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PREVALENCE OF LATEX ALLERGY
Correspondence PREVALENCE OF LATEX ALLERGY To the Editor: I am writing in response to Dr. Yeang’s article “Prevalence of latex allergy may be vastly overestimated when determined by in vitro assays.”1 Positive predictive value (PPV) is dependent on both test specificity and the prevalence of the condition in the population. As prevalence declines, so does the PPV; therefore, the author is correct in stating that the prevalence may be overestimated when the true prevalence is low. Alternatively, imperfect sensitivity leads to underestimates of prevalence. However, this is also true when determining the prevalence by skin prick testing (SPT). SPT is not 100% sensitive and specific. SPTs can be falsely negative or positive.2 The Allergy Report states that some patients who have a strong history of systemic reactions may have negative skin tests for IgE to suspected allergens3; clinical symptoms strongly suggestive of latex allergy can often not be confirmed with SPT.4 Up to 60% of positive SPTs to foods and up to 50% of positive SPTs to latex do not reflect symptomatic allergy.5,6 There is no gold standard for the diagnosis of allergy2; the closest thing is probably challenge testing. However, sensitivity and specificity of available diagnostic testing methods are determined by comparison to clinical history in the case of SPT or clinical history and/or SPT in the case of serologic testing. This has led to reporting of a wide variety of sensitivities and specificities of both SPT and in vitro testing. My review of the literature on the prevalence of latex sensitization has not revealed major differences between studies using SPT or in vitro tests. A wide range of prevalence rates are reported for both methods. Rates in healthcare workers range from 2.9% to
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22% when determined by SPT, and 2.9% to 12% when determined by in vitro methods. Rates in persons without occupational exposure to latex have rates ranging from 0.12% to 9% when determined by SPT, and 2% to 12% when using in vitro testing. In conclusion, it is clear that both SPT and in vitro tests have less than perfect sensitivity and specificity. However, exclusive emphasis on specificity without regard for sensitivity adds little to further understanding of the prevalence of latex allergy. ELENA H. PAGE, MD, MPH Hazard Evaluations and Technical Assistance Branch National Institute for Occupational Safety and Health Cincinnati, Ohio REFERENCES 1. Yeang HY. Prevalence of latex allergy may be vastly overestimated when determined by in vitro assays. Ann Allergy Asthma Immunol 2000;84: 628 – 632. 2. Ownby DR, Magera B, Williams PB. A blinded, multi-center evaluation of two commercial in vitro tests for latexspecific IgE antibodies. Ann Allergy Asthma Immunol 2000;84:193–196. 3. American Academy of Allergy, Asthma, and Immunology. The Allergy Report. Volume 1. Diagnostic Testing. 2000:31– 40. 4. Smedley J, Jury A, Bendall H, et al. Prevalence and risk factors for latex allergy: a cross sectional study in a United Kingdom hospital. Occup Environ Med 1999;56:833– 836. 5. Sampson HA. Food allergy. JAMA 1997;278:1888 –1894. 6. Arellano R, Bradley J, Sussman G. Prevalence of latex sensitization among hospital physicians occupationally exposed to latex gloves. Anesthesiology 1992;77:905–908.
Response: Dr. Page feels that I have placed undue emphasis on test specificity while neglecting test sensitivity in interpreting
latex allergy prevalence estimated from in vitro assays. It is true that, just as imperfect specificity of an assay can inflate the apparent prevalence, imperfect sensitivity can also lead to a decreased estimate. However, in the low-prevalence situation that I draw attention to, the potential error in underestimation generated by imperfect sensitivity pales in comparison to the potential error in overestimation that can result from imperfect specificity. An example here will serve to illustrate the point. To begin with, let us average up the test sensitivities and specificities claimed by manufacturers of the three Food and Drug Administration-endorsed commercial latex diagnostics to derive representative sensitivity and specificity figures. We arrive at 84% for sensitivity and 92% for specificity. Let us say that the true prevalence of latex allergy in the general population were 1 in 1,000, or 0.1% (ie, of an order reported by some research groups1,2). According to Equation 1 in my paper, a hypothetical assay with 84% sensitivity and perfect specificity would give a prevalence estimate of 0.084%, which is approximately 5/6 by proportion of the true prevalence. Thus, the imperfect sensitivity alone does not place the prevalence estimate outside the ballpark. In contrast, an assay with perfect sensitivity and 92% specificity would give an estimate of 8.092%, representing a massive 80fold inflation. The figure hardly shifts although both assay sensitivity and specificity were imperfect. Thus, an assay with 84% sensitivity and 92% specificity gives a prevalence estimate of 8.076%. It can be seen from this that the influence of imperfect sensitivity is negligible where the true prevalence is very low, and the overwhelming weight of the error comes from the overestimate that has resulted from imperfect test specificity. This example underscores how imperfect test speci-
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
ficity can greatly inflate the apparent prevalence of latex allergy and the fact that prevalence estimated from serologic assays alone may have little bearing to the true figure. The foregoing refers to assays with test sensitivities and specificities typical of the assays that are commercially available. Of course, if the positive/ negative threshold of the assay readings were pushed upwards to make the assay much more stringent (and increase test specificity at the expense of sensitivity as a result), the impact of low test sensitivity might then emerge. Dr. Page also asserts that skin prick tests for latex allergy are not beyond reproach, notwithstanding their broad acceptance. Although some researchers actually define latex allergy by the skin prick test result, I agree that they are not infallible. There can be many reasons for this, one of which is the choice of the test reagent. In the case of skin prick tests for latex allergy, the allergen source is commonly natural rubber latex. This seems a logical choice, except for one small detail. Pa-
VOLUME 87, AUGUST, 2001
tients in Europe and the United States, where most latex allergy cases are reported, have in all probability never come into contact with rubber tree latex all their lives. What they are likely to encounter frequently are latex products. The common belief is, of course, that whatever allergenic proteins that are present in latex products must also be present in the latex preparation used in the skin test. This is probably true as a rule, but the matter deserves thought. Only a small proportion of latex proteins are residual in finished products, such as gloves. Is the composition of latex allergens in gloves comparable with that in whole latex? How about the relative proportions of the different latex allergens? There are now eleven officially recognized allergens. Are they the same in gloves as in latex? Are certain proteins preferentially retained on the finished product? Would a glove user be more likely to be exposed to a higher level of a particular allergen than he would be to whole latex? Hence, are some proteins present in gloves at levels high enough
to induce an allergic reaction, yet might these same proteins be below the level of sensitivity in latex, and vice versa? Do novel epitopes arise in the course of manufacturing the product? Using glove extracts in place of latex preparations does not resolve all the issues because different brands of gloves are variable in the relative content and composition of the individual latex allergens. HOONG-YEET YEANG, PhD Rubber Research Institute of Malaysia Malaysian Rubber Board Kuala Lumpur, Malaysia REFERENCES 1. Turjanmaa K, Alenius H, Ma¨kinenKiljunen S, et al. Natural rubber latex allergy. Allergy 1996;51:593– 602. 2. Moneret-Vautrin DA, Beaudouin E, Widmer S, et al. Prospective study of risk factors in natural rubber latex hypersensitivity. J Allergy Clin Immunol 1993;92:668 – 677.
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22% when determined by SPT, and 2.9% to 12% when determined by in vitro methods. Rates in persons without occupational exposure to latex have rates ranging from 0.12% to 9% when determined by SPT, and 2% to 12% when using in vitro testing. In conclusion, it is clear that both SPT and in vitro tests have less than perfect sensitivity and specificity. However, exclusive emphasis on specificity without regard for sensitivity adds little to further understanding of the prevalence of latex allergy. ELENA H. PAGE, MD, MPH Hazard Evaluations and Technical Assistance Branch National Institute for Occupational Safety and Health Cincinnati, Ohio REFERENCES 1. Yeang HY. Prevalence of latex allergy may be vastly overestimated when determined by in vitro assays. Ann Allergy Asthma Immunol 2000;84: 628 – 632. 2. Ownby DR, Magera B, Williams PB. A blinded, multi-center evaluation of two commercial in vitro tests for latexspecific IgE antibodies. Ann Allergy Asthma Immunol 2000;84:193–196. 3. American Academy of Allergy, Asthma, and Immunology. The Allergy Report. Volume 1. Diagnostic Testing. 2000:31– 40. 4. Smedley J, Jury A, Bendall H, et al. Prevalence and risk factors for latex allergy: a cross sectional study in a United Kingdom hospital. Occup Environ Med 1999;56:833– 836. 5. Sampson HA. Food allergy. JAMA 1997;278:1888 –1894. 6. Arellano R, Bradley J, Sussman G. Prevalence of latex sensitization among hospital physicians occupationally exposed to latex gloves. Anesthesiology 1992;77:905–908.
Response: Dr. Page feels that I have placed undue emphasis on test specificity while neglecting test sensitivity in interpreting
latex allergy prevalence estimated from in vitro assays. It is true that, just as imperfect specificity of an assay can inflate the apparent prevalence, imperfect sensitivity can also lead to a decreased estimate. However, in the low-prevalence situation that I draw attention to, the potential error in underestimation generated by imperfect sensitivity pales in comparison to the potential error in overestimation that can result from imperfect specificity. An example here will serve to illustrate the point. To begin with, let us average up the test sensitivities and specificities claimed by manufacturers of the three Food and Drug Administration-endorsed commercial latex diagnostics to derive representative sensitivity and specificity figures. We arrive at 84% for sensitivity and 92% for specificity. Let us say that the true prevalence of latex allergy in the general population were 1 in 1,000, or 0.1% (ie, of an order reported by some research groups1,2). According to Equation 1 in my paper, a hypothetical assay with 84% sensitivity and perfect specificity would give a prevalence estimate of 0.084%, which is approximately 5/6 by proportion of the true prevalence. Thus, the imperfect sensitivity alone does not place the prevalence estimate outside the ballpark. In contrast, an assay with perfect sensitivity and 92% specificity would give an estimate of 8.092%, representing a massive 80fold inflation. The figure hardly shifts although both assay sensitivity and specificity were imperfect. Thus, an assay with 84% sensitivity and 92% specificity gives a prevalence estimate of 8.076%. It can be seen from this that the influence of imperfect sensitivity is negligible where the true prevalence is very low, and the overwhelming weight of the error comes from the overestimate that has resulted from imperfect test specificity. This example underscores how imperfect test speci-
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
ficity can greatly inflate the apparent prevalence of latex allergy and the fact that prevalence estimated from serologic assays alone may have little bearing to the true figure. The foregoing refers to assays with test sensitivities and specificities typical of the assays that are commercially available. Of course, if the positive/ negative threshold of the assay readings were pushed upwards to make the assay much more stringent (and increase test specificity at the expense of sensitivity as a result), the impact of low test sensitivity might then emerge. Dr. Page also asserts that skin prick tests for latex allergy are not beyond reproach, notwithstanding their broad acceptance. Although some researchers actually define latex allergy by the skin prick test result, I agree that they are not infallible. There can be many reasons for this, one of which is the choice of the test reagent. In the case of skin prick tests for latex allergy, the allergen source is commonly natural rubber latex. This seems a logical choice, except for one small detail. Pa-
VOLUME 87, AUGUST, 2001
tients in Europe and the United States, where most latex allergy cases are reported, have in all probability never come into contact with rubber tree latex all their lives. What they are likely to encounter frequently are latex products. The common belief is, of course, that whatever allergenic proteins that are present in latex products must also be present in the latex preparation used in the skin test. This is probably true as a rule, but the matter deserves thought. Only a small proportion of latex proteins are residual in finished products, such as gloves. Is the composition of latex allergens in gloves comparable with that in whole latex? How about the relative proportions of the different latex allergens? There are now eleven officially recognized allergens. Are they the same in gloves as in latex? Are certain proteins preferentially retained on the finished product? Would a glove user be more likely to be exposed to a higher level of a particular allergen than he would be to whole latex? Hence, are some proteins present in gloves at levels high enough
to induce an allergic reaction, yet might these same proteins be below the level of sensitivity in latex, and vice versa? Do novel epitopes arise in the course of manufacturing the product? Using glove extracts in place of latex preparations does not resolve all the issues because different brands of gloves are variable in the relative content and composition of the individual latex allergens. HOONG-YEET YEANG, PhD Rubber Research Institute of Malaysia Malaysian Rubber Board Kuala Lumpur, Malaysia REFERENCES 1. Turjanmaa K, Alenius H, Ma¨kinenKiljunen S, et al. Natural rubber latex allergy. Allergy 1996;51:593– 602. 2. Moneret-Vautrin DA, Beaudouin E, Widmer S, et al. Prospective study of risk factors in natural rubber latex hypersensitivity. J Allergy Clin Immunol 1993;92:668 – 677.
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