Allergic Manifestations in the Oral Cavity

Usha Dayanarayana, MDS; Shilpa Padar Shastry, MDS; Chetan Shankar, MDS; Naveen Kumar N, MDS; Rama Murthy TK, MDS; and Mahesh BS, MDS

Usha Dayanarayana, MDS, is a senior lecturer in the department of oral medicine and radiology at the Vydehi Institute of Dental Sciences and Research Center in Bengaluru, India. Conflict of Interest Disclosure: None reported.

Shilpa Padar Shastry, MDS, is a reader in the department of oral medicine and radiology at the Vydehi Institute of Dental Sciences and Research Center in Bengaluru, India. Conflict of Interest Disclosure: None reported.

Chetan Shankar, MDS, is a professor and the head of the department of orthodontics at the Vydehi Institute of Dental Sciences and Research Center in Bengaluru, India. Conflict of Interest Disclosure: None reported.

Naveen Kumar N, MDS, is a senior lecturer in the department of oral medicine and radiology at the Vydehi Institute of Dental Sciences and Research Center in Bengaluru, India. Conflict of Interest Disclosure: None reported.

Rama Murthy TK, MDS, is a professor and the head of the department of oral medicine and radiology at the Vydehi Institute of Dental Sciences and Research Center in Bengaluru, India. Conflict of Interest Disclosure: None reported.

Mahesh BS, MDS, is a reader in the department of oral medicine and radiology at the Vydehi Institute of Dental Sciences and Research Center in Bengaluru, India. Conflict of Interest Disclosure: None reported.

ABSTRACT

Background: Allergic reactions in the oral cavity can be triggered by a wide range of common allergens, dental materials and medications that can cause oral and systemic clinical manifestations. Diverse symptoms and signs of allergic reactions in the oral cavity mimic other common diseases, making diagnosis difficult. Hence, early diagnosis and management are necessary to reduce the risk of serious complications.

Types of articles reviewed: This review was performed by compiling information available from various popular search engines on the internet, in textbooks and in bibliographic databases such as Google Scholar, PubMed (Medline) and Scopus.

Results: This article aims to enumerate various types of hypersensitivity reactions based on algorithmic approach. The duration, recurrent nature, morphology, location and systemic symptoms that are useful in evaluating etiology, signs and symptoms of allergic reactions in the oral cavity are discussed.

Practical implications: In general, a detailed history of the patient’s diet, drugs and systemic features is essential for correct diagnosis and management of their condition. This review updates the dentist to understand and enhance their knowledge for better diagnosis and treatment.

Keywords: Allergens, allergies, allergic reaction, oral manifestations, hypersensitivity reactions

__________

Allergy is defined as a hypersensitive state acquired through exposure to a particular allergen. Reexposure to the allergen produces a heightened capacity for reaction. 1 Contact with the allergen can be through the skin, the oral mucosa, the eyes, lung inhalation, swallowing or injecting. The phenomenon of allergy was discovered in 1906 by Clemens von Pirquet. 2 The word allergy comes from the Greek words “allos” meaning other and “ergos” meaning work. The human oral mucosa is often subjected to a wide spectrum of foreign agents, including hot or cold foods, acidic or alkaline substances, spicy foods, drugs, microorganisms, cosmetics, metals in utensils, dental materials, toothpaste, tobacco and alcohol taken through the mouth. Allergic reactions to such agents can manifest in diverse ways.

Allergic reactions are an inappropriate immune response to a normally harmless substance. The immune system, which includes antibodies, white blood cells, mast cells, complement proteins and other substances, normally defends the body against foreign substances called antigens. However, certain antigens (called allergens) can stimulate the immune system to exaggerate, which can cause harm in susceptible people. The result is an allergic reaction. Some people are allergic to only one substance while others are allergic to many.

Incidence of allergic or hypersensitivity reaction is difficult to ascertain, as many allergic reactions go unreported. However, Tannol et al. (2018) 3 suggested 15% of the world’s population will be affected by a type of allergic reaction during their lifetime. European data estimated that 0.3% of the population will be troubled by anaphylaxis at some point in their lives. In the U.S, 1 in 3,000 inpatients annually experience a severe allergic reaction. Worldwide epidemiological data of anaphylaxis are scant and remain unavailable in many countries. 4

Additionally, articles with a compilation of allergic manifestations affecting the oral cavity are few. As dentists, we must be aware of different types of oral features of hypersensitivity reactions for timely diagnosis and management. Hence, this article aims to bring together different allergic manifestations of the oral cavity, their clinical expressions, types, oral manifestations, various allergens and management.

Methods of Literature Search This review was performed by compiling information available from various search engines on the internet, in textbooks and in bibliographic databases such as Google Scholar, PubMed (Medline) and Scopus. We also analyzed the cross references of these articles and included them if necessary. The duration of included articles was from 1982 to 2021, and only those articles published in English were included for this review. Keywords used for the search were “allergy,” “hypersensitivity reactions,” “oral manifestation,” “dental materials,” “allergens” and combinations of these words. A total of 58 articles that fulfilled our criteria were included in this review

Classification

Based on the time required for a sensitized host to develop clinical reactions on reexposure to the antigen, hypersensitivity reactions are divided into two types: 1) immediate hypersensitivity reaction — B cell or antibody mediated (anaphylaxis, atopy, antibody-mediated cell damage, Arthus phenomenon, serum sickness) and 2) delayed hypersensitivity reaction — T cell-mediated (infection type, contact dermatitis type). 5 Another classification followed for allergy and hypersensitivity is Coombs and Gell’s classification 6 (TABLE 1). Common allergens and dental allergens are listed in TABLE 2. A compilation of clinical/oral manifestations of allergic reactions affecting the oral cavity is cited in TABLE 3.

Anaphylaxis

Anaphylaxis is defined as “a serious allergic reaction that is rapid in onset and may cause death.” 7 It is a severe immediate-type systemic generalized hypersensitivity reaction affecting multiple organ systems that can lead to acute, life-threatening respiratory failure, bronchospasm, cyanosis, hypotension and shock. It is an immunoglobulin (IgE) mediated process that leads to mast cells and basophil activation resulting in the sudden release of a large amount of histamine and, later, leukotrienes, 8 tumor necrosis factor and various cytokines leading to the allergic response. Most anaphylaxis is triggered by food (peanuts, tree nuts, shellfish and fish, cow’s milk, eggs and wheat), medications (most commonly penicillin and other antibiotics) or insect venoms. 9 In children, food allergy is the most common cause and is responsible for about 80% of anaphylactic reactions; whereas in adults, it accounts for up to 20% to 30%10,11 of cases. Venom- and drug-induced anaphylaxis are more common in adults.

The onset of anaphylaxis is a generalized systemic reaction involving at least two organ systems. Respiratory (obstruction) and cutaneous (urticaria, angioedema, erythema, pruritus), cutaneous and cardiovascular (hypotension, dizziness, syncope, tachycardia) or cutaneous and gastrointestinal (nausea, vomiting, abdominal pain, diarrhea). Signs and symptoms of anaphylaxis are unpredictable and may vary from patient to patient and from one reaction to another.

Treatment

Acute treatment of anaphylaxis begins with a rapid assessment of the airway, breathing and circulation followed by the immediate administration of epinephrine. The recommended dose of epinephrine for anaphylaxis is 0.01 mg/kg body weight up to a maximum dose of 0.5 mg (0.5 ml) administered intramuscularly every five to 15 minutes as necessary .12,13 If resuscitation using intramuscular epinephrine is ineffective, intravenous epinephrine may be required. Oxygen therapy is recommended for those with prolonged reactions. Intravenous crystalloid solutions (IV fluids) volume replacement should be provided in massive fluid shifts, which occur rapidly in anaphylaxis leading to hypotension due to increased vascular permeability. Inhaled beta 2-agonists (for patients experiencing bronchospasm) and antihistamines (for control of cutaneous symptoms) can also be useful. Intramuscular or intravenous administration of methylprednisolone is considered in severe cases. 14

Atopy

Atopy is a familial tendency to produce IgE-mediated disease that affects the skin and has an immunopathogenesis very similar to that of allergic asthma and rhinitis in response to ordinary exposure to the allergen, usually proteins. 15

Arthus Reaction

An Arthus reaction is a localized reaction that occurs at the site of an injection when a small quantity of antigen is injected into the skin. The reaction occurs in the presence of a high level of circulating antibodies due to repeated injection. This is characterized by marked edema and pain and swelling at the site of injection beginning several hours after immunization. It is self-limiting; severity and frequency can be reduced by spacing out the injections. 16,17

Serum Sickness

Serum sickness is a type III systemic hypersensitivity reaction that results from the injection of a heterologous or foreign protein or serum. The circulating immune complex infiltrates the blood vessels and tissues causing increased vascular permeability leading to an inflammatory process such as vasculitis and arthritis. Certain medications like penicillin and nonsteroidal anti-inflammatory drugs produce clinically similar serum sickness-like reactions. These reactions typically occur one to three weeks after exposure to the drug but may occur as early as one to 24 hours afterward. 18

Angioedema

Angioedema is diffuse edematous swelling of soft tissues commonly involving the subcutaneous tissue and submucosal connective tissues due to vascular leakage (FIGURE 1, TABLE 4). It results in death when the gastrointestinal or respiratory tract is involved. Allergic angioedema is due to mast cell degranulation, which leads to histamine release and typical manifestations that are seen commonly in Ig-E-mediated type I hypersensitivity reactions caused by drugs, foods (especially eggs, mussels, milk, shellfish and nuts), 19 cosmetics, topical medications and even dental rubber dams. It can also result from physical stimuli such as heat, cold, exercise, emotional stress, solar exposure and significant vibration.

Angioedema manifests as a soft, nontender, diffuse edematous swelling with relatively rapid onset that may be solitary or multiple. It most commonly involves the face around the lips, chin, eyes, tongue, pharynx and larynx. The symptoms appear rapidly, within one to two hours of exposure to the allergens. The eyes may be swollen shut and the lips extremely puffy. The enlargement usually resolves within 24 to 72 hours, but some cases persist for several days. Avoidance of the allergen and the use of antihistamines may prevent future attacks. Chronic cases require steroid therapy, which generally provides a good response. In cases where the allergic attack is progressing toward airway obstruction, epinephrine may be lifesaving.

Lichenoid Reactions

Lichenoid reactions have been associated with numerous drugs including antihypertensives, antimicrobials, anxiolytics, NSAIDs and oral hypoglycemic agents. They are also associated with tobacco chewing and dental materials such as amalgam, gold, casting alloys and flavoring agents. Clinically, a lichenoid reaction exhibits similar patterns of reactions as those seen in oral lichen planus (OLP), that is papules, reticulum, plaque type, erythema and ulcers. The most distinguishing feature between OLP and lichenoid contact reaction (LCR) is the site and extension of the lesions. Lesions are usually restricted to the areas where there is regular contact with dental materials. The most common sites are the buccal mucosa and the border of the tongue. Gingiva, the floor of the mouth, the dorsum of the tongue and palatal mucosa are the least affected sites. 20,21 Most LCRs are nonsymptomatic. In some cases, the patient may experience an uneasy burning sensation when erythematous or ulcerative lesions are present (FIGURE 2, TABLE 4). When in contact with composite restorations of the anterior teeth, LCRs are observed in both upper and lower lip mucosa. 22 Most types of LCR resolve after removal of the restoration that is in direct contact with the lesion followed by replacement of biocompatible dental materials.

Tobacco Chewing

Arya S et al. (2017) 23 observed quid-induced lichenoid oral lesions among betel quid chewers. This lesion consisted of white, linear, wavy, parallel, nonelevated streaks that could not be scraped off (FIGURE 3, TABLE 4). The fine lesion did not overlap or crisscross as in a lichen planus. The lesion, found at the site of betel quid placement, has the proposed term “betel quid lichenoid lesion.” 22 There may be complete lesion regression if the user ceases betel quid chewing.

Contact Stomatitis

A contact stomatitis is a type of allergic reaction on the oral mucosa that can occur in a localized area or can be polymorphic as a consequence of repeated contact with many causative agents like mercury-based products, nickel sulfate, cobalt chloride and gold, bonding agents (composites), ethereal oils, silicone and polyester impression materials. 24 The oral manifestations of contact allergy are gingivitis, stomatitis, cheilitis, perioral dermatitis, burning mouth syndrome, lichenoid reaction and orofacial granulomatosis. 25

The treatment for contact stomatitis is avoidance of the allergen. When the contact stomatitis is due to a dental restoration or an orthodontic wire, replacement of the restoration may be considered. If it is due to a flavoring or preservative in food or a dental hygiene product, the patient should be advised to stop eating the food or using the product. The lesions usually disappear once the allergen is removed. Topical application of corticosteroids is indicated in persistent severe or chronic cases.

Stomatitis (Cheilitis) Venenata

Stomatitis (cheilitis) venenata is a contact allergic reaction caused by different chemical and cosmetic substances that cause inflammation of the labia and of the entire oral mucosa. There can be pronounced edema with multiple forms of small erosions 0.5 mm in diameter. With chronic local irritation on the labia, exfoliative cheilitis with strong exudation can be expected. 24

The treatment involves elimination of the offending allergen. The complete resolution of the lesions can take up to two weeks. Patients presenting with extensive lesions are treated with antihistamines, topical or systemic corticosteroids and mouthwashes.

Recurrent Aphthous Stomatitis

Recurrent aphthous stomatitis (RAS) is one of the most common oral mucosal diseases. Studies have shown that food ingredients contribute to some cases of RAS. 26 However, an outbreak of aphthae following ingestion of certain foods or drugs by different patients has been reported so frequently that allergy must be considered a precipitating factor. 27

The aphthous ulcer begins as a single or multiple superficial erosions covered by a pseudomembrane. The ulcer generally has a wellcircumscribed margin surrounded by an erythematous halo (FIGURE 4, TABLE 4). 28 The lesions are usually painful, vary in size from 2 mm to 3 mm to over 10 mm in diameter. The most common sites of occurrence are the buccal mucosa, labial mucosa, buccal and lingual sulci, tongue, soft palate, pharynx, gingiva and all locations of labile mucosa not bound to the periosteum. 27 Three clinical variations have been recognized: minor, major and herpetiforme ulcers. Minor form and herpetiforme ulcers heal without scarring in seven to12 days while the major form persists for three to six weeks. 29 Topical steroids are used for treatment, and in severe cases, intralesional steroid injection or lowdose systemic steroids are prescribed.

Perioral Dermatitis

Perioral dermatitis is a unique inflammatory idiosyncratic disease of the skin affecting the circumoral area precipitated because of tartar, toothpaste, bubble gum, cosmetic products, nasal steroids, flavoring agents and hormonal factors. A study has shown that patients with oral mucosal diseases are significantly more likely to have hypersensitivity to food additives (especially benzoic acid), perfumes and flavorings (especially cinnamaldehyde). 30 Treatment includes the use of metronidazole cream or gel, clindamycin lotion or gel, erythromycin gel, topical sulfur preparations and azelaic acid gel. Topical calcineurin inhibitors such as tacrolimus ointment or pimecrolimus cream can also be effective. 31–33 If topical treatment is not helpful, 250 mg to 500 mg of tetracycline twice a day, 100 mg of doxycycline once or twice a day and 100 mg of minocycline once or twice a day for an eight- to 12-week tapering course can be prescribed. 34,35

Erythema Multiforme

Erythema multiforme (EM) is an acute reactive mucocutaneous inflammatory and hypersensitivity reaction characterized by a skin eruption, with symmetrical erythematous edematous or bullous lesions of the skin or mucous membranes. EM is a disorder with variants ranging from self-limited, mild, exanthematous, cutaneous lesions with minimal oral involvement to a progressive, fulminating and severe disease with extensive mucocutaneous epithelial necrosis. More than half of the cases have no known cause; other causes include medications, infections, immunotherapy or illnesses. 36 Drugs are responsible for 4% of EM cases and 80% of Stevens-Johnson syndrome cases. The oral lesions disappear within two weeks of drug withdrawal. 37 The most common drug reaction seen in the oral cavity is caused by NSAIDs, penicillin, sulfonamides and barbiturates. 38 EM primarily involves oral mucosa but subsequent attacks can produce more severe forms of EM involving the skin. At times, oral and lip ulcerations can occur without any skin target lesions (FIGURE 5, TABLE 4).

Management of EM depends on the underlying etiology and the disease severity. Acute, uncomplicated erythema multiforme involves symptomatic treatment with highpotency topical corticosteroids, antihistamines, antiseptic mouthwash and anesthetic solutions. 39 If drugs are the cause of erythema multiforme, then discontinuation of the offending drug is recommended. In herpes simplex virus infections, oral acyclovir is recommended to reduce the severity and duration of EM. 40

Food Allergy

Food allergy is a type of immune response triggered by eggs, peanuts, milk, shellfish, soy, tree nuts, wheat or food additives such as dyes, thickeners and preservatives. Other specific foods can cause an allergy. 41 Signs and symptoms include hives, nausea, stomachache, diarrhea, shortness of breath, swelling of the airways, tingling or itching in the mouth, swelling of the lips, face, tongue and throat or other parts of the body, gastrointestinal and respiratory tracts and the cardiovascular system. Symptoms can range from mild to severe based on the amount of food necessary to trigger the allergic reaction, which varies from person to person. Reaction to food allergy usually develops within a few minutes to two hours after eating the offending food. 42

Intraoral allergic reactions to food, candy and chewing gum can result from potent flavoring agents, such as cinnamon, or fresh fruits and vegetables. The lesions in the oral cavity are focal and usually develop at sites with direct and prolonged contact with the cinnamon agent. The labial and buccal mucosa and lateral tongue are most commonly affected; the floor of the mouth and the gingiva may also be involved. Once a food allergy has developed, the best way to prevent an allergic reaction is to know and avoid foods that cause signs and symptoms. In the case of accidental exposure, the treatment of choice is epinephrine administered by intramuscular injection into the lateral thigh. 43 Patients with food allergies can wear medical alert bracelets or necklaces to indicate their allergy.

Oral Allergy Syndrome

A localized IgE-mediated reaction is also known as the pollen-food syndrome, which causes tingling and itching of the mouth and pharynx. Swelling of the lips, tongue, palate and throat along with oral pruritis and irritations sometimes associated with other allergic clinical features, including rhinoconjunctivitis, urticaria and even anaphylaxis, have been referred to as oral allergy syndrome. It seems to be precipitated by fresh foods, including apples, in people who have been sensitized to cross-reacting allergens in pollens,

A localized IgE-mediated reaction is also known as the pollen-food syndrome.

particularly birch. 44 Patients with this allergy should avoid eating raw fruits and vegetables; fruits and vegetables are tolerated when they are cooked, baked or processed. Antihistamines are given to relieve the itching or mouth tingling.

Fixed Drug Reaction

A fixed drug reaction is a localized or fixed allergic reaction specific to an allergic reaction to drugs. Usually, it is a localized erosion with thick pseudomembrane mostly solitary and may involve two different sites of the oral mucosa. Localized lesions are to be expected on the hard palate mucosa, labial mucosa or the dorsum of the tongue. 45,46 The lesions always appear in the same spot after repeated contact with the antigen. Discontinuation of suspected medication and topical application of steroids resolve this condition.

Stomatitis Medicamentosa — Drug Allergy

Drug allergies include a wide range of variant sensitivity reactions to numerous drugs and chemicals. Oral drug reactions often manifest as nonspecific diffuse erosions and ulcerations with or without vesicle or bulla formation, 47 but they may mimic pemphigus vulgaris or lichenoid reactions. In drug-induced reactions, the relatively fragile vesicles are rarely observed at clinical examination, and most cases are characterized by irregular ulcerations with ragged borders that may coalesce to involve large areas of the mucosa. 48 But in lichenoid reactions, shallow, irregular ulcerations or erosions with a peripheral border of fine keratotic striae that radiate from the center of the lesion adjacent to dental restorations are observed. Moreover, lichenoid reactions tend to be erosive and unilateral. Clinically, pemphigus lesions appear as relatively sturdy vesicles or bullae that break down into shallow ulcerations. Pressure exerted to an apparently normal area results in the formation of a new lesion. These phenomena are called Nikolsky’s sign. Diagnosis is facilitated by detailed history, clinical findings and immunohistological findings. Discontinuation of the offending agent is the treatment of choice; glycerine mouthwash, artificial saliva for xerostomia, xylocaine, benzocaine orabase for pain and antibiotics if there is infection can be administered as supportive therapy. 47

Common drugs used in dentistry that cause allergic reactions, their etiopathogenesis and oral manifestations 49,50 are listed in TABLE 5.

Allergic Reactions to Dental Materials Acrylic

“Denture sore mouth” is the inflammatory change of mucous membranes developing beneath the dentures.

When the allergic reaction is caused by a prosthetic component material allergy, it is called prosthetic allergic stomatitis. This form rarely occurs as an expression of contact allergy to acrylate, denture furnish, metal denture alloys and cobaltchromium pastes for denture fixation. Thereby, stomatitis lesions are found on the areas where the prosthesis base comes in contact, causing erythema, edema, vesicles, bullae, erosions and ulcerations 24 (FIGURE 6).

Self-cured acrylics are more frequently associated with the allergy than heat-cured ones. Most frequently, the palatal oral mucosa and maxillary ridges are involved and tissue appears bright red and edematous. Patients report soreness, dryness and burning.

Dental Amalgam

Allergy to dental amalgam has been reported in many cases. The allergy is caused by mercury leaching. This can develop over a prolonged period when the amalgam is in direct contact with the oral mucosa. The site affected has a close relationship to the amalgam filling. 51 It manifests as oral lichenoid lesions related to the contact area. Thornhill et al. (2003) found that 70% of the amalgam contact hypersensitivity reactions were patch positive for amalgam or mercury. 22

Latex

Allergic reactions to latex have increased in the last few years. It is still unclear whether the components of latex or the cornstarch/borax powder incorporated are responsible for it. Latex can also cause different reactions including allergic contact dermatitis (Type IV) and true latex allergy (Type I). 52 Latex allergy reactions can vary from localized stomatitis to life-threatening airway compromise. Abdollahi et al. (2008) stated that latex-free environments to reduce the incidence of latex issues relating to both the surgical team and patients need to be created. 36 Alternative materials such as vinyl or nitryl should be considered whenever latex allergy is suspected. 53

Nickel

Nickel is the most common metal to cause contact dermatitis. Nickel-titanium alloy used in orthodontic treatment contains around 55% of nickel, which can release enough nickel in the oral environment to elicit Type IV delayed hypersensitivity immune response. 54 However, orthodontic auxiliaries made of stainless steel have lower nickel content (8%), and the nickel is bound in a crystal lattice, so it is not available to react. Nickelinduced allergy is also seen with frequent use of nickel-containing jewelry and intraoral piercings. 55 Severe intraoral manifestations of nickel allergy are rare. However, diffuse erosions and ulceration are seen intraorally extending to the perioral area. Skin reactions include urticaria and eczematic reactions in the face. High-content nickeltitanium wires should be avoided in nickel-sensitive patients, as nickel-free alternatives are available and should be considered for these patients. 56

Oral Hygiene Products

Flavoring agents 57,58 are the main cause of allergy for toothpaste and mouthwash use and can manifest as:

■ Allergic contact cheilitis.

■ Perioral eczema due to contact allergic dermatitis.

■ Contact leukoderma and urticaria. Common allergens found in toothpaste are unspecified flavors, cocamidopropyl betaine, propylene glycol, essential oils and biological additives, parabens, peppermint, vitamin E, spearmint, grape extract, specific flavors, propolis and tea tree oil. 58 After contact, the mucosa becomes remarkably inflamed and edematous. The surface appears smooth and shiny. Vesicles rupture to form small areas of erosion and ulceration, which may become extensive. Lips will have a tingling sensation, edema and ulcerations. In chronic cases, widespread erythema on the mucosa with erosions, dry, cracking and fissuring lips is seen.

Conclusion

As dental practitioners, we use many dental materials and drugs that may cause allergic reactions that can do harm in our patients. Thus, it is necessary to act with caution during the use of these dental materials and drugs. A detailed medical and dental history and material knowledge are crucial in preventing sensitization of individual material components and side effects. The diagnosis of oral complaints suspected to be connected to oral allergies remains a challenge. A better understanding of history and clinical manifestations play a pivotal role in diagnosing and managing the conditions effectively. In dentistry, Type I and Type IV reactions are the most commonly encountered allergic phenomena. As such, dentists should not only know the most frequent elicitors but also their safest alternatives whenever removing an allergen is indicated.

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THE CORRESPONDING AUTHOR, Shilpa Padar Shastry, MDS, can be reached at shilpa.keshav@gmail.com.