The allergic response is a defensive reaction of the immune system against certain innocuous substances – called allergens – that the body mistakes for harmful parasites. An estimated 20% to 25% of Americans suffer from this misguided reaction against inoffensive substances that include pollens, animal danders, foods, insects and their venoms, and medications. The economic cost alone to our society is billions of dollars for medical care.
Symptoms of allergy are highly varied, because different allergens stimulate the immune system at different sites in the body. The respiratory system is the most common site of allergic reactions, with allergens in the upper airways causing sneezing and nasal congestion (allergic rhinitis, including hay fever), while allergens in the lower airways cause bronchoconstriction and wheezing (asthma). Food allergens cause immune activation in the gastrointestinal (GI) tract, leading to nausea, vomiting, abdominal cramps, and diarrhea. Local immune activation in the skin results in contact dermatitis. The most serious form of allergic reaction – anaphylaxis – occurs when an allergen enters the circulation and causes allergic manifestations at sites distant from the site of entry. In severe anaphylaxis, normal bodily functions are so disrupted that the patient may die.
Physiologically, the allergic response occurs in three stages: sensitization, mast cell activation, and prolonged immune activation. During Stage 1, when the allergen first meets the immune system, no allergic reaction is produced; instead, the system is primed for subsequent encounters with that particular allergen. Macrophages degrade the allergen and display the fragments to T lymphocytes (T cells); T cells secrete interleukin-4, which promotes maturation of B lymphocytes into plasma cells; plasma cells secrete immunoglobulin E (IgE) antibodies specific for that allergen. These antibodies attach to receptors on circulating basophils and on mast cells (immune cells derived from the bone marrow that reside close to blood vessels and the epithelium).
Stage 2 represents a later encounter between the allergen and the immune system. The allergen binds to IgE antibodies on mast cells. When it connects with two IgE molecules, the result is the activation of various enzymes that induce mast cell granules to release their contents – substances such as histamine, platelet-activating factor, prostaglandins, and leukotrienes – and these substances trigger the allergy attack. Individuals prone to allergies are known to have abnormally high levels of IgE antibodies.
Stage 3 is characterized by prolonged immune activation. Tissue mast cells and neighboring cells synthesize chemotactic and adhesion molecules that induce circulating basophils, eosinophils, and other cells to migrate into that tissue, generating a new wave of symptoms. These recruited cells secrete chemicals of their own that sustain inflammation, cause tissue damage, and recruit other immune cells.
Anaphylaxis occurs when an acute, explosive release of mediators from mast cells causes severe allergic symptoms within minutes of allergen exposure. Anaphylaxis is a medical emergency; without prompt medical attention, death can occur soon after the onset of symptoms. Shock is the major cause of death, although swelling of the vocal cords can kill by closing off the trachea. Other common reactions include pruritus (itching), urticaria (hives), and bronchoconstriction. GI manifestations can also occur, although they are less common. Symptoms may be preceded by an aura, and patients who suffer from recurrent anaphylactic episodes report that the particular symptoms experienced are almost always the same with each attack. Treatment is usually with an injection of epinephrine to inhibit mediator release, open airways, and block vasodilation.
For decades, allergies have been treated with antihistamines, but today researchers at pharmaceutical and biotechnology companies are looking well beyond histamine. They are investigating drugs to block the activity of a wide variety of mediators of the allergic response, including leukotrienes, prostaglandins, cytokines (interleukins, platelet-activating factor, and granulocyte-macrophage colony stimulating factor), adhesion molecules (integrins, selectins, and immunoglobulin adhesion molecules), and the enzymes involved in their production. Enzymes targeted for inhibition include 5-lipoxygenase (involved in the synthesis of leukotrienes), phospholipase A2 (involved in the secretion of both leukotrienes and prostaglandins), protein kinase C (involved in mast cell degranulation), serine protease tryptase (involved in the kinin cascade), and tyrosine kinase (involved in IgE activity). Ultimately, it should be possible to tailor allergy therapy to the individual patient, selecting drugs to alleviate a symptom complex or combat a particular allergen.
Plant allergies: profilins, hay fever, and food hypersensitivities
Plants represent the most common source of allergens. Two major types of allergic reactions triggered by plant allergens are respiratory symptoms from pollen inhalation and GI symptoms from the ingestion of plant foods (fruits, vegetables, grains, and nuts). Both types of allergic response are widespread, and they cross-react; patients with pollen sensitivities often report food allergies, and vice versa. Moreover, pollen immunotherapy (injection with increasing doses of the allergen) has been shown to reduce food hypersensitivity in children.
The most common manifestation of pollen sensitivity – seasonal allergic rhinitis or hay fever – affects some 15% of Americans. (A second type of allergic rhinitis, which is usually perennial rather than seasonal, includes reactions to such “indoor allergens” as animal danders and the house dust mite). Allergic rhinitis is not a dangerous condition, but it causes considerable misery and can lead to complications such as sinusitis, polyps, and asthma. The diagnosis is confirmed by skin testing; a positive result is signalled by the development of a wheal-and-flare reaction after the subcutaneous injection of very small quantities of the suspected allergen. Treatment is with antihistamines or, when these agents are ineffective, inhaled corticosteroids. Severe cases are treated with immunotherapy. These “allergy shots” can be helpful, but protection is rarely complete.
Asthma is a more serious condition, and it is increasing in both incidence and severity. The incidence of asthma and death due to asthma rose dramatically worldwide during the 1980s, presumably because of the worldwide increase in environmental pollutants and allergens. In the United States, asthma and associated mortality increased by 60% during the decade. The condition now costs society about $4 billion annually. Approximately 10% of children have asthma (which may resolve after adolescence), and up to 10% of patients acquire asthma in adulthood. As with allergic rhinitis, there are two types: extrinsic (an offending allergen can be identified) and intrinsic (no substance can be identified that induces the IgE antibody production). Asthmatics show a characteristic airway hypersensitivity (exaggerated response to bronchoconstricting substances, including cold air) and inflammation of the airways. Acute exposure to an allergen further constricts airways that are already partially occluded by the inflammatory process. Treatment is with bronchodilators to relieve acute bronchoconstriction and antiinflammatory steroids to treat the underlying inflammation.
Food allergies are also fairly common, at least in children. Youngsters are most often allergic to proteins in milk, eggs, or nuts (especially peanuts). The reaction may be subtle, such as a skin rash, and difficult to diagnose. When a skin test is positive, it is best to confirm the diagnosis with a double-blind food challenge (feed a capsule of allergen or placebo to the child on Day 1, then alternate allergens and placebo on subsequent days).
Food allergies in adults are fairly uncommon, but they are easier to diagnose because urticaria, rhinitis, asthma, or anaphylaxis usually develop within minutes after ingestion of even a very small quantity of a particular food. Diagnosis can be confirmed by skin testing. Some patients have a delayed reaction to foods (the response occurs 1 or more days after exposure), and sometimes symptoms affect other organs. Diagnosis requires a food challenge. Only 1% to 2% of adults suffer from food allergies, although studies have shown that about 25% of Americans believe they have food allergies that cause a broad range of vague conditions (fatigue, depression, irritability). The most common severe food allergy in adults is to peanuts. Often this allergy appears during childhood and is not outgrown (unlike milk allergy, which is fairly common in children but is usually outgrown).
Many allergic individuals react to both pollens and foods. For example, patients with grass pollen allergy report adverse reactions to specific plant foods (peanuts, garlic, tomato, onion, and various fruits). Patients with latex allergy report cross-reactions to avocados, bananas, and chestnuts. Some latex-sensitive patients may become anaphylactically allergic to fresh fruits. In the “latex- fruit syndrome,” 52% of latex-allergic patients had allergies to fruits, and systemic anaphylaxis occurred in 36%. The fruit allergy may show up first, followed by latex allergy on exposure to latex.
Several investigators have explored the association between pollen allergies and plant food allergies. There is evidence that a family of proteins called profilins, which are present in many plant species, are capable of acting as pan- allergens. Profilin sensitization from birch tree pollen and other pollens has been shown to cross-react with sensitization to many fresh fruits and vegetables. Profilins are usually destroyed by heat, which explains why patients who are anaphylactically sensitive to fresh fruits and vegetables can tolerate these foods when they are cooked. Unfortunately, commercial extracts of fruits and vegetables cannot be used diagnostically for skin testing because profilins are so unstable.
Latex allergy: increasing cause of anaphylaxis
Latex is an emulsion of rubber globules derived from the milky sap of plants of the Euphorbiacea family. It has been widely used for decades in the manufacture of paints, adhesives, gloves, balloons, and other products, yet only within the last 15 years or so has it been recognized as a cause of serious allergic reactions. The major allergen appears to be part of a protein referred to as rubber elongation factor. This protein fragment is an increasingly common and often unrecognized cause of contact dermatitis, pruritus, urticaria, conjunctivitis, rhinitis, and asthma. In recent years, a number of cases of latex-induced anaphylaxis have been described, and several patients have died.
Latex sensitization occurs when the allergen comes into contact with skin (intact or denuded) or the mucosa. Repeated exposure to latex is thus the primary risk factor. Individuals at increased risk include latex industry workers, health-care personnel who wear latex gloves, patients who undergo frequent operations, and patients with neural tube defects (NTD). Also at increased risk are atopic individuals, who have a predisposition to allergic reactions in general. In one study, 36.4% of subjects who had been exposed to latex and who were atopic had immediate cutaneous reactivity to latex, compared with 9.44% of atopic subjects who had not been exposed to latex, 6.85% of subjects who had been exposed but were not atopic, and 0.37% of nonexposed, nonatopic subjects.
The prevalence of latex allergy in the general population is 1%. By comparison, 3% to 9% of health-care workers who must wear latex gloves are allergic to latex. Even members of the hospital housekeeping staff are at increased risk of latex hypersensitivity. Sussman et al. screened 50 members of the housekeeping staff at the University of Toronto Medical Center and skin-tested 20 with possible atopy or symptoms suggestive of latex allergy. Four of the 20 tested positive for latex allergy, an 8% prevalence overall among the housekeeping staff. The patients with positive results all reported extensive exposure to latex gloves and recalled symptoms compatible with latex allergy (hand dermatitis, rhinoconjunctivitis).
NTD patients appear to have a predisposition to latex allergy that goes beyond clinical exposure. In one study, 72% of spina bifida patients had a history of clinical latex allergy and tested positive for latex IgE antibody. By comparison, patients with other neurological problems (spinal cord injury, stroke) and clinical exposure to latex did not show this increased incidence.
Recently Masood et al. described two patients with unrecognized latex hypersensitivity who had an anaphylactic attack that was initially diagnosed as a drug reaction. The first patient was a physician who received an injection of tetanus toxoid for an accidental needle stick; 24 hours later she experienced the abrupt onset of lightheadedness, dyspnea, wheezing, chest tightness, throat tightness, and a rash (generalized, pruritic, and erythematous). Symptoms resolved after treatment with corticosteroids and histamine-1 and -2 blockers. Presumptive diagnosis was anaphylaxis due to tetanus toxoid or possibly due to allergic response to an almond pastry consumed one hour before the anaphylactic episode.
A week later the patient was evaluated at the Northwestern University Allergy-Immunology Service. Tetanus toxoid was thought to be an unlikely cause of the anaphylaxis because of the length of time (24 hours) between injection and anaphylaxis. Almond sensitivity was also ruled out because a skin test was negative to almonds. At that time, a diagnosis of allergic rhinitis and asthma was made, and the patient was found to be skin-test positive to multiple allergens. On questioning, the patient recalled that she had put on a pair of latex gloves two minutes before the anaphylactic reaction. She also described a history of reactions to latex gloves (erythema and urticaria of the hands), and skin testing showed latex hypersensitivity (dilution 1:100,000 wt/vol). She was advised to avoid latex and carry a prefilled epinephrine syringe. Several weeks later she had a second anaphylactic episode – with dyspnea, wheezing, chest tightness, and lightheadedness – after exposure to latex gloves. Symptoms resolved with epinephrine (Adrenalin), prednisone (Deltasone, Liquid Pred), and diphenhydramine (Benadryl).
The second patient was a nurse who had a series of anaphylactic attacks before latex allergy was identified. Her first attack, which occurred 1 hour after ibuprofen ingestion, was characterized by tongue swelling, dyspnea, and throat tightness. Symptoms resolved after therapy with epinephrine, diphenhydramine, and prednisone. Thereafter the patient avoided nonsteroidal antiinflammatory agents, but episodes of anaphylaxis continued. An allergist suspected food allergies, and the patient tested positive on skin prick for multiple allergens (eggs, wheat, chocolate, chicken, and cow’s milk). Even when these foods were avoided, she had recurrent episodes of abdominal pain, diarrhea, diaphoresis, and total body urticaria.
Evaluation at Northwestern Allergy-Immunology Service disclosed that these episodes were correlated with latex exposure. At that point she recalled that merely holding latex IV tubing or an IV bag would result in red, swollen, pruritic hands, while rubbing her eye after removing latex gloves would cause facial swelling and hives, chest tightness, and dyspnea. “The patient was so sensitive,” said Masood et al., “that on several occasions the powder presumably aerosolized from a colleague removing latex gloves would cause acute wheezing, abdominal pain, and pruritic erythema.”
At Northwestern, the nurse was retested for those foods previously identified as triggering her allergic reactions – eggs, chocolate, chicken, codfish, cow’s milk, mustard, mushrooms – and the skin test results were all negative. This time, the tester used vinyl gloves to avoid contaminating the tests, as the doctors suspected that the initial positive results were because the skin tests were administered with latex gloves.
These suspicions were confirmed when the nurse tested positive to a latex glove extract at a dilution of 1:1,000,000 wt/vol. (The solution was prepared by cutting a latex glove into pieces, soaking the pieces in phosphate buffered saline for 12 hours, centrifuging, and running the supernatant through a 0.22-micron filter.) The patient was advised to resume a normal diet, avoid latex, and take hydroxyzine on work days. Because the avoidance of latex in a hospital is next to impossible, she continued to have local cutaneous reactions.
Vinyl gloves are an alternative to latex, although they are not as effective as latex for protecting against acquisition of the human immunodeficiency virus. A better solution may be to use cotton or vinyl glove liners under latex gloves. Masood et al. concluded, “Latex must be considered as a “hidden” cause of anaphylaxis, particularly in health care workers.”
Anaphylaxis during barium enema procedures is not uncommon. Symptoms are usually attributed to allergy to latex in the barium enema device. Recently Tarlo et al. described a patient with anaphylactic symptoms during a barium enema procedure that had been ordered for the evaluation of gastrointestinal symptoms (nausea, vomiting, abdominal bloating, and diarrhea). Within minutes of receiving the enema, the patient had abdominal cramps and mild generalized pruritus, which progressed to generalized urticaria, hypotension, chest tightness, wheezing, cyanosis, and transient loss of consciousness. She was treated for anaphylaxis and released a day later. At first, latex-induced anaphylaxis was suspected, but the barium enema delivery set was found to be free of latex. Subsequent skin testing failed to demonstrate latex sensitivity; however, a skin prick test with the barium enema solution yielded positive results. The manufacturer provided individual components of the barium enema solution for skin prick testing, and the patient was found to be allergic to carrageenan used as a suspending agent in the solution.
Carrageenans are gelatinous substances obtained originally from Irish moss (a species of seaweed), and currently obtained from a number of species of marine algae. Carrageenans are commonly used as emulsifying and suspending agents in pharmaceuticals, foods (ice cream, cream, chocolate milk, yogurt, frozen treats, salad dressings, and barbecue sauces), cosmetics, and polishes, and as clarifying agents in beverages.
On questioning, the patient recalled that her GI symptoms were worse after ingestion of certain milk products (ice cream, yogurt, and chocolate milk), although she tolerated plain milk. She was advised to avoid eating carrageenan- containing products. It is interesting that the patient underwent a barium enema procedure for the evaluation of GI symptoms, and the barium solution itself provided the clue for diagnosis.
