Are You Confident of the Diagnosis?
Allergic contact dermatitis due to rubber can be divided into two main categories: allergy to latex (raw rubber compound) or to chemical accelerators, and antioxidants added to the rubber during processing and manufacturing. Thiurams, mercaptobenzothiazole, thioureas, and carbamates are rubber accelerators known to cause sensitization. An example of a rubber antioxidant is paraphenylenediamine.
What you should be alert for in the history
Diagnosis of latex allergy should be suspected in high-risk populations and in any patients with a history of swelling, erythema, itching, and throat tightness in situations of potential latex exposure. Other potential situations include urticaria/angioedema on the lips when inflating balloons, itching/burning when wearing rubber gloves, adverse reactions to barium enema, dental or gynecologic examinations, or any systemic symptoms associated with latex exposure. It is also important to discuss any food allergies or history of atopy as this increases the risk of developing rubber allergy.
Diagnosis of rubber accelerator allergy is similar in terms of inciting factors, but some important clinical history features include the time course of the physical manifestations in relation to when the rubber exposure occurred and recurrence of symptoms. Generally, the time course would be at least 24-48 hours. Another important consideration in assessing these reactions is that the severity and exposure frequency can vary from patient to patient.
Characteristic findings on physical examination
Latex allergy can physically manifest as erythema, pruritus, hives, and later chronic eczema (Figure 1). If mucosal surfaces are exposed, angioedema can also develop. This is characterized by localized, nonpitting swelling most commonly on lips, face, limbs, and trunk. Other reactions include sneezing, itchy eyes, asthma, throat discomfort, and anaphylaxis.
A delayed type reaction to nonlatex rubber accelerators would, in the acute phase, manifest most commonly as erythema, pruritus, and vesicles in the area of exposure. In the chronic phase, it is characterized by erythema, scaling, fissures, and hyperkeratosis. It is important to note that this eruption usually starts 24 to 48 hours after exposure, but can present from anywhere within 8 hours to 5 days.
Expected results of diagnostic studies
Radioallergosorbent (RAST) immunoassay is an in vitro test that quantifies latex-specific IgE antibodies. The three serologic assays that the FDA has approved include ImmunoCAP (Pharmacia-Upjohn, Uppsala, Sweden), AlaSTAT FEIA (Diagnostic Products Corp, Los Angeles, CA) and HYTEC EIA (Hycor Biomedical, Inc., Farden Grove, CA). Disadvantages of this type of testing include increased cost, lower sensitivity, delay in receiving results and lower accessibility.
It is important to note that the IgE levels may not correlate with symptoms, as they are a marker of allergen exposure. False positive results may occur in patients with a history of atopy; these patients have chronically elevated IgE levels and nonspecific binding of IgE to various allergens. Unlike skin tests, these serologic tests are not influenced by concurrent treatment.
In addition to these aforementioned enzyme immunoassays (EIAs), radioimmunoassays are more specific and expensive tests that involve using radioisotopes to label the antigens within the serum. A recent study demonstrated that sensitivity for EIAs was 95% and sensitivity for RIAs was 100%.
Lymphocyte transformation tests are used to measure the proliferation of T cells when the patient is exposed to certain allergens or sensitizers, such as latex or rubber accelerators. As a result, these tests are usually positive in any typical IgE mediated situation. Ebo et al, found that although this test did confirm significant lymphocyte proliferation when the patients were stimulated with natural rubber latex, it displayed a low sensitivity for specifically detecting latex allergy.
Skin prick testing involves in-vivo tests that serve as the gold standard for diagnosing latex allergy. These tests are cheaper, more sensitive and provide results faster than in vitro serological assays. This test involves scratching/pricking drops of liquid containing latex protein into the skin.
Controls for this test involve the use of saline and histamine. A positive result for the test is indicated by an erythematous, pruritic wheal developing within approximately 15 minutes. Due to the fact that uncharacterized eluates from the rubber vary in quality/allergenic potential and potentially carry a risk of an anaphylactic reaction, the FDA has not approved any reagents for use in the United States.
The Glove-use test involves placing rubber products on one finger at first and then progressing to the entire hand to look for a reaction. A nonlatex finger cot of glove is used on the opposite hand as a control. The main problem with this test is that there is not a standard testing material and there is potential for triggering a systemic reaction.
Patch testing (Figure 2) can help diagnose an allergy to rubber accelerators or antioxidants (delayed type hypersensitivity). Allergen samples are applied to intact skin and then covered with a dressing. Observation for skin reaction occurs at 48 and 96 hours. One such allergen set is the Thin-layer Rapid Use Epicutaneous (T.R.U.E®) test. In addition, other suppliers of more comprehensive allergens for patch testing include Dormer-Chemotechnique® and Allergeaze®.
An important differential to consider is irritant contact dermatitis due to rubber gloves. This is a nonimmunologic reaction on the skin. It is characterized by dry, fissuring patches on the exposed areas most likely due to occlusion, mechanical irritation from the glove or from the alkaline pH present in most powdered gloves. The powder can lower the skin’s hydration levels, leading to dryness. Other important diagnoses to consider include pre-existing hand eczema, irritation from other detergents/soaps, and other occupational exposures.
Who is at Risk for Developing this Disease?
The incidence of latex allergy is 1-2% in the general population. Patients with spina bifida/ myelomeningocele are at the highest risk for developing latex allergy; statistics suggest the prevalence of latex allergy in this population ranges from 20-67%. This is due to the repeated exposure of their mucous membranes to latex during various surgeries and procedures.
The second population most at risk for developing latex allergy is healthcare workers, particularly those that work in the operating room, laboratories, or ambulances. Direct exposure to latex on a regular basis and length of employment in the healthcare industry are all positively correlated with higher risk of latex allergy. Other populations with comparable rates of sensitization are housekeepers, cleaners, and latex doll-manufacturing personnel. A common exposure for many of these workers is the use of rubber gloves. In the 1980s and 1990s there was an increase in the prevalence of NLR sensitization. Fortunately, NLR sensitization rates are decreasing which is thought to be related to the increase use of non-latex gloves.
Another important risk factor to consider is a history of atopy. Latex allergy is four times more common in atopics than non-atopics. A history of hand dermatitis increases the risk of latex allergy due to enhanced penetration of the latex protein through fissures on the skin.
Patients with certain food allergies may also predispose patients to develop of a latex allergy. These foods include avocado, kiwi, bananas, apples, tomatoes, watermelon, peach and chestnuts. This is most likely due to cross-reactivity of epitopes between the latex protein and the fruit protein.
Rubber accelerator or antioxidant allergy
Patients at risk include divers (due to wetsuits), food handlers, healthcare workers and hairdressers.
What is the Cause of the Disease?
Rubber allergy due to latex sensitivity usually results in an immediate Type I hypersensitivity reaction. This is an IgE-mediated reaction to the latex proteins that can manifest as a spectrum of symptoms from contact urticaria to anaphylaxis. Even exposure to latex at low levels can cause allergic reactions in some sensitized individuals.
Rubber allergy due to chemical accelerators and antioxidants most often induces a delayed Type IV hypersensitivity response. This is a cell mediated reaction that develops at least 24 to 48 hours after allergen exposure. Thiurams are the most common accelerator within natural rubber latex gloves that induces a Type IV hypersensitivity reaction. In addition to thiurams, dithiocarbamates and mercaptobenzothiazoles are known allergens. Guanidine-type accelerators including triphenylguanidine and 1,3-diphenylguanide have also been isolated as culprit allergens. In addition, glove powders can take up allergens, such as epichlorohydrin, which can contribute to type IV hypersensitivity reactions.
Aerosolized cornstarch from the use of powdered gloves can also potentially be inhaled to cause an adverse reaction; the cornstarch strongly binds to potential latex allergens. Another consideration is that oil-based hand lotions can cause accelerated glove breakdown and solubilization of latex protein, which increases the risk of allergy with cutaneous exposure.
Systemic Implications and Complications
Systemic disorders associated with the development of rubber allergy include patients with a history of atopy, children with spina bifida, children with urologic abnormalities, and patients with a history of multiple surgeries. It is important to recognize the higher incidence of latex allergy with these coexisting problems to avoid potentially fatal anaphylaxis reactions.
Treatment options are summarized in Table I.
|Natural Rubber Latex Allergy||Allergy to Rubber Accelerators/ Antioxidants|
|Treatment for exposure: epinephrine pen, antihistamines, or prednisoneAvoidanceSubstitution of non-latex agentsIdentifying problem items within home or workplaceConsider sublingual desensitizationCarry an epinephrine pen for emergenciesMedical alert braceletsBe wary of cross reacting fruits and occult sources of latex exposure||Avoidance:Substitution of suspect productsIdentifying particular allergen and then identifying problem areas within home/workplaceTreatment for exposureAcute:· Topical steroids for limited body surface area· Oral prednisone for generalized reactions. Extend taper for 2.5 to 3 weeks.Chronic:- Topical steroids· Barrier creams· NB-UVB light· Systemic agents- Cyclosporine, Azathioprine or pulse prednisone|
Optimal Therapeutic Approach for this Disease
Treatment of acute reaction
Severe type I hypersensitivity with respiratory distress, swelling within the oral cavity and anaphylaxis requires assessment of ABCs (airway, breathing and circulation) and activation of emergency medical services.
Epinephrine pen. If the patient carries this at all times or if available at home/school/work, it can be essential in providing treatment in an acute emergency.
Antihistamines should be used after stabilization of patient in acute emergency. Examples include diphenhydramine 50 mg IV/IM, ranitidine 50 mg IV, epinephrine 0.1-0.5 mg IM and can be repeated after 20 minutes.
Prednisone (125 mg IV/IM) should be used after stabilization of patient in acute emergency.
Treatment of established latex allergy
The primary treatment is avoidance of the allergen. It is essential to identify particular exposure in home/workplace/school. It is especially important to identify common items with latex (such as rubber grip pens) and other environments where exposure could occur (medical setting). The American Latex Allergy Association (www.latexallergyresources.org) website can be accessed for guidance in latex avoidance.
Avoid foods that may cause a cross reaction.
Patients should obtain Medic-Alert identification bracelets and inform healthcare providers and their employers of their diagnoses.
Substitute with non-latex agents. Examples of such agents include nitrile, neoprene, or polyisoprene.
Other options include use of antihistamines or oral corticosteroids (such as prednisone). An important consideration is that the early expression of latex allergy may be masked in patients using these medications for other medical reasons. In addition, these patients should avoid the use of beta blockers as they may decrease the therapeutic response to anaphylaxis treatment. Examples of antihistamines include cetirizine, adult dosing: 10 mg orally daily depending on severity of symptoms; levocetirizine adult dosing: 5 mg orally daily; and fexofenadine adult dosing: 180 mg orally daily. Children 6-11: 30 mg orally twice a day.
Examples of corticosteroids include methylprednisolone 4-48 mg divided four times daily, Medrol Dosepak tapering from 24-0 mg in 7 days and prednisone 5-60 mg/day divided twice a day to four times daily. Topical steroids are useful for localized skin reactions: for hands, use a medium- to high-potency topical steroid. For the face, use a low-potency steroid such as desonide cream 0.05%. Examples of medium-potency corticosteroids include mometasone 0.1% and fluocinolone 0.025%. Examples of high potency topical steroids include betamethasone dipropionate 0.05% or clobetasol 0.05%.
Primarily avoidance. Patient needs to use alternatives rubber products with known allergens and identify occult sources of rubber in home/workplace/school. Be wary of medical environments.
NB-UVB light Systemic agents such as cyclosporine, azathioprine and mycophenolate mofetil. Oral prednisone 0.5-1 mg/kg/day tapered over 2-3 weeks is useful in systemic treatment of chronic reaction. Consider sublingual desensitization therapy.
It is important for patients to realize that because there is no cure for latex allergy, the most effective approach is avoidance and substitution. Realistically, complete avoidance of rubber products is very difficult, but minimizing exposure is extremely important.
While desensitization for latex allergy is frequently performed, several clinical trials have evaluated sublingual and subcutaneous immunotherapy protocols. Sublingual immunotherapy had a better safety profile.
Secondary prevention involves established latex allergic patients. These patients should carry nonlatex products at all times, particularly if they are involved in the healthcare field. In addition, these patients should have a list of latex-safe products, cross reacting foods and other less common sources of latex exposure with them at all times. Medical alert bracelets and epinephrine syringes are also vital for emergency situations. It is also essential for employers to get involved to periodically screen workers with educational programs and to accommodate patients with latex allergies.
Physicians can also recommend other educational material to help educate patients: for example, the American Latex Allergy Association provides educational material and support for patients with rubber allergy.
For patients with delayed-type hypersensitivity reactions to rubber accelerators or antioxidants, primary prevention involves avoidance. Secondary prevention involves barrier creams and use of rubber-free substitute products (Table II).
|Rubber grip pens|
|Grips on exercise equipment|
|Mouse/computer wrist pads|
|Shower caps/surgical bonnets|
Prevention can be divided into two main categories: primary and secondary. Primary prevention involves nonsensitized individuals in high-risk groups whose main goal is to avoid contact with natural rubber latex products. Other important actions include avoidance of oil-based hand creams that break down rubber leading to faster sensitization, washing hands after use of rubber products, and treating concomitant hand eczema.
Unusual Clinical Scenarios to Consider in Patient Management
For latex allergies, patients must be educated to remind all staff at each medical visit that they are latex allergic. They must also stay vigilant to reduce iatrogenic latex exposure. Latex allergic patients need to be cautious when they have their cars serviced or houses cleaned to ensure that these service providers do not wear latex gloves.
Allergic contact dermatitis to temporary tattoo’s in which para-phenylenediamine is the cuprit allergen can be complicated by cross-sensitization to rubber accelerators used in production of black rubber.
What is the Evidence?
Taylor, JS, Erkek, E.. “Latex allergy: diagnosis and management”. Dermatol Ther. vol. 17. 2004. pp. 289-301. (This article provides an update about the pathogenesis, epidemiology, risk factors, clinical manifestations, and various diagnostic and treatment options for latex allergy. It also provides the classification system for the different types of glove reactions.)
Pollart, SM, Warniment, C, Mori, T.. “Latex allergy”. Am Fam Physician. vol. 80. 2009. pp. 1413-8. (This article provides an overview of the incidence/prevalence, etiology, diagnostic and management options for latex allergy. Skin prick testing is stated to be the most sensitive test for diagnosing type I reactions although the United States FDA has not approved any extracts. The most sensitive test for diagnosing type IV hypersensitivity reactions is patch testing where the reaction to various allergens is checked at 30 minutes, 24 hours and 48 hours.)
Kelsey, L, Herron-Rice, L, Anderson, P, Friis, CM, Gauthier, P, Gondzur, N. “Guideline for preventing sensitivity and allergic reactions to natural rubber latex in the workplace”. Gastroenterol Nurs. vol. 31. 2008. pp. 239-46. (This article consists of guidelines about handling latex allergy in the workplace. It offers information about epidemiology, risk factors, diagnostic and treatment options for latex allergy. It particularly focuses on handling latex allergy in the healthcare environment. A full list of protective steps for healthcare workers is also provided.)
Kim, KT, Hussain, H.. “Prevalence of food allergy in 137 latex-allergic patients”. Allergy Asthma Proc. vol. 20. 1999. pp. 957(The authors of this study obtained detailed food allergy history from 137 patients with a history of type I latex allergy. A food allergy was diagnosed based on a convincing history of IgE-mediated symptoms that occurred within 1 hour of ingestion. Foods responsible for these reactions include banana, avocado, shellfish, fish, kiwi, tomato, watermelon, peach, carrot, apple, chestnut, cherry, coconut, apricot, and strawberry.)
Agarwal, S, Gawkrodger, DJ.. “Latex allergy: a health care problem of epidemic proportions”. Eur J Dermatol.. vol. 12. 2002. pp. 3115(This article provides an overview about the various routes of latex allergen exposure, clinical manifestations, diagnostic options, prevention and treatment of latex allergy. The authors state that the most effective preventive measure for healthcare staff is the presence of good quality powder-free latex gloves.)
Alemohammad, MM, Malki, J, Foley, TJ.. “Detection of IgE antibodies to latex allergens in human serum”. Contact Dermatitis. vol. 32. 1995. pp. 298-302. (The purpose of this study was to develop an in vitro test system to detect the presence of IgE antibodies to latex. The authors of this study developed a serologic test for the qualitative determination of specific IgE antibodies to latex. When comparing the performance of the authors’ test using their latex material with that of the latex material obtained from the FDA, it was found that the specificity and sensitivity of the tested assay method approached 100%.)
Ebo, DG, Stevens, WJ, Bridts, CH, De Clerck, LS.. “Latex-specific IgE, skin testing, and lymphocyte transformation to latex in latex allergy”. J Allergy Clin Immunol. vol. 100. 1997. pp. 618-23. (The purpose of this study was to determine the discriminative value to latex-specific IgE tests, latex skin tests and lymphocyte transformation tests (LTTs) to latex and to evaluate the recommended positive cutoff (0.35 kU/L) of two in vitro latex IgE tests. For the latex lymphocyte transformation test, a positive reaction was defined as a value greater than the 95th percentile in the nonatopic control group. The results showed that the latex skin tests and the latex-specific IgE tests are sensitive and specific methods for confirming the presence of latex allergy. The LTT was determined to be insensitive for the diagnosis of latex allergy.)
Nettis, E, Colanardi, MC, Soccio, AL. “Double-blind, placebo controlled study of sublingual immunotherapy in patients with latex-induced urticaria: a 12-month study”. Br J Dermatol. vol. 156. 2007. pp. 674-81. (This double-blind, placebo-controlled study was conducted to determine the efficacy of sublingual immunotherapy (SLIT) with latex. Results revealed that 12 months of SLIT improved the symptoms score and reduced the medications score for the patients who were treated. The latex-specific IgE levels increased slightly in the SLIT group, and skin sensitization was reduced at the end of the trial in all the patients treated with SLIT. The therapy was not complicated by any severe adverse reactions.)
Hald, M, Menne, T, Johansen, JD, Zachariae, C.. “Severe occupational contact dermatitis caused by black rubber as a consequence of p-phenylenediamine allergy resulting from a temporary henna tattoo”. Contact Dermatitis.. vol. 68. 2013. pp. 377-379.
Dahlin, J, Bergendorff, O, Vindenes, HK, Hindsen, M, Svedman, C.. “Triphenylguanidine, a new (old?) rubber accelerator detected in surgical gloves that may cause allergic contact dermatitis”. Contact Dermatitis. vol. 71. 2014. pp. 242-246.
Blaabjerg, MB, Andersen, KE, Bindslev-Jensen, C, Mort, CG.. “Decrease in the rate of sensitization and clinical allergy to natural rubber latex”. Contact Dermatitis. vol. 73. 2015. pp. 21-28. (This study sought to determine if the prevalence of NRL sensitization/clinical NRL allergy changed from 2002-2013. The authors examined in their study population at the Department of Dermatology and Allergy Centre, Odense University Hospital (OUH), the rates of positive NRL prick test reactions (NRL sensitization), clinical NRL allergy (positive NRL prick test reactions and a clinical history of NRL allergy) and positive prick test reactions to birch pollen in three defined time periods (2002-2005, 2006-2009, and 2010-2013). The authors found that the number of patients sensitized to NRL decreased in the periods studied, from 6.1% in 2002-2005, to 1.9% in 2006-2009 and then to 1.2% in 2010-2013 (p<0.0001).
Warburton, KL, Bauer, A, Chowdhury, MM, Cooper, S. “ESSCA results with the baseline series, 2009-2012: rubber allergens”. Contact Dermatitis. vol. 73. 2015 Nov. pp. 305-12. (Analysis of data on rubber allergen sensitivity rates by the European Surveillance System on Contact Allergies (ESSCA) network from 2009 and 2012. Allergy to thiuram mix decreased and carba mix has increased. Sensitization rates for the remainder of the rubber allergens have stayed relatively stable.)
Nettis, E, Delle Donne, P, Di Leo, E, Fantini, P. “Latex immunotherapy: state of the art”. Ann Allergy Asthma Immunol.. vol. 109. 2012 Sep. pp. 160-5. (This article is a review on recent clinical trials utilizing either sublingual or subcutaneous immunotherapy for latex desensitization.)
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