The spectrum of immunologic sensitization in latex allergy

Natural rubber latex (NRL) allergy is a type I respiratory hypersensitivity recognized in individuals exposed to latex allergens (1–9). This form of hypersensitivity has affected a large number of individuals in recent years and has become an important health concern in several occupational groups, including health-care workers, workers in the latex factories, and plantation workers tapping Hevea brasiliensis trees and collecting and processing latex (1, 3, 7, 10). It is assumed that the sensitization usually occurs through skin contact with latex or inhalation of antigen from latex gloves and devices containing allergens (11, 12). In hospitals and other health-care facilities, these products include gloves, balloons, barium enema catheters, tubing, and other accessories (13). However, recent evidence indicates that the exposure to latex allergen results from proteins bound to cornstarch powder used as a lubricant in latex gloves (11, 12). The typical allergic reaction to latex protein is characterized by pruritis, erythema, and edema, as is common with other allergen-IgE, mast-cell sensitivities (14–16). As sensitivity and exposure to allergen increases, urticaria may also develop, initially restricted to the site of the latex contact, but it may eventually spread to the contiguous areas of the skin and finally become systemic (15–18). Like skin contact with latex allergens, oral, vaginal, or rectal exposure also results in the development of localized latex allergic manifestations, which may lead to generalized involvement. Airborne exposure may lead to nasal, ocular, and pulmonary symptoms (11, 12, 19–23). The ocular symptoms usually start with pruritis and progress to tearing, chemosis, and edema (5, 14, 16, 24). Frequently, direct contact with latex products leads to sudden swelling of the eyelids. Nasal symptoms include sneezing, watery rhinorrhea, and congestion. Patients may develop sore throat, irritation of the larynx, or cough (22, 23). Pulmonary symptoms may range from coughing to life-threatening asthma (14, 15). Lung-function changes and chest symptoms may or may not be present in patients exposed to airborne latex allergens (7). Gastrointestinal, cardiovascular, and genitourinary symptoms from latex allergy have been well documented (5, 16, 25, 26). The severe forms of latex allergy are characterized by wheezing, stridor, sneezing, rhinorrhea, ocular itching, urticaria, hypotension, and anaphylaxis (16). Although not very common, latex-induced anaphylaxis occurs soon after exposure to the allergens, and even with prompt intervention latex-induced anaphylaxis can be fatal (27–29). Latex allergy has been reported to be associated with hypersensitivity to a number of fruit and nut allergens, and this cross-reactivity of latex-allergic patients to phylogenetically distant plants is called the “latex-fruit syndrome” (30). These fruits and nuts include banana, avocado, kiwi, papaya, passion fruit, fig, melon, mango, pineapple, peach, and chestnut (30–35). In addition, patients with allergy to other food materials such as potato and tomato, food grains such as wheat and barley, and pollens such as ragweed and grass also may show cross-reactivity to latex allergens (36–41). This widespread cross-reactivity with other plant allergens may be explained by the presence of common epitopes (40–42). However, no detailed study has been conducted to ascertain the clinical and immunologic finding in patients with latex-fruit syndrome. By RAST and RAST inhibition studies, about 70% of latex-allergic patients demonstrate fruit-specific IgE antibody in their sera (43). A number of latex-allergic patients also demonstrate symptoms after ingestion of various fruits, and several of them also show intolerance reactions to the fruits (16). The chitin-binding proteins present in latex have been recognized as allergenic and have been detected in a number of grains, potato, and other tubers (40, 42, 44). Similarly, the latex allergen, profilin, shares similarity with other plant profilins and may be involved in cross-sensitivity and cross-reactivity, as may carbohydrates present in the allergens (46, 47). Another group of proteins implicated in cross-reactivity are defense-related proteins produced by a number of unrelated plants. Some of these significant proteins have enzymatic activities and include hydrolases, enolases, and proteases (48, 49). Contact dermatitis and irritant reactions have been associated with latex products for over 50 years (14, 50). The relevant contact dermatitis is a delayed-type hypersensitivity or cellular immune reaction, typically involving the hands after wearing rubber gloves. The reaction includes scaly eczematous lesions appearing 48–72 h after contact with allergen. The lesions become chronic if the exposure persists, while the reaction disappears gradually if exposure is discontinued. Occasionally, contact dermatitis has been reported with the use of rubber products used in cosmetic application, prosthetics, etc. (51, 52). The hypersensitivity is the result of immune responses to residual low-molecular-weight chemical additives and accelerators including thiurams, carbamates, amines, and benzathiazoles, rather than latex proteins, used in the manufacture of gloves and other rubber products. Such reactions should not be confused with the more common irritant reaction resulting from occlusion of the skin and irritant responses to glove powder or chemicals. The exact prevalence of latex allergy is unknown. It has been reported that the prevalence of latex allergy in a nonatopic normal population is around 1%, while that among those in health-care professions ranges from 3% to 12% (53). However, a wide difference in the prevalence has been reported in various occupational groups. Even within the broad occupational group of hospital employees, 2.9–17% sensitization has been reported (54, 55). The presenting symptoms and evaluation methods frequently influence the accuracy in determining the prevalence. The prevalence also depends on the glove-wearing time and the concentration of latex allergens in the environment. For example, the concentration of latex allergens in surgical areas in hospitals has been determined to be 10–100-fold more than that of nonsurgical areas (56, 57). Atopy and eczema have been considered major contributing factors to allergy to latex. Balloons, toys, and several other latex-containing material have been sporadically involved in asthma due to latex allergy. Studies conducted in rubber-manufacturing plants showed a large number of workers to be sensitized to latex proteins (7). The incidence varied from 6% to 11%, although the reported studies are not conclusive due to the small number of subjects evaluated. The prevalence of NRL allergy has been shown to be significantly higher among patients with spina bifida than in any other patient group. About 18–65% of spina bifida patients showed latex sensitivity as detected by IgE serum antibody and symptoms with latex contact (53, 58). Multiple mucosal and visceral exposures are considered the reason for the high incidence (59). Patients undergoing multiple surgical procedures have shown an enhanced prevalence; however, paraplegic patients with frequent exposure to latex products failed to show any remarkable increase in the incidence. Individuals with no known underlying risk also have experienced allergic reactions to NRL-induced asthma. Individuals with other IgE-mediated reactions such as asthma or allergic rhinitis have also been shown to have an increased risk of developing latex allergy (58). The clinical presentation of latex allergy results from the exposure to antigens by cutaneous, mucosal, and parenteral routes (1, 14, 16). Diagnosis depends mainly on the clinical history of IgE/mast-cell-mediated reactions in patients allergic to latex (14, 56, 60). Clinical history, although important, will not always identify all latex-allergic patients. It is essential to ascertain underlying conditions and disease such as the presence of spina bifida, atopy, multiple surgeries, congenital abnormalities, history of allergy to fruits and mold, and occupational predilections. However, despite advances in the laboratory diagnosis of latex allergy, a detailed history may yield a more definitive diagnosis. A history of redness, itching, or swelling after contact with latex products or unexplained episodes of urticaria may indicate latex allergy. Skin tests with latex allergens, either from crude NRL or from extracts of latex products, may be helpful. Most of the crude preparations are not completely dependable. Although purified allergens are available, no studies have yet been under-taken to evaluate them. The use of exposure tests has also been evaluated, but caution should be exercised in employing the in vivo tests with certain patient groups with underlying diseases such as spina bifida. Clinical diagnosis can be confirmed with laboratory diagnosis (61, 62). Although no standardized antigens are currently available for skin or in vitro testing, purified and well-characterized reagents will be available in the near future for the immunodiagnosis of latex allergy. The treatment of latex allergy follows the same course as for other allergies and includes avoidance as the most important precaution. However, because of the severity of the reaction, more stringent practices of avoidance of exposure to latex allergens are essential (57). The utility of premedication is not clear at this time due to conflicting efficacy reports. It is recommended that corticosteroids with or without ephedrine be used to reduce the severity of intraoperative latex allergic reactions. Patients who have systemic symptoms from latex should have injectable epinephrine readily available at all times. Asthma symptoms are treated with standard anti-inflammatory agents and bronchodilators. Urticaria most often responds to the elimination of the antigen or antihistamine therapy. Refractory symptoms may require corticosteroids. NRL is made up of the processed rubber particles present in the specialized cells (laticifers) of the rubber tree H. brasiliensis. Although over 2000 plants produce latex, over 99% of the latex used commercially comes from H. brasiliensis (63). The protein content varies from 1% to 1.8% according to the clonal origin of the rubber plants, climatic factors, soil types, and fertilizers (63). Particles of the rubber hydrocarbon, polyisoprene, constitutes 25–45% of the latex content. Although the actual number of the individual proteins may exceed more than 200, hevein and hevamine constitute the majority of the proteins (64, 65). The latex also contains lipids, carbohydrates, and many inorganic constituents including potassium, magnesium, calcium, sodium, zinc, manganese, copper, and iron (63). A number of proteins with an apparent role in latex allergy have been isolated from NRL. The genes encoding several of these allergens have been cloned, sequenced, and expressed in appropriate vectors. A list of latex allergens approved by the IUIS Nomenclature Committee is given in Table 1 (66, 67). A majority of the proteins detected in NRL have also appeared in the finished latex products in the natural form, or occasionally in an altered configuration. Chemical treatment during manufacture results in the fragmentation of latex proteins. In nonammoniated latex, over 240 separate polypeptides have been detected by two-dimensional electrophoresis (64, 68). However, only 25% of these peptides showed binding to IgE from latex-allergic patients (68). The protein content of NRL depends on a number of factors including genetic background and the physiologic characteristics of the rubber plant. The analysis of NRL proteins in SDS–PAGE demonstrated a wide range of peptides with molecular masses of The IgE antibody in the sera of latex-allergic patients showed in these The of the allergens with IgE varied from to to the of the in the allergens with molecular of 14, and have been to be significant in latex allergy proteins which not present in NRL have also been reported in the finished products IgE binding reported with latex proteins of 14, and by allergic patients with spina bifida in latex proteins only health-care workers have also been reported and may a role in their disease The immune responses have been with purified allergens in allergic patients The results the and of the purified allergens in the immunodiagnosis of latex allergy. these allergens, the reagents can be standardized to more results and Latex proteins show cross-reactivity with a number of other proteins, and it is to the cross-reactivity to anaphylaxis after skin or other in vivo for latex allergy. The list of allergens with latex is and includes a number of fruits, and grains The cross-reactivity among these antigens may be explained in of the in plants. The chitin-binding protein present in a number of plants to the from plants (48, 49). It has been that the chitin-binding is the of many proteins with However, it is not clear the cross-reactivity detected allergens from fruits, plants, and the latex from H. brasiliensis is due to chitin-binding proteins or and this can only be by studies (40, 42, the cross-reactivity or more allergens can be by inhibition of the antibody of the sera from patients with latex allergy. IgE from of various food allergens showed only a of cross-reactivity results have been with and RAST inhibition fruit because of the of fruit and latex allergy, it has been recommended that patients be allergy to antigen is present (43). A standardized skin antigen to latex allergy is currently not In most crude NRL latex or proteins from gloves or other products are used as skin several antigens have been for but have the or for the of major latex allergens for is a of developing standardized reagents (66, 67). As proteins can be in such allergens should be in skin In all the studies, IgE antibody latex allergens has been demonstrated with crude latex proteins or extracts from gloves or other latex products (61, In most latex-allergic including the major groups health-care workers and spina bifida, of IgE have been detected in their have been demonstrated by (64, The latex protein have been detected at of 14, and However, the chemical treatment and the of the residual or allergens in the finished products the sensitization to products may result in the of The in the in the presence of proteins, and other factors such as be to the of a standardized antigen to demonstrate IgE in the sera of latex-allergic patients. In recent more have been to relevant allergens from latex. These have in of most of the major and allergens by the genes and the proteins Similarly, has on of the of these allergens to latex allergy. are made to use these allergens in to demonstrate IgE in the The allergen Nomenclature of the the of has approved allergens and them in the 1 to Some of these allergens are major latex allergens with with a majority of while frequently with the well-characterized allergen of H. brasiliensis This protein and even role in allergy recognized to large rubber particles and constitutes the after It is a protein and has a form with a molecular of latex-allergic patients and IgE in high in all patients to patients with IgE crude The antibody by inhibition glove powder containing inhibition powder without allergen Another study showed 1 to be a major allergen with of spina bifida patients with latex allergy. of health-care workers showed IgE to this allergen In a of health-care workers and of spina bifida patients with latex allergy showed by RAST or 1 used in of the patients showed In a recent in of but no and the presence of high IgE in the serum isolated from serum containing of NRL This showed binding to IgE in the sera of latex-allergic patients A encoding a protein of However, the expressed protein failed to to the serum IgE from latex-allergic patients. It is not known the of due to of the expressed protein or to However, spina bifida and health-care workers with latex allergy showed to the on the methods the varied from to of the patients. that over of the patients showed to over 70% the IgE in the sera and the with this allergen The protein forms an of the small rubber particles of or showed with latex-allergic patients with spina bifida (64, The of with serum IgE in health-care workers frequent and than in spina bifida patients (64, This protein has a to The of proteins from the small rubber particles showed and demonstrated cross-reactivity with a of the large rubber This allergen has been and but the not to the protein of from spina bifida patients with latex allergy although studies with from health-care workers indicate that only 25% of patients demonstrate by IgE responses and with this protein reported by to be a with a molecular of in about of the health-care workers and of the spina bifida patients with latex allergy demonstrated IgE binding However, a normal subjects also demonstrated IgE to in their The results of RAST varied among patients and normal Although this allergen detected IgE in over of health-care workers, only of those patients showed by It has an apparent molecular of a of and a with demonstrated from of latex-allergic patients. The of showed a with the IgE in the sera This latex protein is considered a major latex protein due to IgE binding in health-care workers and spina bifida patients with latex allergy. also demonstrated responses in patients with latex allergy, health-care workers The and the protein expressed by in This protein has with and defense-related proteins of potato, and It has an of and a of showed with IgE from health-care workers and spina bifida patients with latex allergy and sera from latex-allergic spina bifida patients showed more patients with the than the of The results of skin reactions with the in vitro IgE to latex allergens of the more at the with IgE from health-care workers and spina bifida sera with high and sensitivity This allergen also showed of from latex-allergic health-care workers The protein with a molecular of has been and expressed This protein showed in only a small of health-care workers with latex allergy. bifida patients and health-care workers with latex allergy to this allergen. In a recent that IgE binding to in patients with to other allergens, detected in of the patients with latex allergy, and no be made the IgE content in the sera and of profilins are frequently allergens with molecular The H. brasiliensis showed cross-reactivity with IgE from patients with ragweed allergy The proteins purified and used in skin of spina bifida who all showed a However, only health-care workers showed to this allergen skin and responses to this allergen have not yet been is a with very high with and studies with health-care workers and spina bifida patients with latex allergy failed to show any IgE binding with this protein This protein has not been for cross-reactivity with other and their IgE In of the and of cross-reactivity is but this to be by future has been detected in a number of and has been recognized as a major allergen These allergens also showed In a recent a IgE binding of this antigen in health-care with latex allergy of patient sera This antigen showed with and The results from these studies indicate that in of the with other this allergen showed only a of with sera are several other that may to IgE from patients with latex allergy (66, As are over polypeptides in latex, allergens may (64, 68). Some of them may to be in the while may be of in the sensitization and immune of the to latex allergen results in the of mainly IgE antibody in latex-allergic patients (1, The presence of IgE and in latex-allergic patients indicates that the immune is This by the results in a of latex allergy However, not has been to responses in latex-allergic patients or to the of latex allergy. The results of the studies indicate that the crude such as or nonammoniated latex or extracts from finished latex products used in the antibody are to purified or crude antigens are essential to study responses (66, purified antigens significant has been with a molecular of demonstrated in vitro of from health-care workers with latex allergy has been detected with a latex protein purified by and Although no IgE and with latex allergens, no with this latex antigen cells from normal subjects latex glove latex and 1 in and and in latex-allergic to only and 25% in subjects exposed to latex allergens however, no IgE and the with these allergens crude latex allergens, a higher than in normal subjects and in patients with latex allergy. However, no detected with IgE in the serum and although than of the patients showed studies purified latex allergens demonstrated significant with of the latex allergens the health-care workers failed to the with any of the while the patients showed in their the of all the by which the of of patients. The other purified allergens showed latex showed the of the This study also failed to demonstrate any with IgE binding and significant demonstrated with in health-care workers with latex allergy The major epitopes in the of and include the peptides with and A detected by the as shown by the but not by the with the peptides The of the allergens binding to IgE or to cells depends on the of the on epitopes and their with may be of in and reagents for more diagnosis and patient The epitopes are and while the epitopes are usually and not However, of the epitopes may IgE binding and of allergens on the of and detected epitopes the of the of which in the of the The with and other plant proteins to the evaluation of the of the with Some of these epitopes for IgE binding to spina bifida while the showed to health-care patients. In addition, epitopes binding to the IgE of patients have also been The epitopes showed with the and proteins of potato The epitopes of 1 and with sera from health-care workers and spina bifida patients with latex allergy 1 showed spina bifida patients while showed epitopes from 1 and from with groups of patients. The binding with 1 and allergens may be due to the presence of epitopes and the epitopes in in the while only in the showed epitopes binding to of which the epitopes epitopes from 1 with spina bifida but only showed binding with sera from health-care It is to that at the for spina bifida while the epitopes at the of with health-care and spina bifida patients. The epitopes at the of to spina bifida patients. The results of analysis also demonstrated for or although epitopes binding to and IgE have also been By in a of latex allergy, in a protein of latex, showed major and of the epitopes failed to the of the as an study of the in latex-allergic in evaluation of the it that certain and the of the epitopes by or is or by or IgE in the sera of patients has been by RAST or crude NRL extracts or purified latex allergens In recent a number of methods such as and have become available for patient sera for Although these methods are not according to the to evaluate IgE from the results with from to However, because of the cross-reactivity of latex allergens with fruits, and other allergens, the of the results antibody such as and have also shown electrophoresis yield significant and but are usually and (64, from can be with purified allergens showed significant by this Although are currently several purified and well-characterized allergens available, no has yet been made to them for in vitro diagnosis of latex allergy or in developing a skin preparations and the use of such materials is in skin and in in vitro due to the presence of materials and the of the These factors are major to their use as standard However, for it may be to use more than purified allergen to the and Similarly, well-characterized and allergens may be essential for developing peptides that have be and evaluated. In an a with the characteristics has been by However, studies and peptides are any Similarly, the and appropriate peptides may in the to a This study by and The of is