Allergic Reactions: Increasing Immunological Problems for Health Care Providers and Patients

By John A. Molinari, PhD

An increasing percentage of the general population develops allergy symptoms each year. Many of these harmful immune response manifestations are being directed at a wide variety of drugs and chemicals that are routinely used in dental and medical care facilities. It is, therefore, important for clinicians to be familiar with the major allergic signs and symptoms, understand the mechanism involved in patient sensitization and challenge, and be able to provide appropriate care should an allergic emergency arise during patient care. It is also advisable for clinicians to prepare as much as possible by taking an accurate patient allergy history.

Article copyright 1998 Journal of the California Dental Association.
Photographs copyright of the authors.

When most health care professionals hear the phrase "immune response," they probably think of a protective, beneficial reaction by the body's defenses that is aimed at providing resistance against a vast array of microbial pathogens, toxins, and other potentially harmful substances. As examples, we can demonstrate immunological mechanisms that protect against a variety of stimuli, including bacteria, viruses, fungi, cancer cells, foreign blood types, and parasitic infestations.

Unfortunately, the immune system is a double-edged sword. One of the most common adverse presentations of the negative aspect is grouped under the designation allergy. An allergy is an exaggerated or pathological immune reaction to a wide variety of substances or stimuli, which does not occur in all members of the same species. Also commonly termed hypersensitivity, these responses are the result of normally beneficial mechanisms acting inappropriately, sometimes stimulating tissue damage and inflammatory processes. Basically, the body mistakes certain antigenic substances, called allergens, for harmful, foreign invaders. The ensuing antibody (humoral) or lymphocytic (cell-mediated) response can induce clinically apparent, even life-threatening, symptoms. It has been estimated that 1-in-4 to 1-in-5 people living in the United States suffers from multiple allergies against seemingly innocuous substances, such as animal dander, foods, insect venoms, pollens, metals, ragweeds, antibiotics, and other medications. One of the most striking, classical hypersensitivity examples involves insect venoms. The injection of a small amount of bee or wasp venom from a sting into a person's skin does not normally constitute a serious problem. Yet, a person who is allergic to the venom's components can develop a localized or systemic, potentially life-threatening anaphylactic reaction within minutes after the incident.

Although there may be numerous reasons why allergic responses are of importance to dental professionals, there are three major ones, as follows.

Many chemicals, drugs, latex-containing products, and dental materials can induce hypersensitivity in both care providers and their patients. These can include eugenol-containing products, preservatives in anesthetics, dentifrices, hand-washing antiseptics, antibiotics, acrylic resin, and nickel in metal-based alloys.

Certain hypersensitive reactions directly affect the oral cavity and maxillofacial areas.

Patients may be using anti-allergy medications -- i.e., antihistamines, cromylin or steroids -- that may present problems during certain treatment procedures.

Two classification systems have been developed for hypersensitivity reactions (Tables 1 and 2). The present discussion will be limited to Types I and IV (Table 1) and representative anaphylactic immediate and delayed adverse responses (Table 2). These two groups of hypersensitivity reactions typically represent the most common types of allergic challenges facing the majority of dental and medical practitioners. In addition, because of health care challenges associated with increasing diagnosis and investigation of allergic reactions to latex products, portions of the discussion will also consider clinical and immunological issues related to this occupational problem.

Table 1 Classification of Hypersensitivity
Type	Clinical Manifestations	Major Mediator	Major Effectors	Sensitization	Mechanisms of Injury
I (Anaphylactic)	Local anaphylaxis (atopic allergies); systemic anaphylaxis	IgE	Histamine; SRS-A	Inhalation (respiratory mucosa); ingestion (gastrointestinal mucosa); parenteral	IgE attached to mast cells causes releases of histamine and SRS-A on reacting with specific antigen
II (Cytotoxic)	Hemolytic disease of the newborn, drug-induced hemolytic hypersensitivity, transfusion reactions, graft rejection, autoimmune diseases	IgG	Complement; K cell	Parenteral, ingestion, transplantation	Activation of complement to give lysis and opsonization; K cell cytotoxicity for antibody-coated target cells
III (Immune Complex)	Local: arthus; systemic: serum sickness	lgG	Antigen-antibody complexes; complement; polymorphonuclear leukocytes	Parenteral (inoculation of antigen or antiserum), inhalation (rare)	Activation of complement by antigen-antibody complexes chemotactic for polymorphonuclear leukocytes, which leads to vasculitis
IV (CMI)	Delayed-type hypersensitivity, contact hypersensitivity, cytotoxicity (graft and tumor rejection), autoimmune disease	CMI: T cells	Lymphokines (DH type), cytotoxic T cells	Parenteral, contact, transplanation	Lymphokines: MIF, chemotactic factor, etc., lead to vascular necrotic injury; cell membrane injury by direct cytotoxicity of the cytotoxic cells leads to invasive-destructive injury

Table 2 Comparison of Immediate (Immunoglobulin) and Delayed (T Cell) Hypersensitivities
	Immediate	Delayed
Timing of response after shocking exposure	Appears within a few minutes; fades within a few hours	Develops and fades gradually, maximum at 24 to 72 hours
Special target tissue	Usually smooth muscle, but organ varies with species	Generalized tissue involvement
Tissue death	Quite common	Occurs but not typical of ordinary reaction
Humoral factor involvement	Yes, IgE and IgG	None yet identified
Cellular factor involvement	Only in that immunoglobulins are produced by B lumphocytes and plasma cells; mast cells	T lymphocytes, directly, not via immunoglobin
Passive transfer	With immunoglobulins	With T lymphocytes
Type of tissue involved	Vascular	Vascular, but relatively avascular suitable also
Histology of skin reactions	Predominantly neutrophils early, with some mononuclears; edema obvious, with wheal and erythema	Tendency toward mononuclears, with some neutrophils; species variation; less edema and wheal; erythema and induration
Chemical mechanism	Histamine, serotonin, kinins; species variation	Lymphokines
Chemotherapy	Antihistamines and smooth muscle relaxants (adrenergic compounds)	Steriods (anti-inflammatory compounds)
Immunotherapy (desensitization)	Yes; relatively easy, temporary, via neutralizing antibodies or formation of blocking antibodies	Yes; with difficulty, temporary; usually not attempted

Type I Hypersensitivity

Immune responses categorized as Type I allergies are mediated by the immunoglobulin IgE. The ability of this antibody to specifically bind onto the surfaces of certain granulated cells (i.e., mast cells and basophils) allows IgE to trigger subsequent allergic sequelae described below. The major class of immediate hypersensitivity reactions also involve IgE. These are represented by either cutaneous (localized) or systemic anaphylactic symptomatologies. Both can develop within minutes in allergic individuals. The manifestations of this type of allergy are variable, as reactions can develop at different sites and in target tissues, depending on the route of exposure (Table 3).

Table 3 Clinical Manifestations of Type I (lgE-Mediated) Hypersensitivity
Organ System	Symptom	Sign
Skin	Pruritus, facial swelling, Nasal congestion	Urticaria,* angioedema
Respiratory tract	Itching, sneezing, dyspnea, cough, substernal tightness, abdominal pain	Rhinitis, laryngeal stridor, wheezing, tachycrea
Gastrointestinal	Nausea, vomiting, diarrhea
Eye	Tearing, itching	Conjunctivitis
* Hallmark of the syndrome
Adapted from Lucre WC and Thomas Jr H, J Emer Med 1:83-95, 1983.

There appear to be two groups of antigens that tend to elicit Type I immediate allergic responses. The first consists of haptens, or incomplete antigens. As an example, an antibiotic such as penicillin or its metabolic products bind very efficiently to circulating host carrier proteins. This is a necessary prerequisite to making the hapten immunogenic and, therefore, capable of stimulating the immune system. The other broad group of immunogens includes various plant pollens, spores, insect venoms, medications, animal dander, and microbial products, which are unusually resistant to enzymatic degradation after entering the body. Antigens that stimulate IgE synthesis or trigger other hypersensitivity responses are called allergens. Usually only very low doses are required to stimulate IgE synthesis and set the stage for later allergic symptoms.

IgE is able to bind to specific receptors on the plasma membranes of mast cells and basophils. The high affinity of IgE for these surface sites accounts for the long-term sensitivity of Type I allergic persons to inciting antigens. For mast cells and basophils to be activated during a hypersensitive incident, two conditions must be met:

IgE initially must be bound to cell surface receptors. This requires that the person have had at least one previous exposure to the allergen to stimulate initial synthesis of IgE (i.e., sensitizing dose); and

Allergen during a second or subsequent exposure (i.e., challenge dose) must react with antibody on the granulated cell surface to trigger degranulation.

During degranulation, preformed intracellular granules fuse with the cytoplasmic membrane, emptying their contents to the exterior. These include certain pharmacologically active mediators, such as histamine. In addition, other mediators, such as serotonin, kinins, prostoglandins, leukotrienes, Slow Reacting Substance-Anaphylaxis, Eosinophil Chemotactic Factor-Anaphylaxis, and a number of cytokines, work with histamine to cause clinical manifestations characteristic for Type I, IgE-mediated, immediate hypersensitivity.

Signs and Symptoms of Type I Hypersensitivity

Figure 1. Cutaneous Type I hypersensitivity reaction to animal dander. Localized itching, vasodilation and urticaria developed within 10 minutes after epithelial challenge with allergen.

As outlined in Table 3, physical manifestations of Type I allergies resulting from stimulation of IgE synthesis can develop in multiple tissues and systems. These can present with a range of localized or systemic anaphylactic symptomatologies. In individuals who are mildly sensitized, local skin exposure to the sensitizing allergen would typically produce pruritus and urticaria beginning within minutes post challenge. Affected individuals can experience itching at the site of allergen penetration, very quickly followed by a pale edematous raised zone surrounded by a halo of erythema termed a wheal and flare (Figure 1).

Figure 2. Type I hypersensitivity to natural rubber latex protein exhibited by a dental student. The reaction formed within minutes after the student donned powdered latex gloves and was most intense for erythema and urticaria in those areas of the hands in constant contact with the gloves. Figure 3. Type I allergy in a dental care provider against latex in the elastic band on a face mask.

The response may reach maximal intensity approximately 10 minutes post challenge, persist for another 10 to 20 minutes, and then gradually subside. This phenomenon is referred to as cutaneous anaphylaxis, with lesions described as wheal and erythema, wheal and flare, urticaria, or hives. Individuals with a cutaneous anaphylactic allergy to latex often find that their hands begin to burn and itch soon after donning latex gloves. After gloves are removed, they may also notice the rapid appearance of hives and localized edema in response to latex protein antigens (Figures 2 and 3). Patients allergic to natural rubber latex can also experience similar symptoms during intraoral examination by care providers wearing latex gloves or after placement of a latex dam.

In generalized or systemic anaphylaxis, the effects can range from mild respiratory distress to life-threatening respiratory collapse. Massive edema can develop around the site of antigen injection along with difficulty in breathing and swallowing. These latter manifestations result from bronchial constriction and laryngeal edema. Shock can follow due to sudden peripheral capillary permeability, vasodilation, and rapid decline in the person's blood pressure. Anaphylactic death in extremely sensitized individuals can occur very rapidly despite emergency resuscitation procedures. Fortunately, most people survive episodes of anaphylaxis, with recovery usually complete within an hour.

Systemic manifestations of Type I hypersensitivity can also develop in some individuals who are challenged with airborne allergens such as ragweed pollens and natural rubber latex proteins. In the latter case, latex immunogens can adhere to cornstarch powder particles during product manufacturing processes. As gloves are removed from boxes, aerosolized proteins bound to powder may remain suspended for prolonged periods. The presence of excessive powder on latex gloves, along with frequent removal of gloves from boxes during the day, can cause substantial particle aerosolization in the immediate vicinity. As a result, respiratory and conjunctival exposure of sensitized persons to the offending proteins can stimulate onset of Type I symptoms. Coughing, wheezing, shortness of breath and/or respiratory distress may occur, with the severity being dependent on the extent of the person's sensitization. Severity can range from mild itching, irritation and allergic conjunctivitis to a brief period of difficulty in breathing, all the way to life-threatening anaphylaxis.1,2

Treatment of Type I allergic reactions depends on prompt recognition by the practitioner and ultimate intervention with pharmacological agents. Since histamine is the most active pharmacological mediator during anaphylactic reactions in humans, administration of antihistamines can prevent further progression of many localized allergic episodes. In the case of severe anaphylaxis, injection with epinephrine, monitoring vital signs, and cardiovascular resuscitation are utilized to provide life-saving assistance.

Atopy

There appears to be a heritable predisposition for some individuals to easily become hypersensitive to a wide range of allergens. Hypersensitivity can develop rapidly when these allergens are inhaled, ingested, or contacted via epithelial/mucosal exposure. Airborne plant pollens, particularly ragweed pollen, represent the most common and well-studied allergens. In addition, tree and grass pollens, microbial spores, house dust (composed of epidermal products of man and animals, bacteria, molds, and insect parts/feces), bovine milk constituents, and egg albumin all can act as potent allergens. The two most common physical manifestations of inhalation allergy are hay fever, more properly termed allergic rhinitis, and asthma. Allergic rhinitis is characterized by sneezing, nasal congestion, and watery discharge, as well as increased lacrimation, periorbital edema and conjunctival itching.

Type IV Hypersensitivity

Figure 4. Type IV hypersensitivity reaction manifested as contact dermatitis against nickel in a metal watch band. Note the tissue necrosis evident 72 hours after epithelial challenge.

A host sensitized to the urushiol oil on the surface of the poison ivy leaf; certain metals; microbial antigens; or accelerators, antioxidants, and other chemicals used in the manufacture of latex gloves, will develop a more chronic skin lesion following subsequent exposure of the same allergens. Usually no reaction is seen for at least 10 hours after challenge. Then erythema, swelling, and induration gradually appear with maximal size and intensity being reached at 24 to 72 hours. The lesion resolves over the next several days. In a highly sensitive person, this type of delayed response can cause local necrosis, ulceration, and even scarring (Figure 4).

Histologically, Type IV reactions are readily distinguished from immediate-type hypersensitivities. In a mild to moderate delayed-type hypersensitivity reaction, the earliest cellular infiltrate consists of small- to medium-sized lymphocytes, neutrophils, monocytes, and macrophages that accumulate around postcapillary venules. At the time of maximal tissue response, the entire dermis is involved; and mononuclear cells may be found in the epidermis. Necrosis of blood vessels, muscle, connective tissue, and epidermis may occur to varying degrees, depending on the sensitivity of the individual.

Figure 5. Type IV allergic reaction to a latex dam. The patient reported burning and itching of the lips approximately 24 hours after placement of a latex dam during dental treatment.

A common form of Type IV hypersensitivity encountered by health care providers and their patients is contact dermatitis (Figure 5). The inciting agents are typically a variety of small molecular weight chemicals (< 1,000 daltons) capable of inducing an allergic skin reaction. The catechols of the poison ivy plant, soaps, detergents, drugs, many dental materials, and active chemicals used in the manufacture of latex and other rubber products, all can cause allergic contact dermatitis. The initial exposure to a potential sensitizing substance does not elicit any visible skin response. In some individuals, however, if re-exposure to the same substance occurs anywhere on the skin surface just four to five days after initial exposure, a localized Type IV hypersensitivity response is elicited. In other individuals, several exposures to the substance may be required before any visible manifestation is observed. Occasionally, challenge exposures can lead to intense allergic reactions that can produce necrosis. Sensitization and response to challenge exposures involve sensitized T-lymphocytes, their lymphokine products, and other inflammatory cells attracted to the affected area. Lesions form slowly with a several-hour delay in the onset of symptoms, reaching maximal appearance 24 to 48 hours after challenge. The chronic inflammatory reaction is well-demarcated on the skin and is surrounded by localized edema. Onset of symptoms is prolonged to allow sufficient numbers of antigen-specific lymphocytes to arrive at challenge sites, with the resultant secretion of lymphokines attracting other inflammatory cells, such as macrophages and neutrophils. Contact dermatitis can take a minimum of four days to heal with necrosis, scabbing, and sloughing of affected epithelium.

Historically, Type IV latex hypersensitivity has been found to be the most common natural rubber latex allergy. In contrast to Type I allergies directed against latex protein components, the etiologies of delayed, lymphocyte-mediated reactions are chemicals added to crude milky latex during the manufacture of latex products. Numerous scientific reports have documented the presence of more than 200 chemical additives, although the chief allergens responsible for Type IV hypersensitivity appear to be accelerators and antioxidants.3-5

Treatment for the skin reactions observed with contact dermatitis utilizes antihistamine to minimize itching and topical corticosteroid therapy to reduce the inflammatory response signaled by the sensitized T-lymphocytes.

Summary

Clinicians can expect to treat an increasing number of allergic patients in health care facilities. Although many allergies may be directed at allergens outside of the treatment setting, sensitization and subsequent challenge can also occur against a variety of active chemicals and drugs used in patient care. These include topical medicaments, antibiotics, toothpastes, dental materials and nickel in restoration materials routinely used in dental care.
Dental care providers should be knowledgeable in recognizing early signs and symptoms of allergic reactions during patient care and also be prepared to provide appropriate care when needed.

Author

John A. Molinari, PhD, is a professor and chairman of the Department of Biomedical Sciences at University of Detroit Mercy School of Dentistry.

References

1. Hamann B, Hamann C and Taylor JS, Managing latex allergies in the dental office. J Cal Dent Assoc 23(1):45-50, 1995.
2. American College of Allergy, Asthma and Immunology, Latex allergy -- An emerging health care problem. Ann Allergy, Asthma Immunol 75(1):19-21, 1995.
3. Heese A, van Hintzenstern J et al. Allergic and irritant reactions to rubber gloves in medical health services. Spectrum, diagnostic approach and therapy. J Am Acad Dermatol 25:831-9, 1991.
4. Hamann C, Natural rubber latex protein sensitivity in review. Amer J Contact Derm 4(1):4-21, 1993.
5. Hamann C and Sullivan K, Latex sensitivity in dentistry. Oper Infect Cont Update 2(2):1-8, 1994.

To request a printed copy of this article, please contact/John A. Molinari, PhD, UDM School of Dentistry, 8200 W. Outer Drive, Detroit, MI 48219-0900.