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Positivity rates of in vitro inhalant/respiratory and food allergy tests in the northern midwestern United States.

Abstract

Rates of allergy-test positivity vary by country and by regions within countries. Several studies have looked at allergy test results to determine the most common allergens. Many of these studies have been based on surveys or on studies of small numbers of tests. Positivity rates for allergy tests are poorly defined in the northern midwestern region of the United States. We conducted a study to identify the rates of positive allergy tests for both inhalant/respiratory allergens and food allergens in the upper Midwest. We extracted from our laboratory database the results of all test samples sent for one of eight allergen panels that had been analyzed between Sept. 1, 2014, and Sept. 1, 2015. All testing was performed at The Cleveland Clinic with the Phadia ImtnunoCAP system. The percentage of positive tests, the distribution of the most frequently positive tests, and the class of in vitro responses were identified. A total of 148,628 test results for 63 different allergens were identified. Of the 125,190 tests for inhalant/respiratory allergens, the most frequently positive were dog dander (24% of tests), cat dander (23%), dust mites (23% for both Dermatophagoides pteronyssinus and Dermatophagoides farinae), and June grass (21%). Of the 23,438 food tests, the most frequently positive test results were for milk (18%), peanut (17%), wheat (16%), and egg white (15%). Most of the results fell into classes 1 through 3, although there was still a notable number of very high responses (class 5 and 6). These findings suggest that there is wide variability in the positivity of in vitro allergy tests and that the likelihood of a positive result in screening panels can be estimated. Evaluating such rates will help identify the most and least common allergens and will help to cost-effectively refine allergy screening panels.

Introduction

Allergic disease is a highly prevalent condition with several clinical manifestations, including allergic rhinitis and sinusitis, allergic dermatologic disorders, allergic conjunctivitis, asthma, and food sensitivities. It is difficult to identify its true prevalence because diagnoses may not be confirmed, studies may be looking at only one of the allergic diseases, and many studies rely on survey responses. When looking at allergic rhinitis, for example, its reported prevalence ranges from 10 to 30% in adults and is as high as 40% in children. (1) There is also evidence that the prevalence of allergies may be increasing, particularly in Western countries. (2)

The diagnosis of allergic disease is based on a classic history with confirmation by allergy testing or response to treatment. Allergy testing can be performed either through skin testing or in vitro (blood) testing for specific IgE directed against potential allergens. (3) Recent clinical guidelines for the management of allergic rhinitis developed by the American Academy of Otolaryngology-Head and Neck Surgery state, "Clinicians should perform and interpret, or refer to a clinician who can perform and interpret, specific IgE (skin or blood) allergy testing for patients with a clinical diagnosis of AR who do not respond to empiric treatment, or when the diagnosis is uncertain, or when knowledge of the specific causative allergen is needed to target therapy." (3)

Allergy testing, be it skin or blood testing, can be expensive and is associated with some minor morbidity. Test positivity rates may vary depending on the level of suspicion of the ordering provider, the prevalence of a specific allergy in a given location, and the type of clinical practice. Individual allergens can be pursued on the basis of specific symptoms, or broad panels can be performed to screen for any allergen positivity.

In an attempt to refine a cost-effective allergy test panel, Bousquet et al looked at large numbers of skin allergy tests to identify which were highly positive and to determine the size of the panel that might be necessary to identify most of the positive allergens. (4) They tested approximately 3,000 patients and found that roughly two-thirds were sensitized to at least one allergen, and they identified eight allergens (grass pollen, Dermatophagoidespteronyssinus, birch pollen, cat dander, Artemisia, olive pollen, Blatella, and Alternaria) that allowed them to detect more than 95% of sensitized patients.

Their study overlapped several European countries, which suggested that there were some differences among them. (4) Despite the differences, only 13 allergens were needed to identify all sensitized patients.

Although there have been studies that evaluated the prevalence of food allergies, (5) not many have looked at positivity rates of allergy testing for foods. Moreover, there has been a lack of good studies looking at large numbers of in vitro allergy tests to identify the frequency of positive tests or differences among specific allergens.

We conducted this study to identify positive rates of in vitro allergy testing (both inhalant/respiratory and food) in a reference laboratory in the northern Midwest region of the United States.

Patients and methods

We searched our automated database to identify the results of specimen testing for any of eight large allergen panels offered at The Cleveland Clinic. These included a mixture of results from patients seen at Cleveland Clinic sites throughout northeast Ohio, as well as results sent to us by reference laboratory clients who were primarily located in the upper Midwest (northern Ohio, northern Illinois, and southern Wisconsin). These samples had been analyzed between Sept. 1, 2014, and Sept. 1, 2015.

All specific IgE testing was performed at The Cleveland Clinic with the Phadia ImmunoCAP system (Thermo Fisher Scientific; Uppsala, Sweden) in accordance with manufacturer-specified protocols. The prevalence of each allergen was calculated as the number of positive results of any class (using a lower cutoff of 0.35 kU/L) divided by the total number of times an allergen was assayed across all panels.

Institutional Review Board approval for the study protocol was obtained, and no patient identifiers were included in the study.

Results

A total of 148,628 individual results for 63 different allergens were generated during the study period. A large majority were from respiratory/inhalant panels.

Respiratory/inhalant allergies. The frequency of positive reactions to the inhalant allergens ranged as high as 29%; 30 antigens had positivity rates of at least 10% (table 1). The most commonly found inhalant antigens were dog dander (24%), cat dander (23%), dust mites (23%), and June grass (21%) (table 2).

Food allergies. Two food panels yielded 23,438 individual tests for 14 allergens. The positivity rate for these allergens ranged as high as 18%, with 6 allergens that exceeded 10%. The most common positive allergen tests were for milk (18%), peanut (17%), wheat (16%), and egg white (15%) (table 3).

Allergy class. The distribution of class results was similar across most antigens, with most falling into the class 1 to class 3 range (figure 1). However, a notable number of very high responses (class 5 and 6) were seen for most allergens. Dog dander, cat dander, dust mites, and peanut had the greatest class 4 and 5 responses (figure 2).

Discussion

Identifying the prevalence of allergies is difficult because (1) allergic disorders are fairly common, (2) many patients self-treat and are therefore not identified in the healthcare system or literature, and (3) patients are often diagnosed with an allergy without confirmation by objective testing. In addition, particularly with allergic rhinitis, there is a notable overlap with allergic rhinitis and nonallergic rhinitis, and there is a growing number of reports indicating that there are patients who may have a local allergic response in the nose (local allergic rhinitis) who do not have positive results on either skin or in vitro testing.6 Many of the prevalence studies have relied on surveys, again without objective confirmation.

Allergy testing is routinely performed to confirm a diagnosis, to detect specific allergies, to identify areas for prevention and avoidance, to direct pharmacotherapy, and to identify antigens for immunotherapy. Although there is debate about the effectiveness of skin testing vis-a-vis blood testing for identifying allergies, both are good screening methods, and they have been used interchangeably in guidelines. (3)

A few well-done prevalence studies have been performed. The National Health and Nutrition Examination Survey (NHANES) prospectively evaluated patients in the United States by skin testing to identify the prevalence of allergic disease and specific allergens. NHANES II7 evaluated patients aged 6 to 74 years from 1976 through 1980, and NHANES IIIs looked at patients aged 6 to 59 from 1988 through 1994.

NHANES III investigators looked at 10 inhalant allergies and the rate of skin-test positivity. They found that dust mites were the most frequently positive allergen (27.5% of tests), followed by perennial rye grass (26.9%), short ragweed (26.2%), cockroach (26.1%), Bermuda grass (18.1%), and cat dander (17%). Study participants were positive for at least one indoor allergen 43% of the time and to one outdoor allergen 40% of the time. Some 15% of patients were test-positive for only one allergen, with 4.3% being cockroach and 4.2% being dust mites. (8) These figures represented a dramatic increase in positivity over the rates found during NHANES II, which had been conducted only a few years earlier. In NHANES II, only 20% of participants were positive for one allergen - 7.6% for an indoor allergen, and 17.7% for an outdoor allergen. Positivity rates were 6.2% for house dust mites and 2.3% for both cat and dog dander, while rates were 10.2% for rye grass, 10.1% for ragweed, and 4.4% for Bermuda grass. (7)

It is difficult at times to correlate the true prevalence of allergic disease with positive test results. In most cases, patients are sent for testing with only a suspicion of allergic disease, and a positive test result does not necessarily mean that positivity rates are consistent with the presence of true allergic disease. However, surveys of positive allergen rates do serve to help identify the most common allergens, and they may correlate with the severity of associated diseases such as allergic rhinitis and asthma.

Quest Diagnostics Health Trends investigators analyzed test results from more than 2 million patient encounters over a 4-year period, and they found that the overall allergen-sensitization rate increased by 5.8% during the course of the 4-year study period. (9) The greatest increases were seen in positive test results for ragweed (15%) and molds (12%). (9)

Their study also found wide variability in testing results throughout the United States. (9) For example, ragweed positivity was only 11% in Miami and San Francisco but 29% in Phoenix. Mold positivity was 7% in Seattle and 20% in both Riverside, Calif., and San Bernardino, Calif. The ranking of the five cities with the highest rates by categories of allergen showed that Baltimore was worst for foods, Phoenix for ragweed, Dallas for molds, Miami for dust mites, and Denver for animals.

In addition, there was very little overlap among the top five cities in relationship to the five major allergies, with Boston appearing three times and Las Vegas and Dallas twice among the 25 worst cities for allergies. (9) A broad distribution of positive rates was also seen with foods. These data illustrate the importance of identifying possible allergens that are relevant to the local environment and determining which screening tests and panels are sensitive to the allergies that are common within that geographic area.

Our study represents one of the largest evaluations of screening allergy tests ever reported within a specific region, with 125,190 potential inhalant/respiratory allergens and 23,438 individual food tests. Although there are differences between our study and others regarding both the frequency of positive tests and the most common positive tests, there are some similarities, as well. Dog dander (24%), cat dander (23%), dust mites (23% for both Dfarinae and Dpteronyssinus), and June grass (21%) were the most common inhalant/respiratory allergens in our study, while milk (18%), peanut (17%), wheat (16%), and egg white (15%) were the most commonly positive food allergens. These results are for the most part similar to those reported in other studies, including in the NHANES III study and the Quest Diagnostics Health Trends report, although there are some differences with regard to specific allergens. (7,8,10) The in vitro class responses we found are also similar to those in the Quest study. (9)

On the other hand, our positivity rates were notably lower than those identified in the GA2LEN III study. (4) Of note, cockroach positivity was relatively low (11%) in our study; indeed, it was less than half of that seen in other studies. (8) This might be a bit surprising given the many large industrial cities located in the upper Midwest and the large underprivileged populations in the inner cities.

One of the conclusions of the GA (2) LEN III study was that, depending on the specific country, as few as 8 to 13 allergens were all that were needed to identify all sensitized subjects. (4) This might allow for refinement of screening allergy test batteries in a way that would be more cost-efficient than current methods.

Although treatment paradigms differ between Europe and the United States, and multi-antigen immunotherapy in the United States may result in a desire to identify more positive allergens, there is some cost benefit in trying to reduce the panel size for allergy tests. Our study did not identify a huge opportunity for reducing the size of testing panels since 30 of the inhalant/respiratory allergy tests were positive in at least 10% of tests, although known cross-reactivity among certain allergens, such as grasses, might allow for some reduction in the size of the panels. However, some of the allergens tested yielded very low positivity rates; for example, rates for feather mix and white pine were 1%, rabbit epithelium was 3%, and 18 allergens yielded rates of less than 10%. This suggests that inclusion of these antigens in large panels may not be helpful unless there are specific suggested triggers that might justify them.

Evaluating the prevalence of food allergies is a bit more challenging than doing so for inhalant allergies. Some persons experience reactions to foods that may not be allergic. According to Sampson, "Food intolerances (nonallergic food hypersensitivities) are adverse responses caused by some unique physiologic characteristic of the host, such as metabolic disorders (e.g., lactase deficiency). Food hypersensitivities/allergies are adverse immunologic reactions that might be due to IgE- or non-IgE-mediated immune mechanisms." (5)

Food allergies also vary according to age. While the prevalence of inhalant allergies increases with age, the prevalence of food allergies decreases, so positivity rates of food allergy screening tests would be expected to be much higher in children than in adults. (11) While food allergy positivity rates may be well above 25 to 30% in small children, these rates drop to less than that by the later teenage years. (11) IgE sensitization drops over time for milk and egg in particular. (5) Screening panels for foods, particularly those panels that are performed with in vitro testing, tend to be relatively small, and therefore the opportunity to reduce their size would seem to be limited, other than panels for fish perhaps.

The limitations of our study are related to the inability to correlate our findings with specific symptoms or diagnoses. This study was not a random survey of the population but rather an analysis of ordered tests. We assume that the tests were ordered because patients exhibited symptoms, physical findings, or diagnoses suggestive of allergic disease and therefore some unidentified clinical correlate was involved. It would be likely then that in most patients, positive allergy test results were associated with a clinical allergy.

A potential controversy concerns whether skin tests or in vitro tests should be used for screening. It seems that blood testing is easier to perform in many patient populations, particularly in primary care and emergency department settings. The authors of the recent "International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis" suggest that "Perhaps the strongest statement that can be made on behalf of tIgE [total IgE] is its ability to generally identify patients or populations with atopic or allergic disease." (6) They also wrote, "Based on the reviewed literature, slgE [serum IgE] testing is an acceptable alternative to skin testing...." (6)

Other potential limitations of our study are related to the clinical usefulness of our data in patient care, even though the large number of tests we studied would be useful in identifying the most common potential allergens in patients with allergy-mediated diseases.

Although the reference laboratory we used is in the upper Midwest region of the United States, the large number of allergens and the significant overlap among regions might make seasonal data applicable to most regions throughout the United States and the perennial allergens applicable more broadly.

In conclusion, wide variability in positive in vitro allergy tests exists, and the likelihood of a positive result in screening panels can be estimated. The most common positive antigens in our study were dog dander (24%), cat dander (23%), dust mites (23% each for Dfarinae and D pteronyssinus), and June grass (21%). The most common positive food allergen tests were for milk (18%), peanut (17%), wheat (16%), and egg white (15%). The positivity rates for shellfish ranged from 4 to 9%, and the rates for fish were low (3 to 5%). Evaluating these rates will help further identify the most and least common allergens, and there is potential to use the results to identify opportunities to cost-effectively refine allergy screening panels.

Michael S. Benninger, MD, Thomas Daly, MD; Kevin Graffmiller, MD

From the Head and Neck Institute (Dr. Benninger and Dr. Graffmiller) and the Pathology and Laboratory Medicine Institute (Dr. Daly), The Cleveland Clinic, Cleveland, Ohio.

Corresponding author: Michael S. Benninger, MD, Head and Neck Institute, The Cleveland Clinic, 9500 Euclid Ave., A-71, Cleveland, OH 44139. Email: benninm@ccf.org

Previous presentation: The information in this article has been edited for publication and updated as necessary from its original form as a podium presentation at the 26th Congress of the European Rhinologic Society in conjunction with the 35th Congress of the International Society of Infection and Allergy in the Nose and the 17th Congress of the International Rhinologic Society; July 3-7, 2016; Stockholm.

References

(1.) McCrory DC, Williams JW, Dolor RJ, et al. Management of allergic rhinitis in the working-age population. Evid Rep Technol Assess (Summ) 2003;(67):l-4.

(2.) Andersson M. Emerging treatments for allergic rhinitis. Expert Opin Emerg Drugs 2003;8(l):63-9.

(3.) Seidman MD, Gurgel RK, Lin SY, et al; Guideline Otolaryngology Development Group, AAO-HNSF. Clinical Practice Guideline: Allergic Rhinitis. Otolaryngol Head Neck Surg 2015;152:(1 Suppl):Sl-43.

(4.) Bousquet PJ, Burbach G, Heinzerling LM, et al. GA2LEN skin test study III: Minimum battery of test inhalant allergens needed in epidemiological studies in patients. Allergy 2009;64(11):1656-62.

(5.) Sampson HA. Update on food allergy. J Allergy Clin Immunol 2004;113(5):805-19; quiz 820.

(6.) Wise SK, Lin SY, Toskala E, et al. International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis. Int Forum Allergy Rhinol 2018;8(2):108-352.

(7.) Gergen PJ, Turkeltaub PC, Kovar MG. The prevalence of allergic skin test reactivity to eight common aeroallergens in the U.S. population: Results from the second National Health and Nutrition Examination Survey. J Allergy Clin Immunol 1987;80(5):669-79.

(8.) Arbes SJ Jr., Gergen PJ, Elliott L, Zeldin DC. Prevalence of positive skin test responses to 10 common allergens in the US population: Results from the third National Health and Nutrition Examination Survey. J Allergy Clin Immunol 2005; 116(2):377-83.

(9.) Kaufman HW, Odeh MA, Bost WH, Ragothaman P. Allergies across America. Health Trends Allergy Report 2010. www.QuestDiagnostics.com/HealthTrends, 1-40.

(10.) Kay AB. Allergy and allergic diseases. First of two parts. N Engl J Med 2001;344(l):30-7.

(11.) Osborne NJ, Koplin JJ, Martin PE, et al; HealthNuts Investigators. Prevalence of challenge-proven IgE-mediated food allergy using population-based sampling and predetermined challenge criteria in infants. J Allergy Clin Immunol 201 l;127(3):668-76.el-2.

Caption: Figure 1. Graphs show the in vitro class response for the most common inhalant/respiratory allergens (A) and food allergens (B).

Caption: Figure 2. Scatter plot illustrates the likelihood of a strong positive class response by allergen. The greatest class 4 and 5 responses are seen with dog dander, cat dander, dust mites (D farinae), and peanut.
Table 1. Positivity rates for 48 inhalant/respiratory allergens

Allergen                          Tests, n   Pos, n (%)

Alternaria tenuis                   5,508     884 (16)
Australian pine                       147      4 (3)
Bahia grass                           147     21 (14)
Bermuda grass                       4,124     582 (14)
Birch tree                          1,632     195 (12)
Box elder                           4,369     747 (17)
Cat dander                          5,516    1,285 (23)
Cladosporium herbarum               5,511     387 (7)
Cocklebur                             149      13 (9)
Cockroach                           4,123     461 (11)
Common ragweed                      5,488     944 (17)
Cottonwood tree                     3,077     418 (14)
Dermatophagoides farinae            5,518    1,286 (23)
Dermatophagoides pteronyssinus      4,126     932 (23)
Dog dander                          5,516    1,325 (24)
Elm tree                            4,103     539 (13)
English plantain                    1,021     97 (10)
Epicoccum purpurascens                147      8 (5)
Feather mix                           147      2 (1)
Giant ragweed                         148     16 (11)
Goldenrod                             149      7 (5)
Helminthosporium halodes              146      7 (5)
Hickory/pecan tree                  4,116     449 (11)
Horse dander                          147      10 (7)
House dust                          1,026     299 (29)
(Hollister-Stier)
Johnson grass                       1,188     155 (13)
June grass                          2,580     543 (21)
Lamb's quarters                     2,570     240 (9)
Marsh elder                         2,916     338 (12)
Mountain juniper                    3,072     293 (10)
Mouse epithelium                    2,936     172 (6)
Mucor racemosus                     3,081     124 (4)
Oak tree                            5,493     710 (13)
Orchard grass                         147     25 (17)
Peniciiiium notatum                 4,372     244 (6)
Pigweed                             3,328     307 (9)
Rabbit epithelium                     147      5 (3)
Redtop grass                          147     25 (17)
Russian thistle                     2,918     344 (12)
Sheep sorrel                          411      26 (6)
Sweet vernal grass                    147     24 (16)
Sycamore tree                       3,343     368 (11)
Timothy grass                       4,738     828 (17)
Walnut tree                         4,117     581 (14)
White ash tree                      3,076     510 (17)
White mulberry tree                 2,921     112 (4)
White pine                            147      2 (1)
Willow tree                           147      9 (6)

Table 2. Most common positive inhalant/respiratory allergens

Allergen                     Tests, n   Positive, n (%)

Dog dander                    5,516       1,325 (24)
Cat dander                    5,516       1,285 (23)
Dust mites                    5,518       1,286 (23)
(Dermatophagoides farinae)
June grass                    2,580        543 (21)
Common ragweed                5,488        944 (17)
Timothy grass                 4,738        828 (17)
Alternaria tenuis             5,508        884 (16)
Oak tree                      5,493        710 (13)
Cockroach                     4,123        461 (11)

Table 3. Most common food allergen positivity rates

Food         Tests, n   Positive, n (%)

Milk          2,217        396 (18)
Peanut        2,220        388 (17)
Wheat         2,213        348 (16)
Egg white     2,218        330 (15)
Soybean       2,219        242 (11)
Corn          2,215        242 (11)
Shrimp        2,218         210 (9)
Clam          1,273         56 (4)
Codfish       1,270         43 (3)
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Title Annotation:ORIGINAL ARTICLE
Author:Benninger, Michael S.; Daly, Thomas; Graffmiller, Kevin
Publication:Ear, Nose and Throat Journal
Date:Sep 1, 2018
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