Medications for Allergy

Evidence-based diagnostic and therapeutic practices are currently available to allergists for use with nearly all patients suffering from allergic disease. However, unproved and controversial methods and theories of allergy abound and may appeal to even the most knowledgeable and sophisticated patient. It therefore behooves the practitioner to be aware of these unconventional techniques and concepts in order to counsel those patients who would be tempted to pursue them.

The management of allergic diseases is accomplished most successfully and cost-effectively by the patient’s primary care physician in collaboration with a specialist in allergy/immunology. It is critically important to use methods of diagnosis and treatment that are based on sound scientific principles and that have been validated by proper clinical trials. Physicians who treat allergic patients, therefore, must be aware of the plethora of unproven and controversial methods that are currently promoted by a small group of practitioners, and they should understand the faulty rationale on which they are based. These unproven techniques and their unscientific, or even antiscientific, theories are sometimes deceptively labeled as alternative or complementary forms of medical practice. This implies some measure of efficacy that in fact does not exist.

Table Unproven Allergy Theories

In contrast to the scientifically rigorous immunopathological foundation underlying our present knowledge of human allergy, the theories advanced by the proponents of the controversial methods described in this chapter lack experimental proof. These theories frequently arise from misinterpretations of chance empirical observations.

Unconventional theories of allergy

So-called allergic toxemia is the basis for a number of these practices. It is comprised of two mistaken components. It postulates that allergens are inherently toxic and that virtually any subjective symptom in the absence of objective evidence of pathology can be attributed to allergy. In fact, most allergens are nontoxic in the usual dosage and manner of exposure necessary to either induce or elicit an allergic reaction. The presence or absence of potential toxic properties of an allergen is irrelevant to its ability to evoke an allergic immune response. Furthermore, the manifestations of allergic illness result from inflammation and not toxicity. In contrast, proponents of allergic toxemia in its various forms diagnose this condition not in patients with allergic symptomatology, but rather in patients with multiple vague complaints that usually include fatigue, anxiety, cognitive difficulties with memory and concentration, and a variety of physically unexplained pains and other bodily discomforts.

The allergic toxemia concept originated with patients who attributed their multiple medically unexplained symptoms to their diet. This led (i.e., misled) to the idea that multiple food allergies in a single individual can produce an unlimited number of symptoms and that the specific symptoms and implicated foods are variable and changeable. Other ingested substances, such as food additives and prescribed medications, particularly antibiotics, are often included as causes of allergic toxemia. To explain unpredictable symptom responses, the concepts of masking and overload were devised to rationalize the absence or presence, respectively, of unexpected symptoms. The current terminology for unexplained absence/presence of symptoms is adaptation/de-adaptation. It is clear that these terms are merely descriptive and have yet to be explained by their advocates in a physiologically meaningful way.

Environmental illness and multiple chemical sensitivities are names applied to a condition described as allergic toxemia, but in this case the cause is attributed to numerous common everyday environmental chemicals. In most cases these chemicals include pesticides, solvents, perfumes, new carpets, plastic materials, new clothing, and virtually any synthetic chemical or commercial product with an odor. Occasionally, electromagnetic fields generated by nearby electric power lines or even household appliances are included as causes of symptoms. Some patients believe that their multisystemic polysymptomatic illness represents hypersensitivity to numerous chemicals, foods, and drugs. The term given to this condition is universal allergy. Because symptoms in these patients have never been shown to be in fact related to chemicals, the term idiopathic environmental intolerance is more accurate. The clinical presentation of this condition is often indistinguishable from that of chronic fatigue syndrome and other controversial subjective conditions.

Periodically over the past century, this clinical condition has also been ascribed to the effects of a specific microorganism, usually one that enjoys a normal symbiotic or commensal relationship with the human organism. Formerly called autointoxication, presumably from normal gastrointestinal microbial flora, this concept has reappeared as a presumptive chronic viral disease. In this case, according to one unproved theory, the persistence of a virus such as the Epstein-Barr virus or human herpesvirus 6 (HHV-6) was postulated to cause chronic “activation” of the immune system. There is no substantiated evidence or even a clear definition of what activation means in this context, and there is no proof currently that persistence of any virus can explain the pattern of symptomatology experienced by such patients. A variant of this theory is the so-called Candida hypersensitivity syndrome, attributed to the existence of Candida albicans on certain mucous membranes of many healthy individuals. Recently, toxins from indoor molds have been implicated.

Controversial methods of allergy diagnosis

Controversial treatments for allergy

Discussion

The superficial similarity of many of these unproven methods to scientifically based procedures of diagnosis and treatment of allergic diseases is an opportunity for exploitation by their proponents and a trap for the unwary clinician. The allergic population is very large, and the primary care physician is the first medical contact for most of them. Practitioners of these unconventional procedures are readily available both within and outside the medical profession. They often advertise their services with promises that most physicians cannot and do not make. Only by knowing the specifics of these methods and their claimed theoretical basis can the clinician make an informed decision and give proper advice to the patient about their use. Some of the more common ones are described here.

With the exception of sublingual allergen administration, the methods reviewed in this chapter are not likely to pose an immediate hazard to health. Rather, their danger is more subtle, pervasive, and profound. An incorrect diagnosis made by an unreliable test creates the risk that another disease — physical or psychiatric — will remain undiagnosed and untreated. Diagnosing allergy in a person who truly has none may create a lifelong disability characterized by unnecessary avoidance behavior. An extreme form of this unfortunate iatrogenic phenomenon is seen in patients who accept the idea that they have multiple sensitivities to foods and/or chemicals. Some of these individuals live a life of social and material isolation from which they may never recover. Most allergists would agree that it is far easier to treat an allergy than it is to disabuse a patient of his or her fear of an allergy that does not exist.

The problem of unconventional methods in allergy is of concern to a number of professional societies. In particular, the American Academy of Allergy, Asthma and Immunology has published position statements about many of these procedures. These publications also provide literature citations to appropriate studies and evaluations that document their lack of effectiveness.

To select the most appropriate methods for diagnosis and treatment, the clinician should be familiar with the underlying principles of both legitimate and unproved methods. Controversial diagnostic and treatment procedures will be discussed separately. Some of these procedures are of no proved worth under any circumstance, whereas others may have a legitimate place in some conditions, although not in allergic disease.

The provocation-neutralization procedure consists of “testing” the patient with a small amount of a substance in liquid form administered by either intradermal injection or by sublingual drop. The patient records any symptoms or sensations for a period of 10 min thereafter, and any symptom, regardless of its nature or intensity, is taken as indication that the test is “positive.” If the patient reports no symptom, the test is repeated using the same test substance at a different concentration until there is a “positive” result. Next, the same substance is tested at lower concentrations until the patient again reports no symptom, at which point the allergy (i.e., the symptom) is said to be “neutralized.” The neutralizing dose of the substance is then prescribed as treatment.

Numerous substances are tested, including the common atopic allergens, food extracts, chemicals, drugs, and hormones. Because each test substance must be administered separately to elicit symptoms, testing to multiple substances is extremely time-consuming. It has been shown, however, that patients cannot distinguish test extracts from placebo controls by this procedure, so the basis of a positive test is merely the power of suggestion. It is therefore worthless for diagnosis, and there is the potential danger that delivery by the sublingual route of an allergen to a patient with a true immunoglobulin E-mediated allergy might cause life-threatening angioedema of the buccal mucosa or even systemic anaphylaxis.

Table Unconventional Diagnostic Methods

Table Unconventional Treatment Methods

The cytotoxic test consists of applying a drop of the patient’s blood onto a microscope slide containing a minute quantity of a food or drug. The unstained blood sample is then inspected microscopically for alterations in the morphology of the leukocytes, which is claimed to indicate allergy to the food or drug. There is no standardization for criteria indicating a positive result, time of incubation, pH, temperature, or any other variable that might affect leukocyte viability. There is no reasonable theory linking changes in blood leukocyte appearance and allergic disease. There have been no studies to correlate the result of this test with a rigorous independent proof of allergy, such as the double-blind, placebo-controlled oral food challenge.

The pulse test for food allergy is performed by measuring the pulse rate of the patient before and after food ingestion. Remarkably, advocates of this “test” have claimed at various times that an increase or a decrease is diagnostic of food allergy. There is no independent verification that a pulse change correlates with allergy, nor is there a cogent theory to explain such a phenomenon. The pulse test is an example of a valid medical diagnostic procedure — quantitation of the pulse rate — being misused as an allergy test.

Applied kinesiology is apurported system of health practice that is based on the bizarre concept that a variety of diseases, especially allergy, cause a reduction in the strength of skeletal muscle. The diagnosis of food allergy consists of subjectively testing the ability to resist the forced movement of the patient’s outstretched arm during exposure of the patient to a food. Incredibly, the exposure to the presumed food allergen is usually carried out by placing the food in a container that the patient simply holds during the muscle-strength testing. Not surprisingly, there is no experimental proof of either the diagnostic efficacy of the procedure or validation of its theory.

The suggestive power of a mechanical or electrical apparatus in medical diagnosis is illustrated by electrodermal diagnosis. In this case a device to measure the electrical resistance of the skin is inserted into a circuit that includes a metal container of a food item and a probe applied to the patient’s skin. The probe presumably explores various points on the body surface, and a change in the galvanic resistance of the skin is believed to indicate allergy to that food. The use of a computer-generated printout gives the “results” an aura of high-technology precision.

Treatment regimens that are based on unsubstantiated theories of allergy or unreliable diagnostic tests are clearly not in the patient’s best interest.  The fact that a patient might seemingly benefit from a particular form of treatment, especially if the illness is largely or completely subjective, does not validate the treatment. Clinical efficacy and safety can be evaluated only by a properly designed and executed controlled trial with appropriate measurements and analysis. The controversial forms of allergy “treatment” described here have either failed critical tests of efficacy and safety or they have not been evaluated because of the lack of any compelling reason to do so.

Neutralization therapy is an extension of the provocation-neutralization testing procedure. The so-called neutralizing dose of the test substance is prescribed for self-administration by the patient either to relieve current symptoms or to prevent symptoms when they are believed to be imminent because of an anticipated environmental exposure. The treatment is also recommended on a regular schedule as an ongoing maintenance program. The neutralizing solution is taken by either sublingual drops or subcutaneous injections. There is no evidence of any therapeutic result other than a placebo response.

Avoidance therapy is frequently recommended as a feature of most controversial forms of allergy practice, as it is in conventional practice. The differences, however, are profound with respect to the underlying rationale and the extent and consequences of the recommended program. The unreliable diagnostic tests described here invariably “uncover” an extensive list of nonexistent allergies, leading to the unnecessary elimination of numerous foods and the avoidance of environmental items that are ubiquitous in today’s world. Extreme elimination diets are obviously dangerous, so proponents of the concept of multiple food allergies usually advise their patients to eat (or to avoid eating) specific foods on a prescribed schedule, usually as a 4- or 5-d rotational diet. Proponents of the rotational diet also claim — without substantiation — that such a diet actually prevents the development of food sensitivities. Chemical avoidance for patients with so-called multiple chemical sensitivities may be so extreme that major lifestyle changes are necessary to avoid any possible exposure to all synthetic products and all items that can be detected by odor. Fortunately, most of those individuals in whom multiple food and chemical sensitivities have been diagnosed eventually compromise on these extreme recommendations.

Dietary supplements are frequently a component of these irrational approaches to allergy management. Although there is neither theoretical nor experimental evidence that allergy pathogenesis involves a deficiency of any nutrient, clinicians and others who promote any of these “alternative” programs usually advise their patients to take supplemental vitamins, minerals, amino acids, chemical antioxidants, or some combination of these.

A number of nonmedical, unscientific, and unproven systems of practice offer to help persons with a variety of illnesses, including allergy. The most prevalent today are acupuncture, chiropractic, homeopathy, and naturopathy, but there is also a long list of boutique “therapies” such as crystal therapy and herbalism. In general, each of these treatment-based systems employs a similar if not identical treatment procedure, regardless of the nature of the disease. Needless to say, needling of the skin, spinal manipulation, ingestion of herbs, or any of the other maneuvers embraced by these entities are inconsistent with the known mechanisms of allergy, and proponents of them cannot cite any evidence of effectiveness.

Many of the unconventional treatments discussed above are recommended for patients with presumed allergy in whom the existence of a true hypersensitivity disease is questionable. Recently, an unproved “modification” of allergen immunotherapy for patients with atopic allergy has surfaced. It is called enzyme-potentiated desensitization, and it consists of a single preseasonal subcutaneous injection of a conventional pollen extract mixed with a minute quantity of the enzyme β-glucuronidase. It is claimed to be superior to the usual extended course of immunotherapy that requires graduated increasing doses of allergen leading to a successful long-term maintenance program. Although a single low-dose injection of an allergen is certainly less likely than conventional immunotherapy to cause a systemic reaction, there is no evidence that enzyme-potentiated desensitization favorably affects atopic disease, whereas there are now dozens of well-controlled clinical trials confirming efficacy of the conventional high-dose form of treatment.

Exposure to indoor allergens is a common symptom trigger for patients with allergic rhinoconjunctivitis and asthma. Furthermore, scientific studies suggest that effective avoidance of allergens can improve symptom control. The focus of this chapter is to review current concepts regarding the characteristics of indoor allergens and strategies that have been used to decrease allergen exposure in sensitized patients. Specifically, environmental control measures for dust mite, cockroach, animals, and fungi are discussed. In addition, the current evidence regarding the effectiveness of allergen avoidance strategies is summarized. Although indoor environmental control should be discussed with every affected patient, an individualized approach based on a variety of patient characteristics is recommended.

Potential benefits of environment control

Two events occur prior to the development of symptoms in allergic patients. First, the individual has to become exposed and sensitized to a particular allergen with production of allergen-specific immunoglobulin E. This immunoglobulin E may become affixed to mast cells that are present throughout the body, but are most prominent at mucosal surfaces. The second event is re-exposure to that allergen, stimulating the mast cells to release their inflammatory mediators and triggering many of the symptoms attributed to allergy.

Currently, a primary focus of research is to advance the understanding of why some patients become sensitized to allergens and others do not. The complex interplay between genetics and environment plays a key role in determining an individual’s susceptibility to allergy. Environmental factors such as exposure to allergen, endotoxin, infections, and foods during infancy seem to be important in the development of the immature immune system. This suggests that there is a potential for the environment to be manipulated to decrease a patient’s risk of becoming allergic.

In addition, for previously sensitized patients, avoidance of allergens can prevent allergic symptoms. In many instances, complete avoidance is not possible. However, changes can be made to a patient’s environment to decrease exposure to a specific allergen. Which of these environmental manipulations truly improves patient symptoms, outcomes, and quality of life will be the focus of this chapter.

Allergens that accumulate in the respiratory tract share several characteristics. A typical allergen is a small, stable protein that can gain access to respiratory mucosal surfaces and is also soluble so that it can penetrate into the tissue. Many different trees, weeds, molds, grass, arthropods, and animals produce allergens with these properties. Because the average American spends more than 90% of his or her time indoors, the effective reduction of indoor allergen exposure could have a great impact on decreasing symptoms in sensitized patients.

The goal of allergen avoidance measures is to decrease the exposure level to a point that results in decreased symptoms and lowered medication requirements. The exact amount of allergen that is necessary to exceed an individual’ s symptom threshold is likely both allergen and patient specific. However, we do know that even extremely small (microgram) amounts of these proteins can trigger symptoms in sensitized subjects. What follows is a description of the main indoor allergens, potential environmental control measures for these allergens, and the current understanding of the effectiveness of these measures.

Dust mite allergen

Exposure to house dust in sensitized individuals is a common trigger of allergic symptoms. House dust is a complex mixture of materials and contains many different allergens, including products derived from household animals, bacteria, fungi, and insects. One of the major allergen components of house dustis produced by dustmites. Dust mites are microscopic arthropods related to spiders. There are two major dust mite species: Dermatophagoides pteronyssinus mdDermatophagoidesfarinae. Dustmites are unable to survive in climates with high altitude or low humidity, so they are less prevalent in mountainous regions. Conversely, they are prevalent in areas with high humidity. Dermatophagoides literally means, “skin eater,” and they feed on shed skin cells or other organic material. The life span of a dust mite is typically about 6 weeks.

Because of this need for organic matter, large numbers of dust mites are found in areas that can harbor nests. There are several factors predictive of high levels of dust mites in a house. These include older, single-family homes without central air conditioning. Dust mites are prevalentinmattresses, box springs, pillows, quilts, carpeting, stuffed animals, upholstered furniture, and drapes. The primary allergenic protein from the dust mites comes from their bodies or their fecal pellets and are carried on relatively large particles exceeding 10 µm in diameter. When these particles are vigorously disturbed, they can become airborne. However, because of their size, they again fall to the surface of their reservoir within 15 min and become unmeasurable in the air.

Dust mite products are quite allergenic. Sensitization to dust mite has been shown to occur at concentrations as low as 2 µg of dust mite protein per gram of household dust. Symptoms begin to occur with exposure to concentrations of > 10 µg/g of dust. In additon to symptoms of allergic rhinoconjunctivitis, inhalation of mite particles can cause bronchial hyperresponsiveness (Bronchial hyperresponsiveness), increased airway inflammation, and asthma.

The importance of decreasing exposure to dust mites has been shown in several studies. In one classic study, dust mite-sensitized asthmatics were moved to very low-dust mite environments for a minimum of 2 months. These patients showed a significant reduction in their Bronchial hyperresponsiveness as well as reduced asthma symptoms and medication requirements. These parameters returned to baseline when the patients returned to their previous environment. Similar studies in near mite-free environments have yielded comparable results. Thus, effective dust mite control has the potential to be very beneficial for sensitized patients.

In most homes, the highest exposure to dust mites has been shown to occur in the bedroom. Most people spend approximately eight hours a day in bed while breathing air that is in close proximity to bedding surfaces, where household dust contains a high concentration of dust mite allergen. This is the rationale for the focus of dust mite avoidance in the bedroom.

Traditionally, one method of dust mite avoidance has been to obtain dust impermeable covers for mattress, pillows, and box springs. In theory, as long as their pore size is smaller than the dust mite particles, these tightly woven covers should provide a protective barrier between the patient and the allergen inside the pillows, mattress, and box spring. The vast majority of studies show that the levels of dust mite allergen decreases significantly when such measures are taken.

However, two high-profile publications in the New England Journal of Medicine suggested that the clinical benefit of using bed covers alone is limited. The first of these studies was a randomized trial of mite impermeable vs “control” bed covers in 1122 adult patients with asthma requiring inhaled corticosteroids. Although there was an effect on the mite content of mattress dust, there was no difference in peak flow rates or asthma medication requirements after a year. Interestingly, both treatment and control groups had equal improvement over the yearlong trial. A similar randomized trial was conducted among 279 patients with allergic rhinitis. This trial again reported lower mite content in mattress dust, but no discernible clinical improvement.

Several concerns over these two high-profile trials have surfaced. Neither trial studied patients sensitized only to dust mites, which raises the possibility that persistent exposure to other allergens may have masked potential benefit from the intervention. Also, because improvement in placebo and bed cover groups was reported, there may have been a masking effect from improved medication use and other uncontrolled interventions. In response to these criticisms, both authors agree that the studies do not suggest that allergen avoidance is ineffective, but that the single intervention of using bed covers is unlikely to produce clinical improvement in a substantial number of multisensitized patients.

In discussing dust mite avoidance methods, there are numerous other measures that should be addressed along with the use of impermeable covers. Frequent, perhaps weekly, washing of all bed and pillow coverings in hot water and detergent for one hour can reduce mite allergen levels. Dust mites are unable to survive temperature extremes, yet thrive at ambient temperatures of 65-80° F. Thus, it is beneficial to wash the bedding in water up to 130°F. Washing will also remove the human skin cells, which can be a food source for dust mites. Drying the bedding on high heat is also recommended. Because very cold temperatures can also be lethal to dust mites, placing small mite-laden objects such as stuffed animals in a freezer has also been suggested.

The removal of carpet in the house can also decrease dust mite exposure, although the clinical benefit of this measure is uncertain. Replacement of carpet with hard flooring would remove a nesting site for the mites, as well as a reservoir that contains their food source. Using this same rationale, upholstered furniture can also contain large amounts of dust mites. It may be preferable for a highly mite-sensitized patient to remove upholstered furniture.

For many patients, the removal of carpeting may not be possible. Currently, two chemicals are being marketed in the United States for the purpose of reducing mite allergen in carpeting. Benzyl benzoate is highly effective in killing mites in a laboratory setting. However, it seems to be only modestly effective when applied to carpets, and that effect is short-lived. Tannic acid can denature dust mite proteins. Again, this effect is diminished when applied to carpet. Although compounds in the future may provide beneficial treatments for dust mite allergen, currently available chemicals appear to have limited clinical efficacy.

Vacuuming removes mite allergen from the carpet but it does not remove live mites. Dust mite-allergic patients should avoid vacuuming if possible, because allergen surrounding the vacuum may become airborne. Similarly, a mite-sensitive patient should avoid recently vacuumed rooms. If vacuuming cannot be avoided, a dust mask and use of a “double-bag” or high-efficiency paniculate air (HEPA) filter-equipped vacuum cleaner may be of some benefit.

Environmental humidity is very important to the survival of dust mites. Mites tend to thrive where the ambient humidity exceeds 50-60%. Thus, environmental control measures such as the use of air conditioning or dehumidifiers that keep indoor humidity near levels of 40% have been promoted as a method to decrease mite growth. Successful mite control with dehumidification has been shown in studies performed in areas of very high humidity such as in tropical areas. Its effectiveness in less humid environments needs to be further studied.

When taking into consideration the available data, one realizes that there are many potentially effective methods to decrease mite exposure. Unfortunately, few single methods or combinations of methods have been tested in randomized, controlled trials for their clinical efficacy. The Cochrane Database of Systematic Reviews has summarized the studies done on house dust mite control measures for asthma and perennial allergic rhinitis. According to their analysis, a conclusion cannot be drawn as to the effectiveness of dust mite control measures in the homes of mite-sensitive asthmatics. They did find evidence to suggest that reduction of dust mite exposure in patients with dust mite-allergic rhinitis may be beneficial. Both reviews commented that more studies with larger numbers of patients should be done in order to be able to reach definitive conclusions.

Table Dust Mite-Avoidance Measures

Table Cockroach Allergen-Avoidance Measures

Summary

The clinical question remains: “What control measures for dust mites should be advised?” The reduction in mite allergen necessary to improve a patient’s symptoms is likely to be different for each patient. Because most mite-avoidance measures are safe and relatively economical, I believe dust mite-avoidance measures should be discussed with mite-sensitive patients.

The combination of impermeable pillow, mattress, and box springs covers, frequent laundering of bedding in hot water, removal of dust-laden articles from the bed, and control of humidity should all be considered, depending on symptom severity. For patients with significant symptoms that do not respond to the above recommendations, the removal of carpeting and upholstered furniture can be considered. Although compliance with these instructions requires ahighly motivated patient, the potential rewards in highly symptomatic individuals may favor a trial of these measures.

Cockroach allergen

Exposure to cockroach allergen can contribute to asthma morbidity in sensitized patients. In the National Cooperative Inner City Asthma Study (NCICAS), children who were allergic to cockroach and exposed to high levels of allergen in their homes had a threefold higher asthma hospitalization rate. It has long been known that cockroach allergen can also trigger allergic rhinoconjunctivitis. Thus, treatment strategies for decreasing cockroach allergen exposure for these patients may be helpful.

There are two main species of cockroaches that cause household infestation and allergic sensitization in the United States. Significant cross reactivity is seen between the allergens from the American cockroach and the German cockroach, although most patients are primarily sensitized to the German cockroach. Infestation is most common in inner-city dwellings as well as areas of the United States with a warm, humid climate.

The source(s) of the major cockroach allergens are not completely understood, although they appear to be secreted or excreted proteins originating in the insect’s gastrointestinal tract. Allergens have been detected in the insect’s saliva, feces, and other body parts. The highest levels of cockroach allergen is found in the kitchen, although allergen is often detected throughout the home. It is thought that cockroach allergen levels greater than 2 units/gram of dust can cause sensitization, while levels over 8 units can trigger symptoms. Levels greater than 8 units/gram were found in 50% of the bedroom dust samples in the NCICAS study. Although detectable cockroach allergen was found, no visible cockroaches were apparent in 20-48% of inner-city homes. If roaches are seen, especially during the daytime, it is a sign of heavy infestation.

The characteristics of cockroach allergen appear to be similar to dust mite allergen. Like mite allergen, cockroach allergen is present on large particles with a diameter of more than 10 µm. It is detectable in the air only after ground disturbance, settles after several minutes, and is often found in bedding. It has been proposed that the allergen is carried into the bed on feet and clothing. This bedding contamination is very important, as the bed is likely to be an area of significant exposure.

The first step in cockroach allergen avoidance is extermination with insecticides. This is most effective when done professionally. Concomitantly, food sources for the cockroach such as grease, garbage cans, pet food, and open food containers should be cleaned or removed from the environment. This improves the effectiveness of insecticides, since the cockroaches will be more likely to ingest the applied treatments.

Today’s pesticides are much safer than the organophosphates, which can cause acute neurological toxicity in large doses. Gel baits such as hydromethylnon that are odorless and colorless are not generally attractive to pets or children. They are also more effective than organophosphates or boric acid. A second application is recommended for adequate extermination in one to two weeks. Cleaning should be delayed during this time to make sure none of the insecticide is removed.

Eradication of living cockroaches is only the first step in depleting the reservoir of allergen. Comprehensive household cleaning is then required to further lower levels of allergen. Cleaning should concentrate on countertops, kitchen cabinets, refrigerators, ovens, and other kitchen appliances. Hard surfaces throughout the house should be scrubbed with detergent and water. Vacuuming carpets and washing clothes and bedding are also important. Because cockroach allergen is difficult to remove and often found in cracks and crevices, it can take up to 6 months to see an 80-90% reduction in cockroach-allergen content of settled dust.

Several studies are currently underway examining whether these cleaning methods are clinically effective. One recent study suggested that inner-city asthmatic children who lived in dwellings that received two cockroach and mouse extermination treatments, allergen-proof bedding, and a HEPA air cleaner in the children‘s bedrooms, had decreased wheezing, coughing, and asthma symptoms compared to controls. Thus, there is hope that implementing cockroach-avoidance strategies will have a significant health effect on asthmatic patients living in inner cities.

Pet allergens

Fungal allergen avoidance

Air-filtering devices

Summary of avoidance approaches for patients with environmental allergies

When discussing environmental control measures with allergic patients, several factors must be considered. A patient’s sensitivity and response to allergens in his or her environment is quite individual. Some might realize improvement by instituting just a few simple measures, whereas others may require extensive avoidance measures. The severity of their symptoms in response to these allergens must also be considered. Avoidance measures are not nearly as important for the patient with mild allergic rhinoconjunctivitis as they are for the patient with severe asthma that is triggered by allergen exposure. Other factors such as the patient’s socioeconomic status and ability to manipulate his or her environment are also important. Therefore, advice should be tailored for each individual patient and his or her specific history.

As stated several times throughout this chapter, additional studies currently being completed will help us determine with greater certainty which measures will best help our patients. For the time being, a practical approach includes utilizing simple measures such as allergen-proof bedding, mouse and cockroach extermination, control of indoor humidity, and thorough cleaning practices. More extensive measures should be considered for patients with continuing symptoms or those at high risk of morbidity as a result of exposure to a specific allegen. These avoidance measures, in conjunction with appropriate medications, can be used to achieve optimal patient outcomes and can be an important aspect to the overall management of patients with respiratory allergic disorders.

Humans have kept domesticated animals as pets for thousands of years. In developed countries, pets are often kept indoors in close proximity with their owners. Because of this, we are exposed to large amounts of their secreted/excreted proteins. Unfortunately, many people become sensitized and develop allergic symptoms when exposed to these proteins. It is often quite difficult for these patients to part with the animals that are making them ill. In fact, approximately one-third of all pet-allergic individuals have the offending animal in their home. Cats and dogs are the most common and most studied allergy-inducing pets, but it appears that all fur-bearing animals are potentially allergenic. Allergen-control measures should be similar for all such animals, but the most effective measure is removal of the animal from the home.

Table Pet Allergen-Avoidance Measures

Cat Allergy

Cats produce several potentially sensitizing allergenic proteins. However, the major allergenic protein, Fel d 1 is implicated in 85-95% of cat-sensitized patients. A single cat can produce 3-7 pg/day of this protein, which is secreted by sebaceous, salivary, and perianal glands. The skin and fur are thought to be the primary reservoirs, with the highest concentration of Fel d 1 found on the cat’s face and neck. The function of Fel d 1 is unknown, although it may play a role in epithelial protection or pheromone regulation. Additional cat proteins that may elicit an immunoglobulin E-mediated response include albumin and Fel d 3. Nearly 10-20% of allergic patients can develop sensitivities to these proteins in addition to Fel d 1.

The production of Fel d 1 is greatly influenced by testosterone, so that male cats produce higher Fel d 1 than females. Castrated male cats produce less protein overall, but still enough to induce symptoms in sensitized patients. There is no evidence to suggest that either secreted Fel d 1 or surface-level allergen is correlated with the length of the cat’s hair. Thus, it does not appear that a certain breed of cat, based on hair length, is more or less allergenic than another. However, it has been shown that the degree of variablility in the amount of Fel d 1 that is shed between cats may be greater than 100-fold.

Fel d 1 has several interesting characteristics. The protein itself is carried on both large and small particles. Up to 75% of the total amount will be carried on particles 10 pm or more in diameter, whereas 25% will be carried by particles < 5 pm. Unlike dust mite or cockroach allergen, minimal environment distrubance can cause high levels of allergen to become airborne for long periods of time. Also, the allergen can be quite “sticky,” easily adhering to surfaces, clothes, and walls. These factors are important when designing avoidance techniques.

Because pets are ubiquitous in our society, it can be quite difficult to avoid pet allergen. Indeed, recent studies have shown that significant amounts of cat allergen can be found in the majority of houses where cats have never been kept. In fact, dust from 66% of US homes exceeds the threshold level of cat allergen to cause allergic sensitization, and 35% of homes exceed the level necessary to trigger asthma symptoms. In these homes, the highest levels of Fel d 1 were found on upholstered furniture in the living room. Cat allergen can also be found in public buildings such as airports, schools, theaters, and hospitals. It is generally thought that the allergen is brought to these environments on the clothes of cat owners. Unfortunately, there are no practical avoidance strategies for sensitized patients in these public facilities.

However, effective avoidance measures can be instituted at home. Without a doubt, the highest levels of cat allergen are found in homes with a cat. Concentrations of Fel d 1 are 10-1000 times greater than in catless homes. The highest levels are found in upholstered furniture and carpets, although bedding and mattresses can also have high levels of allergen, especially if that is where the pet chooses to sleep.

The only clearly effective measure for pet allergen avoidance is removal of the pet from the home. This is clearly the correct advice for severely symptomatic patients and should be strongly recommended in this population. A pet produces large amounts of allergen and other control strategies will likely be ineffective. Benefit derived from compromise measures such as designating the bedroom a “cat-free” environment or washing the cat are unproven. Any effect from washing the cat appears transient, as allergen sampling from the animal falls briefly, but often returns to baseline within hours to a few days.

A number of commercial products are available that are designed to spray onto and rub into the cat’s fur. Some of these sprays reportedly contain chemicals capable of denaturing Fel d 1. No convincing studies have been published that prove these products have clinical efficacy.

It should be explained that removal is only the first step. Subsequent thorough and repeated cleaning, including washing floors, walls, hard surfaces, and all clothes that have contacted the cat, is required. Removal of carpet, upholstered furniture, and other reservoirs of allergen may also be necessary. Cat allergen will likely persist in mattresses for extended periods after removal of the animal, so the purchase of new bedding or impermeable encasements should also be advised. Because Fel d 1 is often airborne, use of a HEPA air cleaner seems logical. It is important to remember, however, that allergen levels fall quite slowly even with the above measures. It is likely that high allergen levels will be present for months after removal of the cat.

Studies on the clinical effectiveness of instituting the above measures are few. A Cochrane Review evaluating the effectiveness of air-filtration units on asthma concluded that the available trials were too small to provide evidence for or against the use of air-filtration units to reduce pet-allergen levels in the management of asthma induced by pet exposure. Indeed, no clinical trials have tested the effect of removing apet from the home of a sensitized asthmatic. Thus, studies are greatly needed in this area so that we can confidently counsel our patients on pet-allergen avoidance.

Dog Allergy

Humans develop allergic responses to a variety of proteins that are present in the dander, saliva, urine, and serum derived from dogs. The main identified allergens are dog albumin and a protein named Can f 1. There is some dog breed-specific variability in the production of these allergens, but all dogs have been shown to produce the main allergens. The large number of proteins that are potential allergens and the lack of well-standardized materials for diagnostic and research purposes have made studies on dog allergy difficult.

Can f 1 seems to have similar properties to Fel d 1. It can be carried on both large and small particles. It can also become airborne quite easily and remain so for extended periods of time. Because of these similarities, the avoidance measures discussed for cat allergy are recommended for patients who are sensitive to dogs.

Similar to Fel d 1, Can f 1 levels can be detected even in homes without a dog. A recent study reported that 98% of homes with an indoor dog and 36% of homes without a dog exceeded the threshold limit for allergic sensitizaiton with Can f 1. In addition, 89% of homes with a dog and 9.3% of homes without a dog exceeded the level necessary to trigger asthma symptoms.

Other Animal Exposures

It is likely that nearly every animal can produce proteins to which individuals could become sensitized if adequately exposed. There are documented cases of allergy to numerous mammals ranging from rodents such as rats and mice to large animals such as horses or cows. Sensitization can also occur to pets such as gerbils, hamsters, guinea pigs, or rabbits. Typically, the urine from these animals contains allergenic proteins that can easily become aerosolized. Therefore, allergic patients should avoid contact with contaminated bedding and avoid cleaning the cages of these animals. Although it is relatively easy to reduce one’s exposure to such small caged pets, “natural” exposure to mouse or rat allergen is more common than we would like to think.

Sensitization to rats occurs in up to 30% of laboratory workers who handle these animals, signaling a significant occupational risk. Exposure to increasing concentrations of rat allergen has been associated with increased airway responsiveness in these individuals. However, significant exposure also occurs in many homes. Studies suggest that 20% of inner-city children are sensitized to rats, with one-third of their homes having detectable levels of rat allergen. Interestingly, sensitization was not necessarily associated with the presence of detectable rat allergen in the home. However, a number of asthma morbidity factors such as number of hospitalizations, unscheduled medical visits, and days with limited activity because of asthma were significantly higher in those with both sensitization and exposure to rat allergen.

In the NCICAS study, 18% of the inner-city children were sensitized to mouse. Also, 95% of the homes had detectable mouse allergen in at least one room with the highest levels found in kitchens. However, no statistically identifiable relationship between mouse-allergen exposure and asthma morbidity was seen in the study. Many of the specific characteristics of Mus m 1, the major mouse allergen, have yet to be elucidated, including levels required for sensitization or to trigger symptoms.

Given our present understanding, it would be beneficial for patients with mouse and rat sensitization to minimize their exposure. Our knowledge regarding methods to decrease these allergens is currently lacking, but they are now being studied. A recent study demonstrated that certain measures are effective in lowering Mus m 1 in mouse-infested, inner-city homes. These interventions included filling holes and cracks with copper mesh and caulk sealant, vacuuming with HEPA filters, and cleaning surfaces with mild detergents. Traps and low-toxicity pesticides from professional exterminators were also used. Studies with large numbers of patients will be required to help determine the duration and degree of the clinical effect of these methods.

Table Mold Allergen-Avoidance Measures

Avoidance advice regarding indoor fungi or mold allergens is made more difficult by the poorly understood relationship of mold allergen levels and allergic symptoms. One mold in particular, Alternaria, seems to be important from recent epidemiological studies. In certain areas of the country, sensitivity to Alternaria is associated with increased risk of asthma in children and with sudden, severe asthma episodes in children and young adults. Unfortunately, we have only poorly performing methods to measure fungal exposure levels, which makes the study of fungi and the effectiveness of mold-avoidance measures difficult to study. However, it is clear that damp environments promote the growth of excessive multiple molds, bacteria, or both.

A primary source of indoor mold exposure is the penetration of outdoor fungal spores into the home. Outdoor fungal spores rise during the warm, wet weather months and will significantly decrease during the cold, dry months. During months of high mold exposure, indoor levels can be minimized by simple measures such as keeping doors and windows closed and using air conditioning.

Reducing indoor mold growth can be achieved by controlling excess moisture in the home. The primary source of moisture in many indoor environments is from water that leaks into buildings, or from leaky plumbing, dishwashers, or hot water tanks. Thus, proper house maintenance is required for the prevention of excessive fungal growth. Annual inspection of the roof, as well as keeping gutters and drains clear for proper diversion of rainwater is important. Also, keeping the relative humidity in a house near 40% can limit mold growth. Dehumidifers in moist areas, such as basements, are a potentially effective way to accomplish this. Measures such as increasing ventilation in bathrooms or kitchens, with the installation of exhaust fans or venting a clothes dryer to the outdoors, may also be considered. HEPA air filters may be effective in removing some airborne spores.

Carpets are also known to harbor mold spores. The presense of old wall-to-wall carpeting is associated with higher indoor mold levels. Thus, replacing carpet with hard flooring can be considered. If removing the carpet is unacceptable, frequent vacuuming with a vacuum containing a HEPA filter and double-thickness bags may decrease exposure. Wallpaper and paneling can be treated with a mild bleach and detergent solution as well, so that visible mold should be aggressively removed. Walls with more than 10 square feet of obvious surface mold growth may require professional assessment. Highly sensitive patients should wear protective masks when performing such tasks or better yet, have others do it for them.

Window air conditioners or central humidification units are common sources of mold contamination. These devices can circulate spores throughout the house if proper maintenance is not performed. The condensing coils in window air conditioners can be washed with detergent, and then cleaned with an antifungal agent such as chlorine bleach. Condensation-collection pans should be checked to ensure proper drainage and lack of obstruction to avoid pooling of water. Simple steps such as these can be quite helpful in the treatment or prevention of indoor mold growth. Although studies have yet to be done on the clinical effectiveness of mold avoidance, removal of clearly mold-contaminated materials is important, as these are potential triggers for severe allergy and asthma.

Patients with allergies to indoor allergens often ask whether it is beneficial to buy an air-filtering device. Advertisements for such filters claim improved respiratory health with the use of their devices. Unfortunately, the claims from most of these advertisements have yet to be scientifically substantiated. In addressing this issue with patients, there is no clear answer applicable to every situation. Several factors may play a role in determining the effectiveness of air cleaners on the levels of indoor allergens, and these factors will be discussed here.

As mentioned throughout this post, the aerobiology of allergens plays a significant role in determining the extent and location of the allergen in the environment. Many allergens from cockroach and dust mites are carried on relatively large particles that are found on surfaces and only become airborne after significant disturbance. These particles then settle after 10-15 minutes. Therefore, air filters will be of limited use for these allergens, especially in areas with low traffic. The allergens themselves are not in the air long enough to be effectively filtered.

Mold allergens and much of the cat and dog allergens are carried on small particles that can remain airborne for longer periods of time and are more amenable to being filtered from the air. However, only a small percentage of the allergen is likely to be in the air at any one time. Most of the allergen will continue to be found in a reservoir, which can continually replace the airborne allergen. Thus, air-cleaning devices alone are unlikely to provide significant benefit.

Another factor is the type of air filter. There are three basic classifications of air cleaner to consider:

1.  Mechanical filters that clean the air by having air pass through porous material, where particles are trapped based on size.

2.  Electrostatic precipitators that impart an electrical charge on particles, which then adhere to surfaces that hold the opposite electrical charge.

3.  Chemical filters that rely on substances such as activated charcoal to absorb gases and odors.

The most efficient mechanical filters are the HEPA filters. They can remove particles as small as 3 |am at more than 99.9% efficiency. However, as with all filters, only airborne allergens can be removed, and only air from a limited area of the home will be drawn to the filter. The activated charcoal and chemical filters are of limited value in the removal of allergen from the air, although the removal of odors and irritants by these cleaners may be of benefit to some patients.

To date, scientific studies investigating the clinical effects of air cleaners have been inconclusive. A1997 report by the American Lung Association concluded that if allergen sources were present in a residence, then air cleaning by itself was not effective at reducing allergen particles to levels that would improve symptoms. Thus, it is uncertain whether air cleaners should be a universal recommendation to patients for control of indoor allergens. If a patient insists on purchasing such a device, the use of a HEPA filter unit can be recommended, as it is likely to capture the relevant allergen particles to some extent. Future studies should focus on the use of these cleaners, along with other environmental control measures, to see if they truly provide additional benefit.

Anaphylaxis resulting from insect stings is estimated to affect 0.3-3% of the population and is responsible for at least 40 deaths a year in the United States. In addition, increasing numbers of reactions are caused by stings of the fire ant, a nonwinged Hymenoptera present primarily in the southeastern United States. Anaphylactic symptoms are typical of those occurring from any cause. The majority of reactions in children are mild, with dermal (hives, angioedema) symptoms only. The more severe reactions, such as shock and loss of consciousness, can occur at any age, but are relatively more common in adults. After an initial anaphylactic reaction, about 60% of unselected people will continue to have reactions from subsequent re-stings. The natural history of this disease process is influenced by age and severity of anaphylaxis. Children who had dermal reactions only have a very benign course and are unlikely to have recurrent re-sting allergic reactions. People who have had severe symptoms are more likely to have re-sting reactions, usually of similar intensity. People with a history of sting anaphylaxis and positive venom skin tests should have epinephrine available and are candidates for subsequent venom immunotherapy, which provides almost 100% protection against re-sting reactions. Recommendations for the duration of venom immunotherapy are still evolving. Venom immunotherapy can be stopped if skin-test reactions become negative; for most people, 3-5 yr of venom immunotherapy appears adequate, despite the persistence of positive tests. Individuals who have had life-threatening reactions, such as loss of consciousness, and retain positive skin tests should receive venom immunotherapy indefinitely.

Allergic reactions to insect stings are a very common and, occasionally, serious medical problem. The incidence of anaphylaxis in the general population has been estimated to range from 0.3 to 3%. Vital statistic registry data document at least 40 deaths per year as a result of insect sting anaphylaxis, with the likelihood that other episodes of unexplained sudden death are also the result of insect stings. Individuals at risk are often very anxious about further stings and, as a result, make significant changes in their lifestyles.

In recent years, particularly since the availability of purified venoms for diagnosis and therapy, major advances have occurred. The natural history of insect sting allergy is now understood, and tools are available for appropriate diagnosis and for treatment of individuals at risk for insect sting anaphylaxis. For many individuals, this is a self-limited disease, and for others treatment results in a permanent “cure.”

Insects

The stinging insects are members of the order Hymenoptera of the class Insecta. They may be broadly divided into two families; the vespids, which include the yellow jacket, hornet, and wasp; and the apids, which include the honeybee and bumblebee. Individuals may be allergic to one or all of the stinging insects. The identification of the culprit insect responsible for reactions is thus important in terms of specific advice and specific venom immunotherapy (venom immunotherapy; discussed later).

The presence of the different stinging insects varies in different parts of the country. For example, the wasp is most common in Texas, and honeybees may be more common in farm areas, where they are used for plant fertilization.

The yellow jacket is the most common cause of allergic reactions resulting from insect stings. These insects primarily nest in the ground and are easily disturbed in a course of activity, such as lawn mowing and gardening. They are also attracted to food and are thus commonly found around garbage and picnic areas. Yellow jackets are particularly present in the late summer and fall months of the year. Hornets, which are closely related to the yellow jacket, nest in shrubs and are easily provoked by activities such as hedge clipping. Wasps are found in nests, usually hanging from eaves. In general, there are few wasps per nest, and thus stings are relatively uncommon in most of the country. The honeybee hive may contain thousands of honeybees. As a rule, these insects are quite docile, as exemplified by the common picture of the beekeeper handling thousands of bees on his face or other parts of the body. However, if the honeybee hive is disturbed, multiple stings may occur. The bumblebee, which is a solitary bee, is a rare cause for an insect sting reaction.

The problem of multiple insect stings has been intensified by the introduction of the “Africanized” honeybee, the so-called killer bee, into the southwestern United States. The African honeybee was introduced into Brazil from Africa in 1956 for the purpose of providing a more productive bee in tropical climates. These bees are much more aggressive than domesticated European honeybees, which are found throughout the United States. The African honeybee has interbred with the European honeybee, but unfortunately the aggressive characteristics have persisted. These bees are extremely aggressive, and massive stinging incidents have occurred, resulting in death from venom toxicity. The Africanized honeybees entered south Texas in 1990 and are now present in Arizona and California. It is anticipated that these bees will continue to spread through the southern United States. They are unable to survive in colder climates but may make periodic forays into northern United States during the summer months.

The fire ant, which is a nonwinged stinging insect, is found in southeastern and south central United States primarily near the Gulf Coast. These insects are gradually spreading northward and westward. It is anticipated that they will extend as far north as Virginia and have now reached California. The fire ant is increasingly responsible for allergic reactions. It attaches itself by biting with its jaws. It then pivots around its head and stings at multiple sites in a circular pattern. Within 24 h a sterile pustule develops, which is diagnostic of the fire ant sting.

In contrast to stinging insects, biting insects, such as the mosquito, rarely cause serious allergic reactions. These insects deposit salivary gland secretions, which have no relationship to the venom deposited by stinging insects. Anaphylaxis has occurred from bites of the deerfly, kissing bug, and bedbug. Isolated reports also suggest that on rare occasions mosquito and black fly bites have caused anaphylaxis. It is much more common, however, for insect bites to cause large local reactions, which may have an immune pathogenesis.

Reactions to insect stings

Allergy tests

Acute allergic reactions from insect stings result from immunoglobulin E antibodies reacting with insect venoms. These antibodies are best detected by the immediate skin test reaction. Individual insect venoms — yellow jacket, honeybee, white-faced hornet, yellow hornet, and wasp — are commercially available for diagnostic skin tests. A positive skin test is defined as an immediate wheal-and-flare reaction occurring within 10 min after an intra-dermal skin test with venom doses up to 1.0 µm/mL. Higher venom doses cause nonspecific irritative reactions. immunoglobulin E antibodies in the serum can also be measured by the radioallergosorbent test (radioallergosorbent). This in vitro test is more expensive and generally less sensitive than the simple immediate skin test. It is estimated that approx 20% of individuals with positive venom skin tests will not have a positive radioallergosorbent. Thus, the radioallergosorbent is not recommended for routine diagnosis unless a skin test cannot be performed.

There have been isolated observations of people who have had systemic allergic reactions from an insect sting after negative venom skin test reactions. Some of these people have had detectable serum venom-specific immunoglobulin E (radioallergosorbent). As a result of these observations, measurement of serum venom-specific immunoglobulin E is recommended if an individual has a history of moderate-to-severe venom anaphylaxis and has a negative venom skin-test reaction.

Individuals with systemic mastocytosis may have anaphylaxis, usually moderate to severe, from an insect sting, which is a result of nonimmunological release of mediators as the result of the pharmocological properties of venom. These people have elevated baseline serum tryptase levels. It is therefore advisable to search for the possibility of systemic mastocytosis as the explanation for venom-induced anaphylaxis in people with undetectable venom-specific immunoglobulin E (skin test and radioallergosorbent).

At the present time, fire ant venom is not available. The commercial whole-body fire ant extract is reasonably reliable for skin-test diagnosis and immunotherapy for fire ant-allergic individuals.

Therapy

Acute Reaction

The immediate medical treatment for acute anaphylaxis resulting from insect stings is the same as that for anaphylaxis from any other cause.

If the insect stinger remains in the skin, it should be gently flicked off, with care being taken not to squeeze the sac. Unfortunately, the majority of the venom is deposited very quickly after the sting, and removal of the sac will only be helpful if done immediately.

Prophylaxis

Individuals who have had insect sting anaphylaxis and have positive venom skin tests are at risk for further reactions after re-stings. Prophylactic measures include minimizing potential exposure, keeping medication for immediate treatment of anaphylaxis available, and consideration of venom immunotherapy.

Measures that might minimize insect stings include wearing protective clothing when outside, such as shoes, slacks, long sleeves, and gloves. Cosmetics, perfumes, and black or drab clothing, which attract insects, should be avoided. Great care should be taken when eating outdoors because food and garbage do attract insects.

The primary medication for treatment of anaphylaxis is epinephrine. Individuals at potential risk should be given epinephrine, available in preloaded syringes, (Epi-Pen, Center Laboratories, Port Washington, NY; Twinject, Verus Pharmaceuticals Inc., San Diego, CA). Antihistamines, such as diphenhydramine, are also recommended and may be helpful for treatment of hives and edema.

Venom Immunotherapy

Conclusion

Although problems remain, such as prediction or selection of individuals at potential risk for initial anaphylaxis and issues regarding duration of treatment, the understanding and approach to treatment of individuals with insect sting allergy have been defined and effective treatment is available for the majority of individuals.

Normal Reaction

Insect stings, in contrast to insect bites, always cause pain at the sting site. The usual or “normal” reaction is localized pain, swelling, and redness. This reaction usually subsides within a few hours. Little treatment is needed other than analgesics and cold compresses.

Large Local Reactions

Extensive swelling and erythema, extending from the sting site over a large area, is fairly common. The swelling usually peaks in 24-48 h and may last 7-10 d; a sting on the hand may cause swelling extending as far as the elbow. On occasion, when the reaction is severe, fatigue, nausea, and malaise may be present. If mild, these large local reactions can be treated with aspirin and antihistamines. When a reaction is severe or disabling, steroids such as prednisone, 40 mg daily for 2-3 d, are very helpful in diminishing the swelling. There is no documentation that the application of papain (meat tenderizer) or “mud” alleviates local swelling. These large local reactions have been confused with infection and cellulitis. Insect sting sites are rarely infected and antibiotic therapy rarely indicated. Tetanus prophylaxis is unnecessary.

The natural history of reactions that occur following subsequent re-stings in individuals who have had large local reactions has been well studied. After subsequent stings large local reactions tend to reoccur in about 80% of individuals. The risk for subsequent insect anaphylaxis is very low, less than 5% Thus, individuals who have had large local reactions are usually not considered candidates for venom immunotherapy (discussed later) as treatment to prevent anaphylaxis and do not require venom skin tests. There are conflicting reports regarding the efficacy of venom immunotherapy to minimize large local reactions. The use of venom immunotherapy might be a consideration for people frequently stung who develop significant local reactions despite appropriate medical therapy.

Anaphylaxis

There are no clinical criteria or risk factors that identify individuals at potential risk for insect sting anaphylaxis other than a history of a prior anaphylactic reaction. The clinical features of anaphylaxis following an insect sting are similar to anaphylaxis from other causes. The most common symptoms are dermal, generalized urticaria, flushing, and angioedema. The most severe symptoms, which may be life-threatening, include respiratory distress as a result of asthma and upper airway swelling, circulatory collapse, and shock. Other symptoms include nausea, bowel cramps, diarrhea, rarely uterine cramps, and a feeling of “impending doom.” Anaphylactic symptoms usually start immediately after a sting, within 10-30 min. On rare occasions reactions have started after a longer time interval.

Estimates of the incidence of anaphylaxis in the general population range as high as 3%. The majority of reactions have occurred in individuals under the age of 20, with a 2:1 male to female ratio. These prevalence data probably reflect exposure rather than any specific age or gender predilection for anaphylaxis. Although the majority of insect sting reactions occur in younger individuals, severe anaphylaxis may occur at any age. Most deaths have occurred in older individuals, many of whom had cardiovascular disease.

The natural history of insect sting anaphylaxis has been the subject of fairly intense investigation. In individuals who have had insect sting anaphylaxis, the recurrence rate after subsequent stings is approx 60%. Viewed from a different perspective, not all individuals presumed to be at risk react to re-stings. The incidence of these re-sting reactions is influenced by age and severity of the initial anaphylactic reaction. In general, children are less likely to have re-sting reactions as compared with adults. The more severe the anaphylactic reaction, the more likely it is to reoccur. For example, children who have had dermal symptoms as the only manifestation of anaphylaxis have a remarkably low re-sting reaction rate. On the other hand, in individuals of any age who have had severe anaphylaxis, the likelihood of repeat reactions is approx 80%. When anaphylaxis does reoccur, the severity of the reaction tends to be similar to the initial reaction. No relationship has been found between the occurrence and degree of anaphylaxis and the intensity of venom skin-test reactions.

Unusual Reactions

Serum-sickness-type reactions, characterized by urticaria, joint pain, and fever, have occurred approx 7 d after an insect sting. Individuals who have this reaction are subsequently at risk for acute anaphylaxis after repeat stings and thus are considered candidates for venom immunotherapy.

There have been isolated reports of other reactions such as vasculitis, nephritis, neuritis, and encephalitis, occurring in a temporal relationship to an insect sting. The specific etiology for these reactions has not been established and in general venom immunotherapy is not indicated.

Toxic Reactions

Many simultaneous insect stings, for example, 100 or more, may lead to toxic reactions owing to venom constituents. The clinical symptoms that characterize these reactions are primarily cardiovascular and respiratory in nature. Immediate treatment is directed to cardiovascular and respiratory support. Following toxic reactions, individuals may develop immunoglobulin E antibody and may then be at risk for subsequent allergic sting reactions. Thus, individuals who have had toxic reactions should be tested for the possibility of potential sensitization and need for specific therapy. The frequency of these toxic reactions has increased because of the Africanized honeybees.

Injection of purified venoms (venom immunotherapy) is extremely effective treatment for individuals at risk for venom anaphylaxis. The overall success rate in preventing subsequent anaphylaxis is more than 98%. Venom immunotherapy reduces the risk for anaphylaxis from approx 50-60% in untreated individuals to about 2% after 3-5 yr of treatment. The guidelines for selection of individuals for treatment and venom immunotherapy dosing are now well established.

Selection of Individuals

All individuals who have severe symptoms of anaphylaxis and have positive venom skin tests should receive venom immunotherapy (Table Indications for Venom Immunotherapy in Patients With Positive Venom Skin). Children who have had very mild reactions with dermal symptoms only do not require therapy. Their families should be advised to keep epinephrine and antihistamines available. Adults who have had similar mild anaphylaxis can probably be treated in a similar fashion, but there is less evidence to support this practice in adults than in children. Currently venom immunotherapy is still recommended for these adults. Those individuals who have had reactions of moderate intensity such as mild asthma, nausea, and urticaria, without serious life-threatening reactions, might also be treated without immunotherapy and with the availability of emergency medication. They are likely to have similar moderate reactions to subsequent stings. This decision is influenced by other factors such as risk of exposure, other disease processes, such as cardiac disease, and medication use.

Following serum sickness reactions, individuals usually have positive skin tests and are then at risk for subsequent anaphylaxis. These observations are similar to the classic horse-serum-induced serum sickness. If skin tests are positive, these individuals should then receive immunotherapy. Because venom is a highly sensitizing agent, individuals who have had toxic reactions may develop immunoglobulin E antibody and then are at potential risk for anaphylaxis. In that situation, immunotherapy is indicated. As already noted, individuals with large local reactions usually are not candidates for venom immunotherapy.

Venom Selection

The product brochure, which has not changed since the availability of commercial venoms in 1979, recommends venom immunotherapy with each venom that elicits a positive skin-test reaction. Studies of venom antigenic crossreactivity explain the common observation of multiple positive venom skin tests despite only one insect sting reaction. For example, an individual who has had an allergic reaction following a yellow jacket sting will almost always have positive skin tests to both yellow jacket and hornet venoms and possibly to wasp venom. Awareness of this crossreactivity allows for more selective venom treatment. The selection of venom for therapy is based on a history of the culprit insect responsible for the reaction and the degree of skin-test reactivity. This approach utilizing single venoms despite multiple positive skin tests is less expensive, requires fewer injections, and is therapeutically as very effective.

Table Indications for Venom Immunotherapy in Patients With Positive Venom Skin Tests ^a

Table General Venom Immunotherapy Dosing

Dosing Schedule

Venom immunotherapy is initiated with injection of small doses of venom followed by increasing doses until the recommended maintenance dose has been reached (Tables General Venom Immunotherapy Dosing and Representative Examples of Venom Immunotherapy Dosing Schedules). The initial dose of venom is based on the degree of skin-test reactivity, not the severity of the anaphylactic reaction. Incremental doses are given according to a number of schedules ranging from once-weekly single doses to rush immunotherapy, which utilizes multiple doses over a 2- to 3-d period. Maintenance doses of 100 µg of single venoms or 300 jag of a mixed vespid preparation (yellow jacket, white-faced hornet, yellow hornet) is the traditional recommendation. Our studies indicate that top doses of 50 µg of individual venoms are effective. Once the maintenance dose is reached, injections are usually given at 4-wk intervals through the first year and then 6- and 8-wk intervals after the second and third years, respectively.

Table Representative Examples of Venom Immunotherapy Dosing Schedules”

^aStarting dose may vary depending on patients’ skin test sensitivity. Subsequent doses modified by local or systemic reactions. Doses expressed in micrograms.

^bSequential venom doses administered on same day at 20- to 30-min intervals

^c 50 ug may be used as top dose.

Reactions to Venom Immunotherapy

Systemic Allergic Reactions

Systemic allergic reactions resulting from venom immunotherapy are relatively uncommon, as compared with reactions that follow other types of allergen immunotherapy. However, because of the possibility of such reactions, it is important that venom immunotherapy, as with other allergenic extracts, only be administered in the setting in which personnel and equipment are available for treatment of an anaphylactic reaction. Following such a reaction, the venom dose is usually decreased about 25-33% and subsequent doses given at lesser increasing increments. If the patient is receiving several different venoms, it is prudent to give only one venom at each treatment time or separate the time of administration. Inability to ultimately tolerate a maintenance venom dose is rare.

Local Reactions

Large local reactions following venom immunotherapy are more common. When othertypes of allergenic extracts are administered, doses are decreased and a smaller dose might be maintained to avoid such reactions. In the case of venom, however, it is necessary to administer a maintenance dose (50-100 µg) in order to assure protection from insect stings. Measures to minimize these local reactions include splitting the venom dose into two injection sites and the addition of a small amount of epinephrine, such as 0.05-0.1 mL, with the venom, a commonly used procedure, although its efficacy has never been documented. When these local reactions are extensive and particularly somewhat delayed in onset, there may be accompanying nausea and fatigue. In this situation, the addition of a small amount of steroid, such as betamethasone 0.05-0.1 mL, to the venom may markedly reduce such reactions.

Fatigue, Malaise

Fatigue, nausea, malaise, and even fever are unusual symptoms that have been reported after venom injections and also after injection of other types of allergenic solutions, such as dust and mold. These symptoms usually start several hours after the venom injection and may last 1-2 d. The concomitant administration of aspirin with the venom injection and then further aspirin doses for the next 24 h may eliminate these reactions. If the reactions persist despite aspirin, then a small dose of oral steroids, such as prednisone 20 mg, given with the venom dose and repeated once in 6-8 h has been very helpful.

Long-Term Therapy

There have been no reported adverse reactions from long-term venom immunotherapy.

Pregnancy

Venom injections appear to be safe for use during pregnancy.

Monitoring During Venom Immunotherapy

Venom Skin Tests

In a minority of venom-treated patients the venom skin test becomes negative. The loss of skin test reactivity indicates that venom-specific immunoglobulin E is not present and, thus, the need for continued venom treatment is unnecessary. As a general rule it is reasonable to retest individuals with venom every 1-2 yr to examine this possibility.

Measurement of Serum Venom-Specific IgG

Venom-specific IgG has been associated with immunity to insect stings. During the course of venom immunotherapy, venom-specific IgG is stimulated. It has been suggested that individuals receiving venom immunotherapy should have serial monitoring of this antibody titer and those individuals who have failed to develop adequate titers should have a modification in dosing. In my opinion, careful review of these data does not support that recommendation. Because venom immunotherapy is 98% effective in preventing subsequent sting reactions, it does not seem reasonable to monitor any type of immune parameter looking for possible treatment failures. In addition, published data do not indicate that for an individual patient there is that close a correlation between absolute antibody titers and the success of venom immunotherapy.

Table Cessation of Venom Immunotherapy

Treatment Failures

Persistent allergic reactions following insect stings in individuals receiving venom immunotherapy are most uncommon. As noted previously, the success rate of venom immunotherapy exceeds 98%. When these reactions do occur, it is first necessary to determine whether the patient has been treated with the correct venom. This might require reassessment by history and repeat skin tests. If other insects are suspect, then venom immunotherapy should be modified. If it appears that the patient is receiving the correct venom, then the dose of the venom must be increased. For example, if the individual is receiving 100 µg of venom, the dose should be increased to 150-200 µg.

Cessation of Venom Immunotherapy

Definitive criteria for safe cessation of venom immunotherapy are still evolving. These include immuno-logical criteria and a specific period of treatment unrelated to the persistence of immunoglobulin E antibody.

Conversion to a Negative Skin Test

In my opinion, conversion to a negative skin test is an absolute criterion for stopping therapy, indicating that the immunoglobulin E antibody, the immune mediator of this reaction, is no longer present. In my experience approx 20% of individuals will convert to a negative skin test after 3-5 yr of venom immunotherapy.

Specific Time Period

Three to five years of venom immunotherapy appears adequate for the large majority of individuals who have had mild-to-moderate anaphylactic reactions, despite the persistence of a positive venom skin test. The re-sting reaction rate after cessation of venom immunotherapy is low, generally in the range of 5-10%. Individuals who have had severe anaphylactic symptoms such as hypotension, laryngeal edema, or loss of consciousness have a higher risk of a repeat systemic reaction, often of similar severity, if therapy is discontinued. For this reason, I currently recommend that individuals who have had severe symptoms and retain positive venom skin tests, receive venom immunotherapy indefinitely, which at this point can be administered every 8-12 wk. Other risk factors associated with the occurrence of re-sting reactions after cessation of venom immunotherapy include systemic reactions to venom immunotherapy, persistence of significant skin-test reactivity, and honey bee venom allergy as compared to vespid venom allergy. These decisions regarding cessation of therapy should include consideration of other medical problems, concomitant medication, patient lifestyle, and patient preference.