethral preparation containing chlorhexidine Br J Urol 1992; cine is increasing. The recent heightened rhexidine hand washes such as povidone 70: 451–452. awareness of hospital acquired infections iodine or 70% ethanol-based products. For 10. Cheung J, O’Leary J J. Allergic reaction to chlorhex‑ idine in an anaesthetised patient. Anaesth Intensive has encouraged frequent hand decontami- such healthcare workers, chlorhexidine- Care 1985 13: 429–430. nation among healthcare workers. Many containing household products such as 11. Evans R J. Acute anaphylaxis due to topical chlo‑ rhexidine acetate. BMJ 1992; 304: 686. ® of the products used contain chlorhex- Savlon antiseptic should be avoided and 12. Medical emergencies and resuscitation ‑ standards idine and concern has been raised that chlorhexidine should not be used at all for clinical practice and training for dental practitioners and dental care professionals in general the incidence of chlorhexidine allergy will during their clinical practice. dental practice. London: Resuscitation Council increase in parallel with increased expo- It is unclear whether the incidence of UK, 2006 (revised 2012). Online article available at http://www.resus.org.uk/pages/MEdental.pdf sure to chlorhexidine. There are concerns chlorhexidine-related allergy is increasing (accessed November 2012). that the incidence of chlorhexidine allergy in healthcare workers or in the popula- 13. Scottish Dental Clinical Effectiveness Programme. Drug prescribing for dentistry. 2nd ed. Dundee: may follow the epidemiological history of tion in general. It is clear, however, that SDCEP, 2011. latex allergy. Although delayed hyper- hypersensitivity can occur to this widely 14. Heinemann C, Sinaiko R, Maibach H I. Immunological contact urticaria and anaphylaxis sensitivity to latex is long established, used antiseptic, and dental healthcare pro- to chlorhexidine: overview. Exog Dermatol 2002; immediate hypersensitivity to latex only fessionals need to be aware of this possi- 1: 186–194. 15. Chisholm D G, Calder I, Peterson D, Powell M, Moult first appeared in the medical literature in bility. In January 2012, the UK Medicines P. Intranasal chlorhexidine resulting in anaphylactic 1979.28 Following that report, the num- and Healthcare products Regulatory circulatory arrest. BMJ 1997; 315: 785. 16. Okano M, Nomura M, Hata S et al. Anaphylactic ber of reported cases of allergy to latex Agency released a drug safety update to symptoms due to chlorhexidine gluconate. Arch increased alarmingly, with peak incidence all healthcare workers on the potential for Dermatol 1989; 125: 50–52. 17. World Health Organization. Central venous cath- in the 1980s and 1990s. This was attrib- chlorhexidine to induce hypersensitivity, eters (Arrowguard®) recalled: anaphylactic shock. 33 Alert No. 62. Geneva: WHO, 1997. uted to the greatly increased use of latex as a reminder of this risk. Chlorhexidine 18. Stephens R, Mythen M, Kallis P, Davies D W, Egner in healthcare, especially latex gloves, as is a very commonly used product in many W, Rickards A. Two episodes of life-threatening 29 anaphylaxis in the same patient to a chlorhexidine- well as greater awareness of the problem. areas of dental practice and it is easy to sulphadiazine-coated central venous catheter. Br J After patients with spina bifida, healthcare forget that such everyday products have Anaesth 2001; 87: 306–308.

19. Bonesvoll P, Lokken P, Rölla G, Paus P N. Retention Charles Russell, 2011. Online article available by natural rubber latex allergy in German health of chlorhexidine in the human oral cavity after at www.charlesrussell.co.uk/UserFiles/file/pdf/ care workers. J Allergy Clin Immunol 2004; mouth rinses. Arch Oral Biol 1974; 19: 209–212. Healthcare/Death_Dentist.pdf (accessed 114: 347–351. 20. Winrow M J. Metabolic studies with radiolabelled November 2012). 31. Garvey L H, Roed-Petersen J, Husum B. Is there a chlorhexidine in animals and man. J Periodontal Res 26. BBC News. Mouthwash reaction killed Brighton risk of sensitization and allergy to chlorhexidine in Suppl 1973; 12: 45–48. dental patient. BBC, 2011. Online article available health care workers? Acta Anaesthesiol Scand 2003; 21. Flötra L, Gjermo P, Rölla G, Waerhaug J. Side effects at http://www.bbc.co.uk/news/mobile/uk-england- 47: 720–724. of chlorhexidine mouth washes. Scand J Dent Res sussex-14951073 (accessed November 2012). 32. Nagendran V, Wicking J, Ekbote A, Onyekwe T, 1971; 79: 119–125. 27. Freedman N. Brighton woman dies at dentist. Garvey L H. IgE-mediated chlorhexidine allergy: a 22. Yaacob H, Jalil R. An unusual hypersensitivity reac‑ Brighton: The Argus, 2011. http://www.theargus. new occupational hazard? Occup Med (Lond) 2009; tion to chlorhexidine. J Oral Med 1986; 41: 145–146. co.uk/news/9251198.Brighton_woman_dies_at_ 59: 270–272. 23. Thune P. Two patients with chlorhexidine allergy dentist/ (accessed November 2012). 33. Medicines and Healthcare products Regulatory – anaphylactic reactions and eczema. Tidsskr Nor 28. Nutter A F. Contact urticaria to rubber. Br J Agency. Drug safety update: Chlorhexidine: Laegeforen 1998; 118: 3295–3296. Dermatol 1979; 101: 597–598. reminder of potential for hypersensitivity. London: 24. Sharma A, Chopra H. Chlorhexidine urticaria: a rare 29. Pollart S M, Warniment C, Mori T. Latex Allergy. Am Department of Health, 2012. Online article occurrence with a common mouthwash. Indian J Fam Physician 2009; 80: 1413–1418. available at http://www.mhra.gov.uk/ Dent Res 2009; 20: 377–379. 30. Allmers H, Schmengler J, John S M. Decreasing Safetyinformation/DrugSafetyUpdate/CON140701 25. Reissner D, Khanam J. Death at the dentist. London: incidence of occupational contact urticaria caused (accessed November 2012).