Summary

Chlorhexidine is an antiseptic and disinfectant used against bacteria, viruses and fungi. Many health professionals are unaware of its presence in different products, so it is often a ‘hidden’ allergen. Anaphylaxis to chlorhexidine is a rare but potentially life-threatening complication. Allergic reactions are reported with increasing frequency. Considering the widespread use of chlorhexidine, allergic reactions are rare, but due to a lack of knowledge about the allergenic potential, chlorhexidine may be overlooked as a potential cause.

Epidemiology

Worldwide distribution

In 1984, the first case of chlorhexidine induced anaphylaxis in the perioperative setting was reported in a 9-year-old Japanese boy. The true prevalence of chlorhexidine allergy is still unknown and is thought to be under-recognized. Chlorhexidine allergy has recently been increasingly reported particularly in the perioperative and medical procedural settings. The prevalence of perioperative allergic reactions was 9–10% in the United Kingdom, Denmark, and Belgium. A survey from 13 centers reported 252 cases of anaphylaxis to chlorhexidine, and it was within the top four most commonly diagnosed causes of perioperative anaphylaxis (along with neuromuscular blocking agents, antibiotics, and latex).

Although rare, the number of clinical case reports of anaphylaxis (type I hypersensitivity) to this antiseptic is increasing: from 1994 to 2013, 65 case reports of chlorhexidine-related anaphylaxis were diagnosed, the majority was among surgical patients (urology and cardiothoracic). From 1984 to 2014, 36 cases of perioperative anaphylaxis to chlorhexidine were published. From 2014 to 2018, a total of 24 cases of chlorhexidine-related anaphylaxis were published. The male gender is the most affected (83%), mean age was 51 ± 15 years (range, 3–78 years). True incidence of chlorhexidine anaphylaxis is likely to be underestimated in view of its large use as a disinfectant.

Other topics

Health care worker sensitivity to chlorhexidine-based hand hygiene solutions

In a cross-sectional online survey of all workers at a single health service (N: 1050), over 95% used chlorhexidine-based hand hygiene products in their workplace. Nurses and midwives most frequently reported asthma (13.7%), contact dermatitis (27.8%), and previous testing for allergy to chlorhexidine (4.9%). There was a correlation between both the presence of atopy, eczema, or dermatitis and the self-reporting of dry skin, eczema, or dermatitis attributed to chlorhexidine use.

The prevalence of chlorhexidine contact allergy by performing a patch test was 0.47–1% of patients. Despite its widespread use in the healthcare settings, the prevalence of chlorhexidine-induced anaphylaxis in healthcare workers is still relatively low. Nevertheless, the true prevalence in healthcare workers may be underestimated.

Route Of Exposure

Chlorhexidine was introduced in healthcare use in 1954, and due to good antiseptic properties and a favorable safety profile, it is now widely used and is contained in many healthcare products, including mouthwashes, oral paste, eye drops, lubricating gels for medical procedures, powder, dressings, scrubs, and central venous catheters. Furthermore, it is also increasingly used as a preservative in cosmetic and daily-used products, which probably can cause sensitization.

There are many routes of exposure to chlorhexidine such as skin, mucous membrane, and the parenteral route. Topical exposure in preoperative skin preparation or dressing wound can cause both immediate and non-immediate reactions. Mucous membrane exposure through the transurethral, rectal, and vaginal routes could elicit the reactions in both delayed and immediate types, including anaphylaxis. Exposures through the oral and ophthalmic routes generally present with mild immediate reactions, such as localized urticaria. Allergy to chlorhexidine-based mouthwash was reported as contact dermatitis. Exposure by the parenteral route from the chlorhexidine-coated venous or arterial catheters, and epidural catheters can cause both immediate and delayed types, the clinical features of which may range from localized cutaneous lesions to anaphylaxis.

Among patients with chlorhexidine-induced anaphylaxis reported in literature, the most common chlorhexidine-containing product exposure was urinary catheter lubricant (44%), followed by chlorhexidine-coated central venous catheter (35%), and topical chlorhexidine solution (16%).

Occupational airway allergy from chlorhexidine was also reported in three nurses confirmed by inhalation challenge.

Clinical Relevance

Chlorhexidine is the third most common cause of perioperative anaphylaxis in the UK.

Adverse reactions involve both immediate and non-immediate hypersensitivity, ranging from mild cutaneous reactions to anaphylaxis or even death.

The clinical presentation is variable. In most cases patients developed erythematous rash/urticarial at the time of reaction and hypotension, up to cardiorespiratory arrest. Bronchospasm is rarely reported. Undervaluation of previous chlorhexidine reactions increases the risk of a possibly fatal outcome for the patient after re-exposure in future medical-surgical procedures. A prompt referral to a specialist consultation and detailed allergy study is important.

Delayed reactions

The most common allergic reactions described to chlorhexidine are delayed reactions (type IV hypersensitivity), T cell mediated, and occur after exposure to the antiseptic for topical use. Contact dermatitis is the most frequent manifestation. The delayed cutaneous rash generally occurs in patients with a history of prolonged use of chlorhexidine-containing products or multiple exposure events of antiseptic use. The most common delayed rash is contact dermatitis while fixed drug eruption was reported in patients with allergy to chlorhexidine-mouth wash.

Immediate reactions

Immediate reactions (type I hypersensitivity, IgE mediated), have also been reported, but much less frequently, and symptoms can range from urticaria to anaphylaxis with a risk of cardiorespiratory arrest and death.

Most reactions have been reported after application of chlorhexidine to damaged skin surfaces (wounds, burns, surgical incision); and to mucous membranes (urethra, eyes, nose) or after insertion of medical devices (central venous catheters, CVC) impregnated with chlorhexidine.

Pediatric issues

Allergic contact dermatitis to chlorhexidine is common in adults but is quite rare in the pediatric population. Its diagnosis is important because it can mimic other dermatoses common during childhood, and it can also lead to acute immediate hypersensitivity reactions following successive exposures.

Diagnostics

According to some guidelines allergy tests should be carried out in patients with a history suspicious of chlorhexidine allergy, in patients with allergic reactions in the healthcare setting where exposure to chlorhexidine cannot be excluded with certainty and in all patients with perioperative allergic reactions. Allergy to chlorhexidine should be diagnosed based on a relevant clinical reaction in combination with two positive diagnostic tests, according to Danish Anaesthesia Allergy Centre, where sIgE and skin prick test are recommended as the minimum.

Although a provocation test is the gold standard for diagnosis of drug allergy in both immediate and delayed types, it is contraindicated in patients with previous severe reactions or anaphylaxis.

Chlorhexidine allergy carries unique features:

• Often unrecognized.
• Reaction onset in the perioperative setting varies (rapid or delayed).
• Patients with anaphylaxis have a history of mild localized reaction to earlier exposure.
• A skin test may have to be read 20–30 mins after.
• Single allergy test may be insufficient to exclude allergy.
• May be coincident with other drug allergies.

Investigations for chlorhexidine allergy comprise in vivo and in vitro tests. The tests should be carried out in patients with a history suspicious of chlorhexidine allergy, in patients with allergic reactions in the healthcare setting where exposure to chlorhexidine cannot be excluded with certainty and in all patients with perioperative allergic reactions. In a large single-centre study 22 patients with chlorhexidine allergy were identified of 228 patients (9.6%) systematically investigated for suspected perioperative allergic reactions.

In vitro diagnostics

In vitro tests include specific IgE test (sIgE), histamine release test (HRT), and basophil activation test (BAT).

Specific IgE: is generally increased in most patients at the time of the reaction. If negative, it should be repeated between 1–4 months after the event. The sensitivity and specificity on the cut-offs recommended by manufacturers range from 84–100% and 93–97%, respectively.

HRT and BAT: require a fresh blood sample. Both tests have a sensitivity of 50% and specificity of up to 99% Therefore, they are generally used as additional tests to confirm the diagnosis after other tests have shown equivocal results.

In vivo diagnostics

Include skin prick test, intradermal test for immediate reactions and patch tests for delayed reactions.

Skin prick test: a concentration of 5 mg/mL of chlorhexidine di gluconate was recommended. A wheal size of 3 mm or greater developing within 20–30 mins is considered a positive result.

Intradermal test (for immediate reaction): A result is considered positive if the wheal size is 3 mm or greater compared to negative control.

Patch test (for delayed reaction)

Challenge test: No standard protocol of the chlorhexidine challenge test is currently available.

Prevention And Therapy

Prevention Strategies

Prevention of sensitization

Populations that are repetitively exposed to chlorhexidine are at risk of sensitization. These include health care workers, patients with chronic leg ulcers or eczema, and those undergoing frequent surgical interventions.

Impairment of the skin barrier is thought to be the immunologic basis of allergic sensitization in other allergens, such as food, although there is no firm conclusion on the mechanism of allergic sensitization to chlorhexidine.

When first introduced into health care services, the sensitization rate to chlorhexidine was considered low. However, the increasing use of chlorhexidine hand hygiene solutions in health settings has seen a corresponding increase in reports of hypersensitivity.

The importance of preventing healthcare-associated infections is acknowledged, but it is argued that chlorhexidine should not be used prior to short-term intravenous (IV) cannulation, or for disinfecting needleless connector access points, or in impregnated central venous catheters used for routine cardiac surgery where the expected dwell time is less than seven days.

Prevention of re-exposure in patients with suspected or proven pre-existing allergy

The frequency of exposure to chlorhexidine by at least one route is very high. Therefore, the possibility of accidental exposure remains challenging. Most of the patients with chlorhexidine-induced anaphylaxis have had previous mild reactions to its exposure, however mild reactions are also observed in many patients without chlorhexidine allergy.