Key Points
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Natural rubber latex (NRL) is contained in thousands of consumer and medical products and is responsible for an epidemic of IgE-mediated latex allergy in the past three decades. Products made by a dipping method (e.g. gloves, condoms) have the highest content of allergenic protein that may result in urticaria, angioedema, asthma, rhinoconjunctivitis and anaphylaxis. Latex finished products contain multiple chemicals that may induce cell-mediated contact dermatitis, although this is uncommon in pediatric practice.
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Latex proteins may have clinical cross-reactivity with multiple foods and lead to clinical allergic responses, especially to banana, avocado and/or kiwi, in nearly 50% of latex-allergic subjects. A small subset of patients with fruit and vegetable allergies may develop allergic reactions from cross-reactions to latex but these occur in less than 15% of patients.
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Patients with spina bifida are at highest risk of developing latex allergy. Occupational asthma is a common problem seen in adult workers exposed to latex materials that use a cornstarch donning powder, which may carry latex protein into the ambient environment.
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Diagnosis is best achieved by performance of a history, physical examination and allergy tests using skin test, serologic tests and provocation tests, although standard reagents are lacking. Serologic tests may produce false-positive results by a variety of mechanisms while up to 25% of serologic tests may be falsely negative.
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Avoidance of latex through ‘latex safe precautions’ is essential for the treatment of latex allergy.
Introduction
In the 1980s a worldwide epidemic of immunoglobulin E (IgE)-mediated allergy to natural rubber latex (referred to as NRL or latex) occurred. A marked increase in personal exposure to latex with the implementation of healthcare standard precautions and manufacturing changes in latex production resulted in sensitization to protein allergens retained in finished products. This chapter reviews the clinical presentation of latex allergy (LA), production of latex products, patterns of latex use in the context of clinical symptoms, allergens, diagnosis, clinical and laboratory cross-reactivity with foods and pollens, and treatment options.
Clinical Manifestations – Initial Observations
The clinical circumstances in patients who develop LA are highly variable and may not be readily recognized by patients. This requires clinicians to have a high index of suspicion and astute diagnostic skills.
In 1927, a single case of chronic urticaria from contact with rubber prosthetics was reported in the German literature. It was not until 1979 that the first clear case of LA was reported in a homemaker. The diagnosis was confirmed by a medical history of intense pruritus and atopic dermatitis after the use of rubber gloves, with confirmation by patch test and prick test-induced hives from a latex glove. The clinical spectrum of LA was broadened by the first report of latex exposure in a healthcare worker causing urticaria, rhinitis and ocular symptoms.
The introduction of standard precautions saw an exponential rise in latex exam glove use, paralleling a rise in reporting of LA but latex is now being replaced by nitrile butadiene rubber ( Figure 56-1 ) in exam gloves. A 1987 prevalence study confirmed the presence of LA in 15/512 (2.9%) hospital employees screened by prick test to latex. A subset of individuals (operating room personnel) had the highest prevalence at 6.2%. Atopy was found to be a strong contributing factor to LA development with 10/15 (66.7%) of subjects having environmental allergies. In 1987, Axelsson et al reported five individuals with systemic reactions to latex gloves; only one was a healthcare worker. Seaton and Cherrie completed the medical literature spectrum of latex allergy manifestations a decade after the first modern publication, when a case of occupational asthma caused by latex gloves was confirmed, and suggested that latex exposure came from airborne allergen. Previous mucosal reactions of conjunctivitis and rhinitis were believed to have come from direct allergen transfer by hand contact. This report moved the medical community toward an understanding that the environment could be contaminated by allergen-carrying glove powder.
After these earliest observations, specific risk groups emerged with common exposures. Throughout the first decade of reporting this disorder, women, healthcare workers and atopic individuals were identified as being at risk. Reports identified individuals undergoing surgical operations having severe allergic reactions during anesthesia. Two children with spina bifida suffered anaphylactic reactions when undergoing anesthesia in two completely different clinical scenarios. One child experienced systemic symptoms within 15 minutes of anesthesia induction and prior to surgical incision while the other child’s reaction occurred at the time of closure of the surgical incision. These reactions were characterized by generalized flushing, expiratory wheezing, marked increase in airway pressure needed to mechanically ventilate, and severe hypotension requiring epinephrine for symptom reversal. These observations were confirmed in the next 3 years by multiple clinical observations of allergic reactions in spina bifida patients undergoing surgery.
Spina Bifida
Children with spina bifida (SB) emerged in the early 1990s as the group at highest risk for developing LA. Recurrent exposure to latex products in their daily care, multiple surgeries, atopic disposition and epigenetic factors may all contribute to this response. Patients with SB seem exceptionally capable of mounting an IgE response to latex proteins, with subjects undergoing surgery in a prior year having a 68% prevalence of NRL sensitization. Alarmingly, one of every eight patients with SB in one hospital, prior to the use of latex avoidance precautions in the operating room, developed systemic allergic reactions during anesthesia, representing a 500-fold higher rate of anaphylaxis than expected during general anesthesia and surgery. Two case series reported anaphylaxis occurring 40 to 220 minutes into surgery with direct mucosal glove contact, while another series noted anaphylaxis within 30 minutes of the induction of anesthesia. One case series compared differences between SB patients who developed intraoperative anaphylaxis and those who did not, while a second case series compared SB to atopic and nonatopic control groups. SB groups developed LA more frequently than atopic subjects (40.5% vs 11.4%) and at > 20 times the rate of healthy controls (40.5% vs 1.9%). Other case series without control groups suggest that atopy, > 5 surgeries, high antilatex IgE (> 3.5 kU/L), and skin test reactivity to foods (kiwi, pear or tomato) are important factors.
Recently, sensitization to latex in SB patients has declined significantly (5% vs 55%) with the introduction of latex safe conditions. Therefore, latex avoidance measures have been extremely successful in reducing sensitization and allergy in patients with SB.
Latex Allergy in Patients with Urologic or Neurologic Defects
In addition to patients with SB, patients with cloacal anomalies, chronic renal failure or bladder anomalies are at risk for latex anaphylaxis. Two studies published in the same year reached opposite conclusions about the risk of LA or sensitization in patients with spinal cord injuries. Konz et al performed a cross-sectional study of 36 SB patients, 50 patients with spinal cord injury, 10 patients with cerebrovascular accidents and 10 healthy control patients. While 72% of the SB subjects had clinical histories and confirming tests compatible with LA, no positive histories were identified in either of the other two groups with neural disease. Antilatex IgE was noted in 4% of spinal cord-injured patients despite no history of latex-induced reactions. Vogel et al reported only 2/67 spinal cord-injured patients with a clinical history of latex reactions, but 10 (15%) with evidence of latex sensitization, a historically higher rate than the general population. Regardless, there appear to be significant differences between neurologically injured patients and patients with SB.
Healthcare Workers
The clinical manifestations of healthcare workers’ (HCW) disease are quite different from other groups. While most children with LA do not have irritant dermatitis or contact dermatitis, the majority of latex-allergic healthcare workers show evidence of dermatitis, with the irritant type being the most prevalent. Hand symptoms have been correlated closely with latex sensitization. In fact, HCW with more than two hand symptoms are 11 times more likely to have positive skin prick tests. Dermatitis often heralds the development of IgE-mediated symptoms of urticaria, angioedema, occupational asthma, rhinoconjunctivitis and anaphylaxis, but is not a prerequisite for the development of LA. The prevalence of HCW disease has ranged from 5% to 17% with >50% having latex-induced asthma. Several reasons for LA development in this group include frequent use of latex gloves, manufacturing changes that lead to higher allergen content of gloves, processing changes or manufacturing changes. Airborne antigen exposure has been found to be a significant source of latex sensitization among HCWs. The use of powder-free examination gloves reduces the risk of sensitization 16-fold.
Surgery
Multiple reports suggest that surgical intervention increases LA risk. In addition, children with cerebral palsy, esophageal atresia, gastroschisis and omphalocoele may be at higher risk. Since these diseases are confounded by frequent latex glove use and multiple surgeries, the contribution of each variable is unclear.
Latex Allergy in the General Population
Multiple reports and clinical experience have shown that individuals with no apparent risk factors of exposure, SB, healthcare work or surgery may develop LA. The symptoms in these individuals are usually predicted by the route of exposure: rhinitis, conjunctivitis and asthma occur after inhalation, while anaphylaxis occurs after abdominal mucosa or intravenous exposure. The most dramatic presentations were the first cases of anaphylaxis seen after rectal mucosal surface exposure to latex balloons, glove or condom materials. In the 1980s, air contrast barium enema procedures used a catheter that was inflated to help retain the air and barium in the colon. Rectal manometry with a catheter tipped with a balloon or covered by condom material was common. Case series described severe anaphylaxis, including deaths, associated with these procedures. Only in retrospect were these cases identified as LA, with most occurring in non-healthcare workers, although some were atopic or had had prior surgery. One particular catheter was implicated in barium enema-induced anaphylaxis (E-Z-Em Company) with as many as 148 episodes of anaphylaxis and 9 deaths. Most of these subjects were not from identified risk groups, raising significant concern about the risk in the general population.
Two large studies showed a prevalence of LA in children of 0.7% to 1.1%, well below the reported prevalence in children with SB and healthcare workers. These observations were contrasted by serologic studies from blood donors, non-healthcare workers, and consecutive emergency department patients that demonstrated antilatex IgE presence in the blood of 4% to 8% of these subjects. Whether this represents a predictable rate of false-positive tests in low-prevalence populations, or accurate results in subjects at risk of latex-allergic reactions following future exposures, is unclear.
Fruit Allergy and Concurrent Latex Allergy
Clinical observations raised the question of pan-allergens and clinical cross-reactivity of fruit and latex. Multiple clinical reactions to bananas, kiwi, avocado, mango, chestnut, papaya and stone fruits such as cherries or peaches have been published in known latex-allergic subjects. In addition, individuals with primary food allergy have had clinical reactions to latex, but much less frequently than might have been expected from the initial frequency of in vitro allergen cross-reactions. This syndrome has been termed the ‘latex-fruit syndrome’ and was extended to the ‘latex-vegetable syndrome’ when cross-reactions were found between a number of vegetables and latex proteins.
Over 50% of individuals with LA may have clinical reactions to fruit ( Table 56-1 ) due to specific cross-reacting allergens. A common tertiary structure of Hev b 6 (hevein) is shared with two banana proteins, avocado and chestnut. Kiwi has significant homology with Hev b 5. While Hev b 7 has structural similarity to patatin from potato, the clinical relevance may be minor. Hev b 8, a profilin, may cross-react with other plant profilins. Hev b 2 is a pathogen-related protein β-1,3-glucan with cross-reactive homology. Hev b 12 is a lipid transfer protein that has been a common protein type to cause clinical reactions to vegetables and fruit in patients who are pollen reactive.
| Primary Food Allergies Causing Latex Reactions | Clinical Cross-Reacting Foods |
|---|---|
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| FOODS WITH IN VITRO CROSS-REACTIVITY BUT UNCOMMON IN VIVO SYMPTOMS IN LATEX ALLERGY | |
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Latex-fruit syndrome was investigated from the perspective of whether individuals with primary fruit allergy have concurrent LA. Of 57 subjects with primary fruit allergy, 49 (86%) had IgE reactivity in serum and/or skin test. Only 6 (12.2%) reported prior symptoms from latex exposure; however, fruit allergy symptoms preceded these.
The concern of hidden food allergen has been brought to light by multiple reports of transfer of allergen to food (a bagel, cheese, lettuce and doughnut) by handlers wearing latex gloves.
Diabetes and Latex Allergy
The development of LA in patients with type 1 diabetes was unexpected. In 1995, anaphylaxis was reported during surgery and was presumed to be from latex contamination of injectable medication drawn from a latex rubber-topped bottle during anesthesia. A series of case reports and a prevalence study investigating the risk of LA in individuals who require insulin injection were subsequently reported. Local allergic reactions at the site of insulin injection occurred after the needle used to draw up the insulin was inserted through a rubber-stopped bottle containing latex. Removal of the latex top and subsequent drawing up of the insulin into the syringe did not produce allergic reactions in any of these cases. These observations suggest that the latex stopper does not contaminate the medication vial, but does contaminate the needle during insertion. One report in the pharmacy literature found that multiple needle punctures of multidose vials did not elute allergen in sufficient quantity to result in allergic reactions. Serum samples from children with type 1 diabetes demonstrated that latex-specific IgE was detectable only in atopic diabetic children, but was not more prevalent than in nondiabetic atopic subjects. In this study, 7/112 (6%) of subjects had IgE antibody and were all derived from the atopic group of 42 subjects (17%). In contrast, none (0/70) of the nonatopic subjects had antilatex IgE antibody detected in the serum.
Latex Production
Produced by nearly 2,000 lactiferous plants and trees, the polymer cis-1,4 polyisoprene has been exploited for broad commercial use from the tree Hevea brasiliensis and recently from other lactiferous plants such as guayule latex. Charles Goodyear’s critical discovery of sulfur heat vulcanization, a method that effectively cross-links the rubber polyisoprene while reducing the tackiness and sensitivity to temperature change of latex, catapulted NRL use into one of the most important industries in the world. Worldwide latex consumption has increased dramatically, with nearly 6 million tons/year produced in 1995 and over 21 million tons/year utilized, mainly due to China’s spectacular economic growth. Latex demand for NRL in Japan, Europe and North America has remained stable. Whether a new epidemic of LA will emerge in China is unknown.
Rubber hydrocarbon (cis-1,4 polyisoprene) makes up the majority of the latex suspension while protein, carbohydrate, lipids, inorganic constituents and amino acids are a minor percentage of the mix. Despite proteins being a minor portion of NRL, the retention of these proteins in finished products is the cause of IgE-mediated reactions in humans. During the manufacturing of latex products, over 200 different chemicals have been utilized and fall into broad categories of accelerators of cross-linking, antioxidants, antiozonates, biocides, colorants, epoxies and plasticizers. It is the accelerator class of chemicals, including thiurams, thiazoles and carbamates, that most frequently causes type IV cell-mediated contact dermatitis of the skin from latex. Synthetic rubber materials and alternative medical glove materials may retain these same chemicals, resulting in contact dermatitis. Gloves made of polyvinyl chloride, styrene butadiene rubber or Tactylon ® (styrene ethylene butylene styrene) may not contain these accelerators.
Latex Collection
NRL flows through a circulation system of the tree and is collected when bark is shaved off just short of the cambium layer. Latex is treated with a stabilizer such as sodium sulfite, formaldehyde, ammonia (0.05–0.2%) or ammonia with a 1 : 1 mixture of zinc oxide and tetramethylthiuram disulfide (TMTD). A number of chemicals can be used to enhance the yield of latex. Such chemicals (e.g. 2-chloroethylphosphonic acid or ethepon) may enhance the quantity and type of allergenic proteins. Demand to produce more medical-grade latex with the advent of standard precautions in the 1980s resulted in more frequent tapping of trees and reduced storage time of latex. As many allergenic proteins are defense proteins, their production may have been enhanced.
Latex Product Manufacturing
Approximately 88% or more of the world’s harvested latex is acid coagulated, prepared as dry raw rubber in sheets or crumbs of technically specified rubber and dried at 60°C or higher temperature. Allergic IgE reactions have been rarely reported from this type of rubber but contact reactions may be seen.
The other 10% to 12% of NRL is produced in a latex concentrate by centrifugation or creaming to make products such as gloves and condoms from a dipping method. Most latex is concentrated to 60% isoprene, stabilized in either a high concentration of ammonia (0.7%) or low ammonia (0.2%) with TMTD and zinc oxide and stored in tanks for at least 2 to 3 weeks and often longer before being shipped to manufacturers. After shipping, the latex is prepared by the manufacturer, with proprietary methods, for dipping of forms (e.g. gloves) coated with a surface coagulant into latex slurry. The latex adheres to the form, is wet leached, heat vulcanized and dried, and various methods are used to prevent the latex products from sticking to each other. In the past, the most common agent used to prevent sticking was highly cross-linked cornstarch powder or talc. Given its ability to act as a carrier of latex allergen, cornstarch powder has fallen out of favor. Talc was found to induce granulomatous inflammation and decrease wound healing and has mostly been abandoned in medical-grade gloves. Halogenation or surface coating with a synthetic polymer has been useful in replacing donning powder.
Latex Allergens
Field latex varies in its protein content by clonal origin of the rubber plant, climatic factors, soil types, fertilizers and yield enhancers used for the rubber cultivation. Latex-producing trees are susceptible to invasion by a variety of microorganisms, especially fungi, and insects that can injure and kill the tree. NRL contains numerous defense-related proteins and enzymes that are integral in the protection of the plant, biosynthesis of polyisoprene and coagulation of latex, but which cause allergic sensitization and clinical reactions in susceptible hosts. Proteins present in freshly harvested latex are detected in finished latex products, either in their natural configuration or an altered configuration, which may lead to the formation of neo-antigens. Based on their IgE-binding properties, the Allergen Nomenclature Subcommittee of the International Union of Immunological Societies (IUIS) has accepted 13 proteins as latex allergens ( http://www.allergen.org ).
Immunologic Properties
The immunologic properties of individual latex allergens have been evaluated by immune responses in either healthcare workers or patients with SB since those individuals make up the majority of subjects found to have clinical disease. The allergens that the general population reacts to are likely to parallel these current observations ( Table 56-2 ).
| Allergens | Allergen Name | Molecular Weight kDa | Function | Significance as Allergens |
|---|---|---|---|---|
| Hev b 1 | Elongation factor | 14.6 | Rubber biosynthesis | Major |
| Tetramer | 58 | |||
| Hev b 2 | 1,3-glucanase | 34/36 | Defense protein | Major |
| Hev b 3 | Elongation factor | 23 | Rubber biosynthesis | Major |
| Hev b 4 | Microhelix complex | 50–57 | Defense protein | Major |
| Dimer | 100–115 | |||
| Hev b 5 | 16 | Enzyme | Major | |
| Hev b 6.01 | Prohevein | 20 | Defense protein | Major |
| Hev b 6.02 | Hevein | 4.7 | Defense protein | Major |
| Hev b 6.03 | C-terminal hevein | 14 | Defense protein | Major |
| Hev b 7 | Patatin homolog | 42.9 | Defense protein Inhibit rubber biosynthesis | Minor |
| Hev b 8 | Latex profiling | 14 | Structural protein | Minor |
| Hev b 9 | Latex enolase | 51 | Enzyme | Minor |
| Hev b 10 | Mn superoxide dismutase | 26 | Enzyme | Minor |
| Hev b 11 | Class 1 chitinase | 33 | Defense protein | Minor |
| Hev b 12 | Lipid transfer protein | 9.3 | Defense protein | Major |
| Hev b 13 | Latex esterase | 42 | Enzyme | Major |
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