Latex allergies currently affect an estimated 10% to 12% of health care workers^3,5 and up to 24% of anesthesiologists.⁵ It is estimated that 10% of these people are immunoglobulin E (IgE) positive and in the early stages of sensitization, but clinically asymptomatic.⁵ Others, however, estimate that the figure for those sensitized but not clinically having reactions may be as high as 50%.⁶ Based on the most conservative of these estimates, it is possible that an average of 2 to 5 PACU nurses of every 20 may already be sensitized.

Brown et al⁷ noted that latex sensitivity groups were twice as likely to be associated with an inherited or familial heightened sensitivity to allergens (atopy) as compared with nonsensitized groups. Atopy is characterized by a history of asthma, eczema, and allergic rhinitis. Studies show that on average, the first clinical symptoms appeared after 5 years of exposure in those using latex gloves in the workplace.^8,9 This seems reasonable because about 6 years elapsed between the Centers for Disease Control's (CDC) replacement of the “Blood and Body Fluids Precautions” with Universal Precautions in 1983, and the first major reports of latex reactions in 1989. Certain patient populations may offer a glimpse of the potential for developing hypersensitivity by repeated exposure. The theory of hypersensitivity by repeated exposure is further confirmed by the high percentage of reactivity (60% to 70%) found in children with spina bifida.^10-12

Although some controls can be applied to limit exposure to latex allergens for sensitized patients and staff in the perianesthesia and perioperative setting, staff may still be continuously exposed in other areas of the hospital because airborne particulate matter remains an unresolved issue. The amount of particulate does not have to be extreme. Baur et al¹³ noted that the probable threshold for latex aeroallergens is 0.6 ng/m³ for health care workers who have been previously sensitized.

Charous et al¹⁴ noted that even while using personal latex precautions, a dental assistant with latex allergy and occupational asthma was still exposed to latex aeroallergens in the workplace because of latex that had settled into or was part of clinic upholstery fabric, as well as carpet dust. Thus, merely controlling for latex in the particular workstation or job may be insufficient.

Additionally, numerous and ubiquitous cross-reacting allergens exist in most metropolitan and urban environments. Thus, even after removing oneself from the health care workplace, the highly sensitized individual may still be continuously exposed in an office situation in which this form of air pollution is a factor. For example, tire dust, an ubiquitous air pollutant in any metropolitan center, is an agonist allergen and cross reacts in natural rubber latex (NRL) allergy.^15-19 It has also been found that birch pollen and certain other cereal-derived -amylases exacerbate or cross react with rubber product materials.


 

The use of rubber in products is ubiquitous throughout society because the world's natural rubber use currently approximates 4,500,000 tons annually.²⁰ An understanding of rubber products and their cross reactants is crucial in the diagnosis and management of latex hypersensitivity.

Natural rubber latex is one of several products made from rubber. The term latex originally applied only to the sap of rubber-producing plants. With common use, however, the term has come to represent both the uncured natural and the synthetic rubber products. The term rubber is thought to come from an early serendipitous use in which a wad of the raw sap coagulant was found to rub off pencil marks in the British record books on rubber plantations. We now call this an eraser.

The commercial applications of NRL include dipped goods such as gloves and condoms, as well as adhesives in pressure-sensitive tape. Approximately 40,000 household and medical products contain latex, making it difficult, if not impossible, to avoid contact with latex allergens.^21-23

Although most natural rubber latex is obtained commercially from the Hevea braziliensis rubber tree, there are about 200 plant species that produce natural rubber. These include common dandelion, goldenrod, and members of the sunflower family. Sunflower has been shown to contain serious contact allergen contents. Nonetheless, there are several common members of this family that include many edible salad plants such as lettuce, endive, chicory, and artichoke. Other members of this family include chrysanthemums, as well as many common weeds and wildflowers. Also included are cultivated species such as marigolds, daisies, and sunflowers, the oils and seeds of which are found in many baked products.¹⁹

Unfortunately, species within the sunflower group will cross react with the plants within the Umbelliferae family, named for the umbrella-shaped flowering stand.¹⁹ There are a surprisingly large number of plants in this family that are used as foods or spices. Examples include carrots, parsley, celery, and fennel. Additionally, there are discussions about nickel cross reacting with these plant materials.²⁴

The principal protein molecule of rubber is 1-4 cis-polyisoprene (1-4 CP). This molecule, in common with natural rubber, is also found in many plant species. Data indicate that more than 2,000 plant species contain 1-4 CP. This family of isoprenoids comprises more than 200,000 different molecules that are found in cell membranes and cellular structures of both plants and animals. Isoprenoids also act as electron carriers and are important in cellular energy. Numerous isoprenes are also involved in defense proteins built by plants against pests and pathogens.^25,26

Rubber in its natural state generally is not considered an allergen.²⁶ Nonetheless, in harvesting rubber, the trees are scribed to create wounds that drip sap. In response to this repeated wounding, the tree produces defense proteins that are incorporated into the sap that eventually becomes the latex product. Natural latex is comprised of somewhat more than 250 polypeptides, of which 60 have IgE-binding tendencies that may result in allergic reactivity.²⁷ These polypeptides are chains of amino acids, and each protein is made up of one or more polypeptide chains.

Several rubber proteins or their polypeptide fragments have been linked to allergies. Reaction to the 4.7-kDa polypeptide, Hevein, has been detected in enzyme-linked tests in 75% of the sera from health care workers allergic to latex. Positive skin test results to this polypeptide were also noted in 81% of patients with latex allergies.^27-29 The 14-kDa rubber elongation factor (Hev b 1) is also a major player in the allergy.³⁰ Other proteins identified as latex allergens include the following:

• Hevein C domain, 14 kDa
• Prohevein, 20 kDa
• Profilin, 14 to 15 kDa
• Hevamin and other 29- to 33-kDa proteins
• 45-kDa protein
• 27-kDa in patients with spina bifida

These proteins are absorbed in glove powder, which is an allergen carrier. In some gloves, these proteins leach out and become available to the skin.^31,32


 

Rubber processing is a vast complexity of chemical reactions. It requires the blending, at various critical stages, of a large host of chemical additives. These additives are used to give strength, elasticity, longevity, color, texture, and a myriad of other properties to rubber. Such chemicals also include flame retardants, fungicides, ultraviolet absorbers and blocking agents, stabilizers, and dozens of antioxidants to reduce deterioration.^33-35

During the processing of sap from the rubber plant, ammonia is used to prevent coagulation and also to extend storage. Further processing, however, necessitates deammoniation, which requires formaldehyde. Formaldehyde was shown to sensitize up to 24% of patients in one study.³³ In addition, there is also evidence of mutagenicity, as well as cases of lymphomas caused by formaldehyde.^34,35

For these reasons, low ammonia sap processing is preferred. This technique, however, requires different chemicals for stabilization and preservatives. These chemicals may leach from the finished product, causing serious toxic effects. Chemicals associated with the more serious toxic effects are tetramethylthiram disulfide (examples of this chemical family include Antabuse and some commercial agricultural fungicides) and dithiocarbamate (related to the “nerve gas” cholinesterase-inhibiting pesticides). The thirams are in fact derivatives of dithiocarbamates. The combined alcohol-thiram (Antabuse) reaction is not an allergic response, but rather a toxic response accruing to enzyme blockage. When aldehyde dehydrogenase is blocked, this allows for the accumulation of toxic levels of acetaldehyde. Thus, topical exposure through latex gloves to thiram is sufficient to initiate an “Antabuse reaction” and can affect the innocent social drinker. The reaction can also exacerbate lesions of allergic contact dermatitis.²⁶

Latex gloves are relatively easy to manufacture. Because of the high demand for cheap latex gloves, many small and inexperienced foreign firms went into business during the initial peak demand of the mid to late 1980s. These firms attempted to produce high volumes with rushed production, leading to 2 significant results. The necessary wash and rinse cycle for the finished gloves was greatly reduced. More importantly, however, there was a tendency to overdose the latex with accelerators, activators, and sulfur to quicken the reaction time and machine speed. Unfortunately, this excessive use of additives and compounding ingredients exceeded the solubility in the rubber, allowing leaching, which then brought these additives as well as the reacting proteins into direct contact with the user and the patient. This extractable latex allergen level in latex gloves may vary more than 500-fold in different brands.^36,37 These added chemicals can be highly toxic and are a main source of sensitizers. Additionally, rubber products may be admixtures of natural and synthetic rubbers.

The distinction between rubber and plastic can also be spurious because both contain the same antioxidants, stabilizers, and catalysts.²⁶ About one third of the chemicals used in rubber processing are also used in plastics.³⁸ A classic example of the junction between rubber and plastic is polyurethane. This plastic is known to induce tissue reactions that produce very thick wound capsules around implanted devices.³⁹


 

When the immune system mistakenly identifies a similarly shaped protein molecule or chemical composition for an allergen, adverse reactions occur. This is known as cross reactivity. Such cross reactivity is caused by a wide number of structurally related proteins that plants can potentially produce, and that are mimicked in the cellular machinery of humans. Many of these defense proteins arise from ancient ancestral organisms that have common lineages with both plants and animals. Nature has thus produced highly conserved evolutionary processes for defense that worked for most of life's evolution and development, but now conflict with modern chemistry and genetically engineered foods and fibers.¹⁹

There are a wide number of natural and man-made environmental cross reactants that exacerbate latex sensitivity. Defense proteins are genetically engineered proteins for insertion into plant genes to improve their resistance to pests and diseases. More and more genetically modified foods are being produced that contain these defense proteins. Unfortunately, these products constitute major cross-reacting allergens with NRL. IgE-bound reactions occur with “prohevein,” which is one of the major allergens in NRL, and also to other proheveinlike defense proteins in 70% to 88% of persons allergic to NRL.⁴⁰ Prohevein-like defense proteins are also found in tobacco.⁴¹ Thus, once sensitized to NRL, smokers and those exposed to “second-hand” smoke may see their health increasingly affected.


 

Allergic reactions are the most common form of immunologic response and involve the T and B cells in an antibody-immunoglobulin–mediated response to foreign antigens (allergens). The result can range from local tissue inflammation to systemic organ dysfunction. Of the 5 immunoglobulins present in the body, 3 are involved in allergic hypersensitivity reactions. These immunoglobulins are IgG, IgM, and IgE. The reactions stimulated by these immunoglobulins are classified into 4 distinct types (types I through IV).

Type I reaction

A type I reaction is an IgE-mediated hypersensitivity involving antibodies on the mast cells. Reaction with an allergen causes the mast cell to degranulate and release vasoactive and inflammatory mediators. The reaction occurs within minutes, and the result may be seen locally in such responses as allergic rhinitis, angioedema, or atopic dermatitis. Atopic individuals are more prone to experiencing this reaction. Anaphylaxis is also a type I reaction. The antibody response in anaphylaxis is a generalized, whole-body response.

Type II and III reactions

Type II and III reactions involve both IgG and IgM. These types of reactions generally are not involved with latex. A type II reaction is seen in complement reactions associated with cell-bound reactions and generally is not associated with allergens. Type III reactions are an immune complex hypersensitivity associated with an allergen that activates the complement cascade. With high concentrations of both allergen and antibody, an Arthus reaction may occur. This reaction generally results from an injection and is seen as a localized skin inflammation, at times with hemorrhage, and occasionally followed by necrosis and ulceration. In contrast to the more immediate type I reaction, a type III reaction develops over 4 to 10 hours.^42-44

Type IV reaction

Type IV reactions are delayed-type reactions mediated by helper T lymphocytes. These reactions are commonly seen in contact dermatitis with latent developing symptoms. Latex allergens may also be involved. Symptoms may begin to appear within 24 hours of exposure, but there can be a lag of several days. Poison oak would be an example of a type IV reaction. Another example of this reaction is the tuberculin reaction.^44,45


 

Latex reactions fall into either the type I (immediate type reaction) or type IV (delayed reaction) categories. Reactions noted may include vertigo, urticaria, contact dermatitis, naso-rhinitis, upper respiratory tract irritation, conjunctivitis, local angioedema, asthma, hypotension, and anaphylactic shock, which can end in death.

Type I allergic reaction: The immediate reaction

Onset of symptoms for type I, the immediate reaction, may be seen as early as a few minutes after exposure. For example, anaphylaxis in the operating theater usually starts within 30 minutes after the procedure is started. This rapid response is not necessarily the rule, however. A reaction involving complete collapse may also occur a few hours after exposure. Thus, the exposed nurse may finish the shift and be on a congested freeway when hit with anaphylaxis. Type I reactions to latex can include a wide range of signs and symptoms as shown in Table 1.^44-46

Type IV allergic reaction: The delayed reaction

A type IV reaction is a delayed reaction that may occur hours after the exposure to the allergen. Type IV reactions often present as secondary lesions from contact dermatitis and arise from a loss of barrier function in the irritated skin and tissue. Dermatitis related to latex gloves is seen in 2 different forms; however, only one is an allergic response. The most common response is irritant contact dermatitis, which is a nonallergic response making up 75% of cases.⁴³ Signs and symptoms are dry, itchy, irritated areas on the skin of the hands. Marked erythema is sharply demarcated, and this may be associated with numerous vesicles.^42-44 Dermatitis distribution is the single most important clue in distinguishing the 2 reactions. With irritant contact dermatitis, the skin above the glove line is usually spared as the skin reaction arises from the irritation of the gloves and added powders.^42,44

Allergic contact dermatitis is a type IV, T cell–mediated response comprising 25% of cases. Symptoms may appear in 24 hours and crest in about 48 hours. Each exposure builds greater sensitivity.⁴³ This reaction results from the chemicals added to latex during harvesting, processing, or manufacturing. The pathophysiology requires a prior sensitizing contact to a specific allergen. There may be repeated contacts and no apparent reaction. The reaction to the allergen usually occurs at the site of contact anywhere from 5 to 7 days, and occasionally as long as 20 days after the initial or sensitizing contact. The site, once reacting, is characterized by a perivascular accumulation of mononuclear cells causing leaking of endothelial cells and microvascular permeability.⁴⁴ There are no circulatory or otherwise detectable antibodies produced, although there is a local tissue allergy.⁴³ On staining with immunoperoxidase, there is a predominance of CD4 T lymphocytes in the perivascular tissue. These lymphocytes then differentiate into T1 cells that secrete cytokines, the responsible mechanism for the delayed reaction.⁴⁴ Symptoms may then develop in 24 to 48 hours after the second exposure to the allergen (6 hours to 7 days). The first symptoms, however, can develop after years of continued exposure. With removal of the offending allergen, the reaction will generally resolve after 2 to 3 weeks. Unfortunately, this condition is usually, though not invariably, lifelong. Thus, later recontact after a long period of isolation from the offending allergen may instigate the reappearance of the problem.^42-44 Because rubber products are ubiquitous, there may be continued non-workplace exposures.

In allergic eczematous contact dermatitis, the acute lesions may be red, swollen, and weeping. Crusting lesions may appear after a few days. In chronic cases, skin scaling and fissuring are dominant.^42-44 In addition to latex gloves used at the work site, causes may include fabric finishes, dyes, oils, tars, rubber, soap, cosmetics and perfume, insecticides, wood resins, plants, paints, plastics, glues, fiberglass, metals, polishes, and ointments.⁴³ This contact dermatitis may also be associated with medications. The main pharmacotherapeutic agents involved are rheumatologic agents, including NSAIDs. Dermatologic, ophthalmologic, pneumologic, and cardiovascular drugs are also implicated. These medications can include the caine anesthetics; antihistamines such as pyribenzamine; or antibiotics such as neomycin, furacin, penicillin, or sulfa. Because people often unconsciously rub their eyes, the eyelids also can be the site of intense edema and vesiculation with erythema.^42-44

Type IV glove dermatitis can be reduced by switching to eudermic products. Health care workers with type IV allergic responses can obtain the required level of job-related protection from nitrile, vinyl, or other synthetic gloves. When latex gloves are required, powder-free gloves with reduced protein content should be used. The term hypoallergenic does not necessarily mean that the gloves contain lower protein allergen content. Consequently, the designation as hypoallergenic should not be the main criterion in determining alternatives.⁴⁷


 

Most forms of type I allergy caused by environmental allergens other than latex can be treated by pharmacotherapy or specific immunotherapy. The health care industry has adopted a policy of minimizing exposure to latex proteins through the provision of other materials. Originally, this was thought to represent a cost-effective, preventative measure for latex allergy, especially in the hospital setting. Recent available studies, however, now seem to raise some questions as to whether simply replacing latex with nonallergenic materials is sufficient. Williams and Halsey⁴⁸ showed the existence of extremely small respirable particulate matter associated with either the powder or a bacterial contaminate formed during the production of latex gloves. These small particles carry the latex allergen into the air and remain airborne for hours. Once airborne, these particles become part of the internal hospital air supply. The hospital's large ventilation systems then assure that the particles are broadly distributed and recirculated.⁴⁹

The last 2 decades have seen a rise in type I reactions from latex products. Initial reactions may start with relatively vague symptoms that include a suddenly stuffy nose, oropharyngeal swelling, and difficulty swallowing. This may be followed by anxiety, dyspnea, tachypnea, retrosternal pain and tightness of the chest, perspiration, and pallor. From there, full shock can develop. This reaction is now recognized as a rapidly growing clinical crisis.

It is not merely the wearing of latex gloves that can affect the previously sensitized health care worker. The worker may be exposed in many ways that she/he would not suspect because these exposures are not limited to the work environment and may involve the health care worker as a patient. Tan et al⁵⁰ and others^51,52 discuss the perioperative collapse of patients who were previously sensitized to latex and cross reacted with certain anesthetic agents. Additionally, some cross sensitivity may occur with the use of alcohol to clean skin surfaces because alcohol and alcohol-containing lotions may react with thiram, a chemical used in the processing of latex. This reaction can lead to either continued skin sensitivity or an Antabuse reaction. Cross-reacting ingredients must also be considered in the planning and preparation of hospital meals because cases of anaphylactic reactions in hospital patients arising from cross reactivity with food items have been noted.^53,54

Health care workers employed in large publicly funded health care systems may also be at increased risk as these and other systems often depend on the typical “least-cost” contractor for supplied items. Williams and Halsey⁴⁸ showed that gram-negative bacterial endotoxins (GNBE) are a highly significant contaminant of some glove manufacturing processes. The effects of GNBE include skin irritation and the potential for accompanying secondary lesions, induced respiratory problems, fever, and shock. The highest levels of endotoxin were found in nonsterile examination gloves, an item that is often purchased on a “least-cost” contract. Although there was a greater tendency for powdered gloves to contain more endotoxins and reactive proteins, this problem was also noted in nonpowdered gloves in which these highly respirable GNBE particles were mainly found on the inside of the gloves. These particles are not physically associated with the powder and are easily released into the air on the “explosive” snap as the gloves are pulled off. GNBE may be responsible for the disproportionate enhancement of delayed and immediate hypersensitivity reactions to the chemicals and proteins found in latex gloves. This problem may be exacerbated by sterilization, as Shmunes and Darby⁵⁵ reported that sterilization of similar gloves by gamma irradiation actually increased the endotoxin levels. Further, it was found that the use of ethylene oxide caused a reaction with the rubber accelerators in gloves. The new products produced by this reaction were capable of causing irritant dermatitis and chemical burn. These effects did not dissipate with the gas but remained active for months in wrapped and stored materials.^56-61

An initial development of hypersensivity to latex may affect not only one's employment, but everyday activity as well. Numerous allergens of latex are also found to cross react with a broad variety of environmental allergens,^62-64 thus raising the potential for hypersensitivity reactions outside of the work environment as well. Materials known to cross react with and exacerbate latex hypersensitivity are noted in Table 2.

Latex allergy should be ruled out for anyone developing the following symptoms after latex exposure: irritated red hands; irritation involving nasal passages, sinuses, eyes, shortness of breath, coughing, or wheezing; hives; or unexplained shock. Health care workers experiencing these symptoms should be appropriately evaluated because once sensitized, continued exposure may end in a serious allergic reaction.

Diagnosis entails a thorough medical history, physical examination, and laboratory tests. Food and Drug Administration (FDA)–approved blood tests are now available for detecting latex antibodies. Additionally, there are standardized protocols for skin tests; however, no standardized latex extract is currently available. Skin testing extracts to determine latex protein allergy include commercial extracts, latex glove extracts, and extracts of hevea leaves. Testing has to be performed with the allergen against which the patient is presumed to be allergic. The different types of available allergen extracts, however, may not contain the particular allergen. One extract used in Canada (Bencard Laboratories, Mississauga, Ontario) has been reported to have 93% sensitivity to latex.⁶⁵

Glove extracts are made using a standardized method of soaking glove material in diluent. Extreme caution must be used with glove extracts because of variable allergenic protein levels and the potential for serious reactions from skin tests.^66,67 Conversely, false-negative skin tests may also be produced by extracts of gloves with low latex allergen content.

Skin testing with allergen extracts has traditionally been considered the most sensitive means of detecting IgE antibodies. Although often considered the gold standard, this process is not without risk and therefore should be performed only at medical centers with staff that are experienced and equipped to handle severe reactions. The pinprick introduces latex into the skin and a positive result produces dermal edema and reddening. Certain fruits such as banana, avocado, chestnut, and kiwi fruit (Table 2) may cross react with latex in allergy testing in the atopic individual. If the health care worker is also exposed to glutaraldehyde (Cidex, Sporocidin), testing for this should also be included. Allergens that should be routinely tested include the following⁶⁸: black rubber mix, 1%; carba mix, 3%; ethylenediamine 2HCL, 1%; imidazolodinyl urea, 2%; mercaptobenzothiazole, 1%; mercapto mix, 1%; O-phenylenediamine, 1%; thiram mix, 1%; triclosan, 2%; volunteer-supplied latex glove.

In vitro tests are available and are safer because the laboratory can determine the presence of IgE antibodies specific to latex from a drawn blood sample. A number of tests exist in the marketplace that give good results with freedom from the danger of immediate hypersensitivity associated with skin-prick testing.⁶⁹ For the interested reader, more information may be found on the American Society of Anesthesiology Web page, www.asahq.org/Newsletters/1999/05_99/Latex_0599.html.⁷⁰

Once sensitized to latex, individuals may need to considerably alter their current lifestyle to accommodate the ubiquitous nature of latex and cross reactants. At some point, the hypersensitivity may reach a level at which there is a considerable risk for the development of anaphylactic shock. The individual would then need to carry self-injecting equipment for continued safety. With the added insults to the immune system, there is the added risk of multiple chemical sensitivity syndrome.^71-73 This syndrome is controversial but is recognized in worker compensation claims, tort liability, and regulatory actions. Unfortunately, once this level of disability is achieved, little can be done for the lost earning power, and current government support and compensation programs offer a dismal prospect.
 

Latex sensitivities in health care workers continue to rise. Reactions are often dramatic and unpredictable because a mild sensitivity can convert to anaphylactic shock after multiple or continued exposure. An awareness of reaction classifications, exposure routes, and diagnosis techniques is critical in avoiding continued exposure and possible adverse outcomes.