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Original Paper

ORL 2011;73:182–188 DOI: 10.1159/000328344

Correlation of Routine Examinationsfor the Diagnosis of House Dust Mite Allergic Rhinitis

Yuan Zhang   a Chengyao Liu   b Demin Han   a, b Luo Zhang   a, b

a   Key Laboratory of Otolaryngology-Head and Neck Surgery (Ministry of Education of China), Beijing Instituteof Otolaryngology, and b   Department of Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital,Capital Medical University, Beijing , PR China

Introduction

Allergic rhinitis (AR) is a common disease and its prevalence is increasing worldwide. Data on the current prevalence of AR in China were presented in our previous publication [1] . There is also evidence that house dust mites (HDM), which include Dermatophagoides farinae (Der f) and D. pteronyssinus (Der p), are the most impor-tant aeroallergens, especially in Beijing, China [2] . Among people who are sensitive to HDM, exposure to the aller-gens causes persistent AR or asthma with significant health problems. Therefore, accurate and convenient di-agnosis of HDM allergy is critical. The basis for an etio-logical diagnosis of an allergic disease is the demonstra-tion of a sensitization, namely the presence of specificimmunoglobulin E (sIgE) antibodies. Currently avail -able diagnostic tests for HDM sensitization include skin testing and measurement of serum HDM allergen-sIgE. Meanwhile, a clinical history is important to identify causes and judge the severity of the disease.

The skin prick test (SPT) is usually the preferred meth-od for the diagnosis of IgE-mediated hypersensitivity be-cause it is simple and inexpensive, and the results are im-mediately available. As with any laboratory test, however,

Key Words

Allergic rhinitis � Diagnosis � House dust mite � Specific immunoglobulin E � Skin prick test

Abstract

Objective: To evaluate the correlation between the routine diagnostic tests for house dust mite (HDM) sensitization in Chinese allergic rhinitis (AR) patients, including the skin prick test (SPT), serum HDM-specific immunoglobulin E (sIgE) and nasal smear eosinophilia. Methods: The ImmunoCAP assay was employed to detect serum total IgE and sIgE. The SPT and nasal smear eosinophil counts were performed using standard procedures. Results: Of 82 subjects with HDM-re-lated symptoms and positive SPT results, 55 individuals showed an sIgE level equal to or greater than CAP class 1 for both Dermatophagoides pteronyssinus (Der p) and D. farinae (Der f), and 62 individuals demonstrated positive eosinophils in nasal smears. sIgE of Der p and Der f presented a linear correlation, and the level of serum HDM-sIgE was also posi-tively correlated with total IgE. An increasing sIgE level was correlated with higher SPT grades in both Der p and Der f. Meanwhile, the correlation coefficient exhibited an increase in value with aging, and the 31- to 40-year age group dem-onstrated the highest value for both Der p and Der f. Conclu-

sion: The positive correlation between SPT and sIgE reaction to HDM varied according to the age of patients with AR.

Copyright © 2011 S. Karger AG, Basel

Received: January 26, 2011 Accepted after revision: April 5, 2011 Published online: May 27, 2011

Luo Zhang, MD Beijing Institute of Otolaryngology 17, Hougou Hutong, Dongcheng District Beijing 100005 (PR China) Tel. +86 10 6514 1136, E-Mail dr.luozhang   @   gmail.com

© 2011 S. Karger AG, Basel0301–1569/11/0734–0182$38.00/0

Accessible online at:www.karger.com/orl

D.H. and L.Z. contributed equally to this study.

Diagnosis of AR ORL 2011;73:182–188 183

a number of variables can affect the outcome [3] . A better understanding of how the routine tests relate to clinical symptoms and how other diagnostic methods corre-spond to SPT results would help clinicians interpret these commonly used diagnostic tests for HDM AR. In our re-cent study related to the evaluation of serum sIgE for the diagnosis of AR with multi-allergens, we found that well-established serum sIgE tests correlated well with SPT, and setting a class 1 cutoff for positivity of SPT results was better than a class 2 setting for assessing the AR diag-nostic value [4] . Moreover, other research demonstrated that serum sIgE measurement in polysensitized patients seemed to be more appropriate than SPT [5] . Very recent-ly, Jung et al. [6] compared the SPT and Phadia Immuno-CAP assay as tools for diagnosing HDM allergy and they reported that the ImmunoCAP assay was the preferred method for detecting allergy to HDM in patients 1 50 years of age, and that SPT was the recommended first choice for patients ! 30 years old. Here, we evaluate the concordance between the SPT, the ImmunoCAP assay and other routine examinations, and we establish appro-priate guidelines for the clinical diagnosis of HDM AR in the Chinese population.

Subjects and Methods

Study Population Individuals who have significant rhinitis symptoms when they

are indoors, especially when encasing pillows, duvets and mat-tresses, or reading books or papers, were recruited from the AR clinic of Beijing Tongren Hospital. Recruitment occurred be-tween March 2007 and March 2008. A questionnaire was admin-istered to assess HDM-related AR symptoms. Each participant was considered to have HDM-associated symptoms if he or she reported nasal symptoms associated with HDM exposure. Eighty-two individuals who had a positive SPT reaction to HDM allergen were invited to participate in our study. Screening study proce-dures included a questionnaire to assess HDM exposure and re-lated allergic symptoms, SPT, nasal smear eosinophilia and mea-surement of serum HDM-sIgE and total IgE. The study was ap-proved by the ethics committee of Beijing Tongren Hospital, and written informed consent was obtained from all participants.

Assessment of AR Symptoms Nasal symptoms during the previous 14 days as experienced

by the patients were assessed by visual analog scales (VAS) [7] to reflect the severity of the disease to some degree. The patients were asked to evaluate their complaints on a continuous horizon-tal line of 10 cm, where 0 and 10 cm represent no complaints and serious complaints of rhinitis, respectively. HDM-related symp-toms were defined as mainly including nasal itching, nasal ob-struction, continuous sneezing and watery rhinorrhea. The sever-ity of symptoms was estimated from the VAS score for each symp-tom or the sum of VAS scores for the above four symptoms.

Skin Prick Test SPT were performed following established guidelines. The pa-

tients took no antihistamines of any type for at least 1 week before the SPT. Allergen extracts (Allergopharma, Reinbek, Germany), along with appropriate negative (saline solution) and positive con-trols (10 mg/ml histamine) were applied for the SPT with 1-mm single-prick lancets. The following allergens were tested: Der p; Der f; animal hair; Blatella germanica; giant ragweed; mugwort; Lamb’s quarters; Humulus; Chenopodium album; dandelion; grasses; pine; plantain; locust; trees; Aspergillus fumigatus; Peni-cillium notatum; Curvularia lunata; Alternaria tenuis, and Can-dida albicans. The reactions were evaluated based on the mean wheal diameter at 15 min after application of the extracts. A pos-itive SPT result was defined as a wheal greater than or equal to one half of the diameter of the histamine control and at least 3 mm larger than the diameter of the negative control [8] . Patients who were positive only to HDM allergen were enrolled in our study. For HDM allergen, two standardized HDM extracts, Der p and Der f, containing 5,000 standardized biological units per millili-ter, were used for all skin testing.

Measurement of HDM-sIgE Serum Der p- and Der f-sIgE were quantified in all subjects,

using the ImmunoCAP 100 system according to the manufactur-er’s directions (Pharmacia, Uppsala, Sweden). The CAP classifica-tion system divides results into 7 categories from 0 to 6. Addition-al classes are scored as follows: class 1 – 0.35–0.70 kU/l; class 2 – 0.71–3.5 kU/l; class 3 – 3.51–7.5 kU/l; class 4 – 7.6–17.5 kU/l; class 5 – 17.6–50 kU/l, and class 6 – 50 kU/l. This unit reported by CAP was in accordance with the defined WHO serum standard IRP 75/520. For the present analyses, subjects were considered sensitive to HDM allergens if the measurement of IgE was equal to or above 0.35 kU/l. Procedural recommendations for total IgE (Pharmacia, Uppsala, Sweden) were strictly followed. Quantitative results were measured and considered positive if a value was 1 100 kU/l [9] .

Nasal Smear Eosinophilia A wire applicator thinly wound with cotton was gently passed

along the floor of the nose and up under the inferior turbinate 3 times in each nostril. After each wiping, the contents of the probe were gently rolled onto a slide. Every effort was made to roll the same amount of mucus onto each slide, though this was not actu-ally achieved in most instances. The slides were air-dried, stained using the eosin stain for about 10 s, and decolorized with 95% al-cohol for about 3 s; excess stain was allowed to drain. Methylthio-ninium chloride stain was then used for 10 s and decolorized as before. The long edge of the slide was then blotted with a paper towel and the slide allowed to dry. Each slide was scanned using a light microscope (YS100; Nikon, Japan) at high power ( ! 40), and the cellular elements were graded by a single observer. Eosinophils were evaluated per high-power field. Five fields were evaluated on each slide and the mean was determined. The grading system was used as follows: 0 – none or rare; + – a few scattered eosinophils or small clumps; ++ – a moderate number of eosinophils and larger clumps; +++ – still larger clumps, but not covering the entire field; ++++ – large clumps covering the entire field [10] .

Statistics All analyses were performed using Stata version 9.1, and p !

0.05 was considered statistically significant. Correlation analysis

Zhang   /Liu   /Han   /Zhang   ORL 2011;73:182–188184

between the rank variables such as SPT grade, sIgE category and nasal smear eosinophilia classification was undertaken using Spearman’s rank correlation method. Linear regression analysis was applied to test the hypothesis of a relationship between the measurement data, which included IgE level. If the test included measurement data and rank variables, the measurement data first needed to be converted into ranks, and the correlation between the ranks of the observations of the two variables was then calcu-lated. The correlation coefficient is denoted by r s for Spearman’s rank correlation method and r 2 for linear regression analysis. With regard to the correlation analysis between SPT grade and the corresponding HDM-sIgE level, the entire enrolled cohort was taken into account in the first place. The study population was then stratified by age, and concordance was tested among dif-ferent age-specific groups.

Results

Study Population The study population of 82 AR patients had a mean

age of 27.2 years and consisted of more men (57%) than women (43%). All enrolled subjects reported HDM-relat-ed AR symptoms (mean total VAS score: 19.3 8 8.6), and

all had at least 1 positive SPT result for Der p or Der f. Seventy-nine subjects (96.3%) had positive reactions to both allergens. The mean VAS scores for nasal itching, nasal obstruction, continuous sneezing and watery rhi-norrhea were 4.3 8 3.1, 5.0 8 3.1, 4.6 8 3.2 and 5.6 8 2.7, respectively ( table 1 ). Fifty-five patients (67%) demon-strated double-positive serum sIgE results to Der p and Der f allergens, and 19 patients (23%) showed double-neg-ative sIgE to both allergens. Forty individuals (49%) showed concentrations of serum total IgE of 6 100 kU/l.

Correlation between Diagnostic Test Results and AR Symptoms To determine the degree of correlation between the

routine diagnostic test results and the HDM-related AR symptoms, we analyzed the VAS score and SPT grade, serum sIgE level, total IgE level and nasal smear eosino-philia classification. The 4 main nasal symptoms – nasal itching, nasal obstruction, sneezing and watery rhinor-rhea – were evaluated in terms of their respective VAS scores. Although all diagnostic test results suggested a positive or negative correlation with clinical symptoms,

Table 1. Demographic characteristics of the study population (n = 82)

Values

Age1, years 27.2812.8 (8–60)Sex (M/F), n 47 (57.3%)/35 (42.7%)HDM-related symptoms1, VAS score

Nasal itching 4.383.1 (0–10)Nasal obstruction 5.083.1 (0–10)Continuous sneezing 4.683.2 (0–10)Watery rhinorrhea 5.682.7 (0–10)Total 19.388.6 (1.9–40)

SPT, serum IgE and nasal smear eosinophilia statusSPT status, n

Der p+Der f+/Der p+Der f–/Der p–Der f+ 79 (96.3%)/0 (0%)/3 (3.7%)Der p +/++/+++/++++ 4 (4.9%)/18 (21.9%)/25 (30.5%)/35 (42.7%)Der f +/++/+++/++++ 5 (6.3%)/13 (16.5%)/15 (19.0%)/46 (58.2%)

sIgE status, nDer p+Der f+/Der p+Der f–/Der p–Der f+/Der p–Der f– 55 (67.1%)/7 (8.5%)/1 (1.2%)/19 (23.2%)Der p 0/1/2/3/4/5/6 20 (24.4%)/9 (11.0%)/20 (24.4%)/12 (14.6%)/9 (11.0%)/6 (7.3%)/6 (7.3%)Der f 0/1/2/3/4/5/6 26 (31.7%)/5 (6.1%)/16 (19.5%)/12 (14.6%)/8 (9.8%)/9 (11.0%)/6 (7.3%)

Total IgE, n<100 kU/l≥100 kU/l

42 (51.2%)40 (48.8%)

Nasal smear eosinophilia status, nEosinophilia –/+/++/+++/++++ 20 (24.4%)/19 (23.2%)/19 (23.2%)/13 (15.8%)/11 (13.4%)

1 Values denote means 8 SD, with ranges in parentheses unless otherwise indicated.

Diagnosis of AR ORL 2011;73:182–188 185

no statistical significance existed between any two tests ( table 2 ).

Correlation between Allergen-sIgE Test Results and Nasal Smear Eosinophilia Classification The nasal smear for eosinophils was considered to be

an effective method for evaluating the local nasal reac-tion to the allergens tested, contrasting with the SPT and serum sIgE, which are in vitro and in vivo tests, respec-tively, for the sIgE reaction to each allergen. To estimate the relationship between nasal test and SPT results, as well as the systemic reaction, the change in eosinophil number in nasal secretions was calculated using the nasal smear methods described. Sixty-two individuals (76%) exhibited different degrees of increase in nasal eosino-phils, while 20 subjects (24%) were negative in the nasal smear eosinophilia test ( table 1 ). The eosinophilia classi-fication of the nasal smears displayed a nonsignificant relevance of both Der p and Der f to SPT grade and serum sIgE level (data not shown). Interestingly, there existed a highly significant correlation between nasal smear eosin-ophilia grade and Der f-sIgE category (r s = 0.95; p ! 0.01).

Concordance between SPT and Serum sIgE Among the 82 symptomatic AR patients, 58 individu-

als (71%) maintained serum sIgE levels consistent with the SPT reaction; 3 patients were positive to Der f alone, and 55 patients were double positive to Der p and Der f. Serum sIgE of Der p and Der f presented a linear correla-tion (r 2 = 0.87; p ! 0.01) ( fig. 1 ), and the level of serum

HDM-sIgE showed a significant positive correlation with total IgE level as well. The correlation coefficients for Der p, Der f and the sum of the two levels were 0.44, 0.49 and 0.48, respectively ( fig. 2 ). The relationship between SPT grade and serum sIgE level was further described by a nonlinear model, indicated by the shape of the scatter plot for both Der p and Der f (data not shown). The cor-relation between Der p and Der f serum sIgE concentra-tion and category versus corresponding SPT grade ac-cording to age was assessed. The results of the analysis suggested no correlation between SPT grade and serum sIgE category (data not shown). Nevertheless, viewing the

Table 2. H DM-related symptoms versus SPT grade, serum sIgE level, total IgE level and nasal smear eosinophilia classification

V AS

itching obstruc-tion

sneezing rhinor-rhea

total

SPT gradeDer p –0.0059 0.1214 –0.0016 0.0974 0.0470Der f 0.0398 0.0881 –0.0013 –0.0697 –0.0063Der p + Der f 0.0249 0.0865 0.0003 0.0287 0.0268

sIgE levelDer p 0.0841 0.0845 0.0018 –0.0363 0.0196Der f 0.1222 0.1212 0.0254 –0.0640 0.0521Der p + Der f 0.0854 0.0940 –0.0039 –0.528 0.0156

Total IgE level 0.1007 0.0891 0.1375 0.0179 0.0906Eosinophilia

grade 0.1654 0.1110 0.1434 0.1228 0.1846

00 20 40 60 80 100

20

40

60

80

100

120

Der p-sIgE (kU/l)

Der

f-sI

gE (k

U/l

)

00 500 1,000 1,500 2,000

50

100

150

200

250

Total IgE (kU/l)

HD

M-s

IgE

(kU

/l)

Der pDer fDer p + Der f

Fig. 1. Scatter plot of serum Der p- and Der f-sIgE levels in 82 en-rolled subjects. The correlation between serum Der p- and Der f-sIgE levels was assessed by linear regression analysis, and the correlation coefficient r 2 was 0.87 (p ! 0.01).

Fig. 2. Serum total IgE versus Der p- and Der f-sIgE. The correla-tion coefficients for serum Der p-sIgE, Der f-sIgE and the sum of the 2 levels were 0.44 (p ! 0.01), 0.49 (p ! 0.01) and 0.48 (p ! 0.01), respectively. The distribution of the scatter plot indicates a posi-tively correlated trend for serum HDM-sIgE and total IgE.

Zhang   /Liu   /Han   /Zhang   ORL 2011;73:182–188186

study population as a whole, increasing sIgE level was sig-nificantly correlated with higher SPT grades for both Der p (r s = 0.58) and Der f (r s = 0.60). Interestingly, when we divided the patients into four groups on the basis of their age, the correlation revealed an age-dependent pattern and r s value increasing with age, and the 31- to 40-year age group demonstrated the highest correlation coeffi-cients for both Der p (r s = 0.69) and Der f (r s = 0.74) among the different groups ( table 3 ). In the 41- to 60-year age group, the correlation was not statistically significant.

Discussion

In the present study, we evaluated the correlation be-tween routine diagnostic tests for HDM AR in the Chi-nese population. Our findings indicate that none of these tests – SPT, serum sIgE, total IgE and nasal smear eosin-ophilia status – reflect the severity of clinical symptoms directly. Eosinophilia classification of nasal smears re-vealed no relevance to SPT grade and serum sIgE level. sIgE of Der f and Der p presented a linear correlation, and the level of serum HDM-sIgE was positively correlated with total IgE. The significant positive correlation be-tween SPT and sIgE reaction to HDM varied according to the age of the patients. The correlation coefficient in-creased in value with age, up to the 31- to 40-year age group, which demonstrated the highest coefficient for both Der p and Der f among all the different groups; in the 41- to 60-year age group, the correlation was not sta-tistically significant.

We examined the utility of SPT, serum sIgE and nasal smear eosinophil counts for the diagnosis of HDM AR. As with any study of this nature, the greatest difficulty lay in accurately establishing the diagnosis of a clinically significant allergy. The diagnosis of AR has been recom-

mended when there is a strong link between history, pres-ence of symptoms on exposure to allergens, and positive allergometric testing (in vivo and/or in vitro) [11] . Here, we used an HDM AR diagnostic system that was in line with the above criteria.

We did not find an association between reports of HDM-related symptoms and the degree of either in vivo or in vitro allergometric test results. This apparent dis-crepancy between symptom reporting and allergic sensi-tization might be a result of the specific allergen tests, which lack the uniformity needed to detect sensitization among all truly allergic symptomatic individuals, and the fact that the cutoff level for diagnostic grading may be different in each test according to the clinical context. Alternatively, the diagnostic tests might be sufficiently accurate, and the symptoms of AR patients might be due to environmental factors apart from allergens, such as other pollutants, and the occurrence of several different allergens together. Of course, the possibility that patients were reluctant to acknowledge an involvement of their related symptoms cannot be ruled out. For these reasons, symptom reports should be considered only as a refer-ence, not a full reflection of the severity of the disease or an appropriate standard by which to assess diagnostic tests for HDM AR.

The presence of eosinophils in nasal secretions is tak-en as evidence of AR [12] , especially as a marker of the late-phase allergic response [13] . While some believe that there is a significant correlation between a skin sensitiv-ity test and nasal smear eosinophilia [12, 14] in AR, others believe otherwise [15, 16] . In the current study, 76% of the patients with a positive SPT also had a positive eosino-philia result, which is higher than the values reported by Romero and Scadding [14] (71%) and Takwoingi et al. [16] (66%). Negative results may be related to there being no recent exposure to allergens, which leads to a remarkable drop in eosinophil counts. However, such patients re-main positive in skin sensitivity testing because of the presence of fixed cutaneous mast cells [13] . Another ex-planation is that when a patient has a concurrent infec-tion, eosinophil occurrence is less pronounced and neu-trophils predominate since neutrophils can release afactor that inhibits the migration and chemotaxis of eo-sinophils [17] . Therefore, the nasal eosinophil count is a less sensitive test than the SPT, and thus the nasal eosin-ophil count cannot replace skin sensitivity testing. How-ever, it can be used in certain groups of patients, such as those with dermatological problems for whom skin test-ing is contraindicated. Those patients in this study who had a negative skin sensitivity test result but significant

Table 3. C orrelation analysis of serum sIgE level and SPT catego-ry for Der p and Der f according to age

Age range, years sIgE vs. SPT (Der p) sIgE vs. SPT (Der f)

8–20 (n = 28) 0.4125* 0.4291*21–30 (n = 23) 0.6107** 0.5656**31–40 (n = 15) 0.6920** 0.7430**41–60 (n = 16) 0.4797 0.4834

8–60 (n = 82) 0.5761** 0.6049**

* p < 0.05; ** p < 0.01.

Diagnosis of AR ORL 2011;73:182–188 187

eosinophilia (10%) may have been suffering from nonal-lergic rhinitis with eosinophilia syndrome [18] . Besides, our data revealed that nasal smear eosinophilia did not correlate with either AR symptoms or serum sIgE level, contrasting with the report by Takwoingi et al. [16] that both the SPT and nasal smear eosinophilia showed a cor-relation with clinical history, and the finding that nasal eosinophilia and serum allergen-sIgE may be correlated with severity of AR [19] .

It is also important to note that only 58 (71%) of the diagnosed AR patients in our study exhibited positive se-rum sIgE results and maintained consistency with the SPT reaction. Discrepancies between skin testing and IgE antibody assays were reported [20] , showing that more than 80% of the discordances consisted of positive skin reactions without detectable allergen-sIgE antibodies in the serum. This means that although a positive HDM-sIgE test result might be highly suspicious for HDM AR among symptomatic patients, a negative sIgE result does not exclude HDM allergy. As the first-line method for detecting an allergic reaction, the SPT has proved that the setting of the cutoff value is critical for the diagnosis of allergic diseases and assessment of other diagnostic tests [21] . The best expression of skin test results is shown by the reaction areas of the wheal and erythema or the sum of the orthogonal diameters. Another recommended ap-proach is to consider the skin index as a method for re-cording skin reaction [8] . In the present study, we set skin index class 1 as the cutoff value, possibly resulting in low sensitivity of the serum sIgE measurement.

Nevertheless, a significant positive correlation be-tween SPT grade and sIgE reaction to HDM was found in this study, although the correlation coefficient was not high. In fact, there was a study which indicated that SPT and sIgE results were concordant and appeared equiva-lent when using reproducible SPT [22] . Interestingly, we showed an age-dependent pattern for the correlation be-

tween the two tests, which is that the correlation coeffi-cient increased in value with age, except for the 41- to 60-year age group, the correlation for which was not statisti-cally significant. Therefore, we have provided further evidence for the conclusion that in the case of a positive HDM SPT result, additional sIgE testing for sensitization to HDM can be regarded as redundant when Der p and Der f are the major contributors to the allergen content [22] . For patients over 40 years of age, however, both ex-aminations should be recommended to detect allergy to HDM.

Taken together, patients with HDM AR should not simply be evaluated according to self-reported symp-toms. In addition, the diagnostic role of sIgE might be limited to excluding a diagnosis of HDM AR. The posi-tive correlation between SPT and sIgE reaction to HDM varied according to the age of the patients. For patients over 40 years of age, both of the examinations should be recommended to detect allergy to HDM. Future studies are required to determine the positive and negative pre-dictive values of each diagnostic test for HDM AR in a larger population.

Acknowledgments

This study was supported by grants from the National Science Fund for Distinguished Young Scholars (81025007), National Natural Science Foundation of China (30872846 and 30973282), Beijing Science and Technology Program (KZ200910025008), Beijing Natural Science Foundation (7072017) and Special Fund of Sanitation Elite Reconstruction of Beijing (2009-2-007) to L.Z.

Disclosure Statement

The authors have declared that they have no conflict of in-terest.

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