# Artemisia Allergy Research in China

Authors: Rui Tang; Jin-Lu Sun; Jia Yin; Zhi Li
Journal: BioMed Research International
 (2015)

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## Abstract

Artemisia is the most important outdoor allergen throughout China. It can cause allergic rhinitis, asthma, or both of them. Since it was verified as an allergenic pollen in 1960, it was identified two times in the Chinese National Pollen Survey (1984, 2009). The first oral immunotherapy double-blinded trial for Artemisia pollen asthma research was conducted in China in 1989 and published in 1990. 40 years since that study, there have been many published research reports on Chinese Artemisia allergy. This review summarizes the information regarding the discovery of Artemisia as an allergenic pollen, pollen account, epidemiology, allergen components, immunological changes in hay fever patients, natural course from rhinitis to asthma, diagnosis, and immunotherapies in China.


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## Body

## 1. Introduction

Artemisia species, or mugwort, is an anemophilous genus included in the Compositae family. Mugwort plants produce high pollen grain quantities [1–4]. This plant is characterized by a huge production of small pollen grains that can be transported for several hundreds or even thousands of kilometers by large air masses. The occurrence ofArtemisia species is associated with dry or slightly moist habitats and full exposure to light, which are important components of steppes [5].Pollen from the variousArtemisia species is one of the most frequent and serious pollinosis causes in many parts of the world [5–9]. The genusArtemisia includes 57 species in Europe [10] and 187 species in China [11]. In this review, we summarizeArtemisia allergy research in China.


## 2. Discovery ofArtemisia as an Allergenic Pollen

In the 1950’s, Professor Ye in ENT Department of Peking Union Medical College Hospital (PUMCH) had finished his allergy practice training in Johns Hopkins Hospital in USA and learnt that ragweed was the main allergenic pollen in autumn in Europe and United States. He found that many allergy patients showed negative reaction with ragweed prick skin test. Confusingly, there were too many allergic rhinitis patients visiting his clinic every autumn. After then, Ye [12] found that there was a type of weed,Artemisia annua, that grew widely in North China. Further, they found that the most abundant pollen count dates were September 4, August 24, and September 5 in 1962, 1963, and 1972, respectively. The allergic patient numbers and their symptom severities were related to the local pollen counts. By a nasal challenge test withArtemisia annua extract, this study verified thatArtemisia annua is a major outdoor allergen source in North China.To clarify the allergenicity of the nonpollen containing components of the plant, they collected and extractedArtemisia annua leaves and stems before the pollination period in 1987 [13]. They showed that the pollen-free plant extracts did have in vivo allergenic activities.


## 3.Artemisia Allergic Rhinitis and Airway Hyperresponsiveness

To study the relationship betweenArtemisia allergic rhinitis and airway hyperresponsiveness, Ma et al. [14] chose 50Artemisia hay fever patients and 20 normal controls. Each of these subjects was separately engaged with a skin test withArtemisia annua extract. All 50 patients had an intensely positive reaction to theArtemisia annua pollen skin test, but all of the controls were negative. Additionally, they conducted a bronchial provocation test (BPT) with a 1 : 100 (w/v)Artemisia annua pollen dilution. Before and after the BPT, they separately tested the forced expiratory volume in first second (FEV1) and serum eosinophil cationic protein (ECP) levels. They concluded that patients withArtemisia allergic rhinitis not only had chronic inflammation in their nose mucosa that resulted from an allergic reaction but also had chronic bronchial inflammation, leading to airway hyperresponsiveness (AHR). Their results also reveal that most patients with allergic rhinitis have AHR (76%).


## 4. Features of Pollen Prevalence

### 4.1. National Pollen Surveys

From 1984 to 1989, Ye [15], at PUMCH, led the first national pollen survey in mainland China. They found thatArtemisia pollen could be counted in each province in mainland China (Figure 1). At the same time, they gotArtemisia pollen count data from many Chinese cities in 1988 autumn (Table 1). In 2009, Yin, at the same allergy department, led the second national epidemic allergy study from 100,000 populations in 18 provinces and cities in mainland China, and that data will be published soon.Table 1
Artemisia pollen season distribution in Chinese cities (July–October), unit: grain.
Province
City
July
August
September
October
Beijing
Beijing*
85
1773
1492
186
Tianjin
Tianjin*
107
632
631
42
Hebei
Baoding*
81
778
1852
185
Hebei
Shijiazhuang*
42
282
590
164
Shanxi
Taiyuan*
52
3203
1518
26
Shanxi
Yuncheng*
0
81
581
972
Inner Mongolia
Hohhot*
1071
1639
1088
152
Inner Mongolia
kerqinzuoyihou*
467
1156
896
25
Liaoning
Shenyang*
72
1330
327
39
Liaoning
Dalian*
72
554
802
169
Jilin
Changchun*
822
1620
210
5
Jilin
Tonghua*
6
385
171
6
Heilongjiang
Harbin*
14
1977
139
99
Heilongjiang
Jiamusi*
2
2178
47
24
Heilongjiang
Qiqihar*
18
1748
43
22
Shandong
Ji'nan*
31
421
1936
131
Shandong
Qingdao*
96
106
319
86
The Ningxia
Yinchuan*
377
2805
533
101
Shaanxi
Xi'an*
8
256
1132
431
Gansu
Jiuquan*
5
24
8
5
Qinghai
Xining*
49
1048
1673
84
Xinjiang
Urumqi*
10
711
1555
196
Xinjiang
Hami*
21
34
68
75
Tibet
Lhasa*
1325
1817
549
93
Henan
Zhengzhou*
28
35
836
249
Hubei
Wuhan#
23
37
221
61
Hubei
Xiangyang#
3
1150
1194
354
Anhui
Hefei*
3
62
24
8
Sichuan
Chengdu*
16
114
28
3
Shanghai
Shanghai#
8
7
207
64
Jiangsu
Nanjing#
2
71
643
35
Jiangsu
Suzhou#
0
0
58
13
Zhejiang
Hangzhou#
0
0
0
6
Jiangxi
Nanchang#
2
52
1050
45
Fujian
Fuzhou#
0
53
77
48
Guizhou
Guiyang#
0
1
1
0
Yunnan
Kunming#
23
13
97
324
Hunan
Changsha#
0
0
56
27
Guangdong
Guangzhou#
0
0
14
20
Guangxi
Nanning#
0
3
226
156
*Cities in north of the Yangtze River; #Cities in south of the Yangtze River.Figure 1
Distribution ofArtemisia pollen in China.


### 4.2. Other Pollen Count Studies

During the periods that occurred between 1983 and 1986 and between 1999 and 2007, daily airborne pollen monitoring was performed by the gravitational method, using Ye’s sampler at the top of the Peking Union Medical Hospital Outpatient Department Building, Beijing, China. He et al. [16] found thatArtemisia was the most abundant airborne pollen and showed that it was produced over the longest period within a year, from the beginning of July until the end of September. TheArtemisia levels were followed byHumulus pollen levels. Similar reports were conducted with the Durham gravity method in Xi An city (northwestern region of China) [17] in the 1980’s and in Wuhan city (central region of China) in the 1990’s [18]. From March 31, 2001–April 1, 2002, pollen counts were evaluated in Nanchang city (central region of China). Additionally, Xie et al. [19] found that the highest airborne presence (the percent of total yearly pollen counts) was fromAmbrosia (35.73%), followed byPinaceae andArtemisia (11.94%).The Burkard volumetric trap was used to sample airborne pollen in Beijing city from August 1, 2007 to October 10, 2007. Yao [20] determined that (1)Artemisia andHumulus (includingCannabis sativa L.) were the main airborne pollen types observed during August and September in Beijing city, which accounted for 31% and 51% of the total pollen levels, respectively; (2) theArtemisia pollen season was from August 8th to October 8th; (3) the daily peak mugwort pollen concentration was 267 grain/m3, with an average of 71 g/m3; and (4) 88.5% of the outpatients that suffered from hay fever or asthma during the Autumn season were allergic toArtemisia. This was the first time that the Burkard volumetric sampler was employed forArtemisia andHumulus concentration monitoring in Beijing city.In 2005, Qiao et al. [4] published a color atlas of airborne pollens and plants that are prevalent in China. In this book, the mainArtemisia species on the China mainland were described, which includedArtemisia argyiLevl. Et Vant.,Artemisia sieversianaWilld.,Artemisia annuaL.,Artemisia capillarisThunb., andArtemisia lavandulaefoliaDC.


## 4.1. National Pollen Surveys

From 1984 to 1989, Ye [15], at PUMCH, led the first national pollen survey in mainland China. They found thatArtemisia pollen could be counted in each province in mainland China (Figure 1). At the same time, they gotArtemisia pollen count data from many Chinese cities in 1988 autumn (Table 1). In 2009, Yin, at the same allergy department, led the second national epidemic allergy study from 100,000 populations in 18 provinces and cities in mainland China, and that data will be published soon.Table 1
Artemisia pollen season distribution in Chinese cities (July–October), unit: grain.
Province
City
July
August
September
October
Beijing
Beijing*
85
1773
1492
186
Tianjin
Tianjin*
107
632
631
42
Hebei
Baoding*
81
778
1852
185
Hebei
Shijiazhuang*
42
282
590
164
Shanxi
Taiyuan*
52
3203
1518
26
Shanxi
Yuncheng*
0
81
581
972
Inner Mongolia
Hohhot*
1071
1639
1088
152
Inner Mongolia
kerqinzuoyihou*
467
1156
896
25
Liaoning
Shenyang*
72
1330
327
39
Liaoning
Dalian*
72
554
802
169
Jilin
Changchun*
822
1620
210
5
Jilin
Tonghua*
6
385
171
6
Heilongjiang
Harbin*
14
1977
139
99
Heilongjiang
Jiamusi*
2
2178
47
24
Heilongjiang
Qiqihar*
18
1748
43
22
Shandong
Ji'nan*
31
421
1936
131
Shandong
Qingdao*
96
106
319
86
The Ningxia
Yinchuan*
377
2805
533
101
Shaanxi
Xi'an*
8
256
1132
431
Gansu
Jiuquan*
5
24
8
5
Qinghai
Xining*
49
1048
1673
84
Xinjiang
Urumqi*
10
711
1555
196
Xinjiang
Hami*
21
34
68
75
Tibet
Lhasa*
1325
1817
549
93
Henan
Zhengzhou*
28
35
836
249
Hubei
Wuhan#
23
37
221
61
Hubei
Xiangyang#
3
1150
1194
354
Anhui
Hefei*
3
62
24
8
Sichuan
Chengdu*
16
114
28
3
Shanghai
Shanghai#
8
7
207
64
Jiangsu
Nanjing#
2
71
643
35
Jiangsu
Suzhou#
0
0
58
13
Zhejiang
Hangzhou#
0
0
0
6
Jiangxi
Nanchang#
2
52
1050
45
Fujian
Fuzhou#
0
53
77
48
Guizhou
Guiyang#
0
1
1
0
Yunnan
Kunming#
23
13
97
324
Hunan
Changsha#
0
0
56
27
Guangdong
Guangzhou#
0
0
14
20
Guangxi
Nanning#
0
3
226
156
*Cities in north of the Yangtze River; #Cities in south of the Yangtze River.Figure 1
Distribution ofArtemisia pollen in China.


## 4.2. Other Pollen Count Studies

During the periods that occurred between 1983 and 1986 and between 1999 and 2007, daily airborne pollen monitoring was performed by the gravitational method, using Ye’s sampler at the top of the Peking Union Medical Hospital Outpatient Department Building, Beijing, China. He et al. [16] found thatArtemisia was the most abundant airborne pollen and showed that it was produced over the longest period within a year, from the beginning of July until the end of September. TheArtemisia levels were followed byHumulus pollen levels. Similar reports were conducted with the Durham gravity method in Xi An city (northwestern region of China) [17] in the 1980’s and in Wuhan city (central region of China) in the 1990’s [18]. From March 31, 2001–April 1, 2002, pollen counts were evaluated in Nanchang city (central region of China). Additionally, Xie et al. [19] found that the highest airborne presence (the percent of total yearly pollen counts) was fromAmbrosia (35.73%), followed byPinaceae andArtemisia (11.94%).The Burkard volumetric trap was used to sample airborne pollen in Beijing city from August 1, 2007 to October 10, 2007. Yao [20] determined that (1)Artemisia andHumulus (includingCannabis sativa L.) were the main airborne pollen types observed during August and September in Beijing city, which accounted for 31% and 51% of the total pollen levels, respectively; (2) theArtemisia pollen season was from August 8th to October 8th; (3) the daily peak mugwort pollen concentration was 267 grain/m3, with an average of 71 g/m3; and (4) 88.5% of the outpatients that suffered from hay fever or asthma during the Autumn season were allergic toArtemisia. This was the first time that the Burkard volumetric sampler was employed forArtemisia andHumulus concentration monitoring in Beijing city.In 2005, Qiao et al. [4] published a color atlas of airborne pollens and plants that are prevalent in China. In this book, the mainArtemisia species on the China mainland were described, which includedArtemisia argyiLevl. Et Vant.,Artemisia sieversianaWilld.,Artemisia annuaL.,Artemisia capillarisThunb., andArtemisia lavandulaefoliaDC.


## 5. Epidemiology ofArtemisia Allergy

A cross-sectional survey was performed that included 6,304 patients who suffered from asthma and/or rhinitis in 17 cities across China [21]. These patients completed a standardized questionnaire that determined their respiratory and allergy symptoms. They also underwent skin prick tests with 13 common aeroallergens. The overall prevalence of the positive skin prick responses was 11.3% forArtemisia vulgaris, 6.5% forAmbrosia artemisiifolia, 3.5% for mixed grass pollen, and 2.2% for mixed tree pollen. The severity of rhinitis and asthma was significantly correlated with the skin reactivity index toArtemisia vulgaris andAmbrosia artemisiifolia and toD. pteronyssinus,D. farinae, andBlomia tropicalis (P<0.001). The main pollen and spore families in Beijing areArtemisia genus,Ambrosia genus, Chenopodiaceae, and Gramineae. They can reach approximately 307,000 grains of pollen/1000 m3 of air in August [6].A total of 215,210 tests with the ImmunoCAP system were assayed in the past three years in the PUMCH Allergy Department, which is the largest allergy department in China, and 76% were inhalant allergens. Among these allergens, the three most prevalent allergens wereDermatophagoides pteronyssinus, Dermatophagoides farinae, andArtemisia [22].Many studies had been done aboutArtemisia pollen survey and its relationship with allergic diseases in China. The authors showed thatArtemisia pollen was the most allergenic pollen in northern part area of Yangtze River in China (Figure 2) [23–64].Figure 2
Artemisia pollen was the most allergenic pollen in north part area of Yangtze River in China (with skin test or sIgE blood test).A total of 1,144 subjects (aged from 5 to 68) from June to October 2011 underwent intradermal testing using a panel of 25 allergen sources [65]. Of the 1,144 subjects, 170 had positive intradermal reactions to pollen and 144 donated serum for IgE testing from these 170 subjects. The positive intradermal response prevalence toArtemisia sieversiana, Artemisia annua, Ambrosia artemisiifolia, andHumulus scandens pollen was 11.0%, 10.2%, 3.7%, and 6.6%, respectively. Among the intradermal positive subjects, the specific IgE antigen prevalence toArtemisia vulgaris was 58.3%, toAmbrosia artemisiifolia was 14.7%, and toHumulus scandens was 41.0%. The specific IgE antigen prevalence to the Art v 1 allergen was 46.9% and to the Amb a 1 allergen was 11.2%. The correlation between the presence of IgE antibodies that were specific toArtemisia vulgaris and to the Art v 1 antigen was very high. Subjects withAmbrosia artemisiifolia specific IgE also hadArtemisia vulgaris specific IgE but with relatively high levels ofArtemisia vulgaris IgE antibodies. There were no correlations between the presence of IgE antibodies that were specific toHumulus scandens andArtemisia vulgaris. They concluded that the specific IgE antibody correlations suggest that pollen allergens fromArtemisia andHumulus are independent sources for primary sensitization.


## 6.Artemisia Allergens

In 1992, Ou [66] purified the major allergen, A2c, from a wildArtemisia sieversiana extract. Its molecular weight was 31 kDa, and its pI was 5.3 kDa and 6.35 kDa. We verified this finding by evaluating the components of wildArtemisia sieversiana allergen extract with two-dimensional electrophoresis analyses [67].To isolate and identify theArtemisia argyi andArtemisia apiacea pollen, Yang et al. [68] precipitatedArtemisia argyi andArtemisia apiacea pollen extract with saturated ammonium sulfate and then evaluated it with SDS-polyacrylamide gel electrophoresis (SDS-PAGE). They identified the major and minor allergens by western blot analysis. Specifically, they found more than twenty protein bands and 9 allergens in theArtemisia argyi pollen extract. The major allergens were 62 kDa, 43 kDa, and 38 kDa. Similarly, in theArtemisia apiacea pollen extract, there were 11 allergens. The major allergens were 43 kDa and 38 kDa. The pollen from both species shares many allergens. Unique allergen protein bands in each of the pollen allergens were also identified.Wu [69] analyzedArtemisia and ragweed extract antigens with SDS-PAGE and western blot analysis. They found that there were 13 bands between 18 kDa and 100 kDa in theArtemisia extract and 5 bands between 18 kDa and 63 kDa in the ragweed extract. Additionally, cross-reactivity between theArtemisia and ragweed extracts existed in the 18 kDa protein.


## 7. Immunological Characteristic inArtemisia Hay Fever Patients

### 7.1. The Th1 and Th2 Balance

Qiu et al. [70] collected tonsil lymphocytes inArtemisia pollen allergic patients and nonatopic people with a lymphocyte separation medium and incubated these cells withArtemisia pollen antigen. They found that the levels of IL-4 and IL-5 in the tonsil lymphocytes of theArtemisia pollen allergic patients were higher than those in the nonatopic controls after they were stimulated with this specific antigen, but the levels of IFN-γ were lower than those in nonatopic controls (P<0.01). Obvious proliferation for the levels of IL-4 and IL-5 was observed in the allergic group after lymphocytes were stimulated with the specific antigen (P<0.01), but there were no significant changes in the control group. The authors demonstrated that cytokines from Th cells of tonsil lymphocytes fromArtemisia pollen-allergic people after they were specifically stimulated byArtemisia pollen antigen became imbalanced, indicating that Th1 drifts to Th2.


### 7.2. Basophils

With 119 hay fever patients who were allergic toArtemisia and 30 nonallergic patients, Zhang et al. [71] found that basophil numbers (mucosal mast cells) in the nasal mucosa as well as nasal eosinophil numbers increased during the pollen season and decreased during the nonpollen season. They concluded that basophils in the nasal mucosa and nasal eosinophils were related to stimulation byArtemisia in hay fever patients.


### 7.3. ICAM-1

Eleven patients withArtemisia allergic rhinitis were evaluated by Wang et al. [72]. Among them, 8 were studied during pollen season and 3 were studied outside of pollen season. Intercellular adhesion molecule-1 (ICAM-1) was detected on nasal epithelial cells by reverse transcription polymerase chain reaction (RT-PCR). The results showed that ICAM-1 was detectable in all of the pollen season samples. However, during the nonpollen season, 2 of the 3 samples were negative and 1 was positive (this subject was also positive to house dust). It was suggested that ICAM-1 is detectable on nasal epithelial cells during exposure to specific allergens (Artemisia).


### 7.4. HLA-DR

To investigate whether susceptibility or resistance toArtemisia allergic rhinitis is associated with HLA-DRB alleles or not, Xing [73] tested the frequency distribution of HLA-DRB alleles in 41 patients withArtemisia allergic rhinitis (AR) and in 41 healthy controls from Beijing, China, using PCR-SSP (sequence-specific primer polymerase chain reaction). The frequency of HLA-DRB1∗ 0301.2 and HLA-DRB4∗ 0101 was lower in the AR subjects than the controls (2.44% versus 17.07%, P<0.05; 29.27% versus 51.22%, P<0.05). They showed that the HLA-DRB1∗ 0301.2 and HLA-DRB4∗ 0101 alleles might confer protection against AR.To determine whether alleles at one or more of the HLA loci were associated withArtemisia pollen hypersensitivity in allergic rhinitis patients, Xing et al. [74] also tested the frequency distribution of the HLA-DQA1 and DQB alleles in 41 patients with allergic rhinitis (AR) and in 41 healthy controls from Beijing with PCR-SSP. They demonstrated that the frequency of HLA-DQA1∗ 0201 and DQB1∗ 0602 was lower in the AR subjects than the controls (24.39% and 4.88% versus 46.34% and 26.83%, resp.) and the frequency of DQA1∗ 0302 was increased among the AR patients (58.54% versus 14.63%). They concluded that the HLA-DQA1∗ 0201 and DQB1∗ 0602 alleles might confer protection against AR and that DQA1∗ 0302 may be anArtemisia pollen hypersensitivity susceptibility factor.


## 7.1. The Th1 and Th2 Balance

Qiu et al. [70] collected tonsil lymphocytes inArtemisia pollen allergic patients and nonatopic people with a lymphocyte separation medium and incubated these cells withArtemisia pollen antigen. They found that the levels of IL-4 and IL-5 in the tonsil lymphocytes of theArtemisia pollen allergic patients were higher than those in the nonatopic controls after they were stimulated with this specific antigen, but the levels of IFN-γ were lower than those in nonatopic controls (P<0.01). Obvious proliferation for the levels of IL-4 and IL-5 was observed in the allergic group after lymphocytes were stimulated with the specific antigen (P<0.01), but there were no significant changes in the control group. The authors demonstrated that cytokines from Th cells of tonsil lymphocytes fromArtemisia pollen-allergic people after they were specifically stimulated byArtemisia pollen antigen became imbalanced, indicating that Th1 drifts to Th2.


## 7.2. Basophils

With 119 hay fever patients who were allergic toArtemisia and 30 nonallergic patients, Zhang et al. [71] found that basophil numbers (mucosal mast cells) in the nasal mucosa as well as nasal eosinophil numbers increased during the pollen season and decreased during the nonpollen season. They concluded that basophils in the nasal mucosa and nasal eosinophils were related to stimulation byArtemisia in hay fever patients.


## 7.3. ICAM-1

Eleven patients withArtemisia allergic rhinitis were evaluated by Wang et al. [72]. Among them, 8 were studied during pollen season and 3 were studied outside of pollen season. Intercellular adhesion molecule-1 (ICAM-1) was detected on nasal epithelial cells by reverse transcription polymerase chain reaction (RT-PCR). The results showed that ICAM-1 was detectable in all of the pollen season samples. However, during the nonpollen season, 2 of the 3 samples were negative and 1 was positive (this subject was also positive to house dust). It was suggested that ICAM-1 is detectable on nasal epithelial cells during exposure to specific allergens (Artemisia).


## 7.4. HLA-DR

To investigate whether susceptibility or resistance toArtemisia allergic rhinitis is associated with HLA-DRB alleles or not, Xing [73] tested the frequency distribution of HLA-DRB alleles in 41 patients withArtemisia allergic rhinitis (AR) and in 41 healthy controls from Beijing, China, using PCR-SSP (sequence-specific primer polymerase chain reaction). The frequency of HLA-DRB1∗ 0301.2 and HLA-DRB4∗ 0101 was lower in the AR subjects than the controls (2.44% versus 17.07%, P<0.05; 29.27% versus 51.22%, P<0.05). They showed that the HLA-DRB1∗ 0301.2 and HLA-DRB4∗ 0101 alleles might confer protection against AR.To determine whether alleles at one or more of the HLA loci were associated withArtemisia pollen hypersensitivity in allergic rhinitis patients, Xing et al. [74] also tested the frequency distribution of the HLA-DQA1 and DQB alleles in 41 patients with allergic rhinitis (AR) and in 41 healthy controls from Beijing with PCR-SSP. They demonstrated that the frequency of HLA-DQA1∗ 0201 and DQB1∗ 0602 was lower in the AR subjects than the controls (24.39% and 4.88% versus 46.34% and 26.83%, resp.) and the frequency of DQA1∗ 0302 was increased among the AR patients (58.54% versus 14.63%). They concluded that the HLA-DQA1∗ 0201 and DQB1∗ 0602 alleles might confer protection against AR and that DQA1∗ 0302 may be anArtemisia pollen hypersensitivity susceptibility factor.


## 8. The Natural Course from Rhinitis to Asthma

A total of 1,096 patients with autumnal pollinosis, which excluded those with typical seasonal rhinitis or asthma symptoms but with positive skin tests and serum IgE specific to dust mites and fungi, included 511 with pure allergic rhinitis and 585 with allergic rhinitis complicated with asthma. These subjects underwent inhalant allergen skin tests, evaluations for serum IgE specific to autumnal pollens, and a questionnaire survey. Yin et al. [75, 76] found that the average onset age of the allergic rhinitis patients induced by autumnal pollens was 27.9 years, and this age was significantly younger than that of the allergic asthma patients (32.6 years, P<0.001). Out of the 1,120 patients, 1,096 (97.9%) had allergic rhinitis, 602 (53.8%) had asthma, 507 (45.3%) only had allergic rhinitis, and 10 (0.9%) only had allergic asthma. Among the 1,096 allergic rhinitis patients, 585 (53.4%) suffered from seasonal asthma. Among the 602 asthma patients, 585 (97.2%) suffered from seasonal rhinitis and 183 of the 602 patients (30.8%) needed emergency treatment. The authors showed that autumnal pollens are very important inducers of asthma during the autumn season in northern China and that almost half of the patients with autumnal pollen allergic rhinitis develop seasonal allergic asthma within 9 years [75–77].From July 1 to October 31, 2006, Wen also observed 18 patients with only allergic rhinitis and 31 patients with allergic rhinitis and asthma [77]. The authors reported that there was a significant correlation between theArtemisia pollen count and the scores for night and daytime asthma symptoms, PEF, and diurnal variation in PEF (rs=0.762, rs=0.682, rs=-0.649, rs=-0.596, rs=0.549, P<0.001). It was also concluded thatArtemisia pollen could trigger autumnal asthma in northern China.


## 9. Diagnostic

To evaluate the value of intradermal skin test (IDT) and serum sIgE detection in diagnosingArtemisia sensitivity, 1,150 patients with autumnal rhinitis or asthma were evaluated by experienced physicians. These subjects then underwent IDT with a 1 : 1,000 dilution of (W/V)Artemisia annua extract [78]. Then, all patients were examined forArtemisia sIgE (w6). The diagnostic standards were established based on the IDT and sIgE results. A reference standard was established according to the typical history and symptoms and a wheal with a diameter ≥ 5 mm and a sIgE level ≥ 0.35 kU(A)/L; a wheal with a diameter ≥ 10 mm alone; or a sIgE level ≥ 0.70 kUa/L alone. When using the reference standard as the criteria, the IDT had better sensitivity (96.2%), specificity (74.2%), positive predictive value (+PV, 93.5%), negative predictive value (−PV, 85.7%), and efficiency (91.6%) than using the sIgE ≥ 0.35 kUa/L alone as the IDT criteria. Additionally, the sIgE detection had better sensitivity (97.6%), specificity (94.9%), +PV (98.7%), −PV (91.1%), and efficiency (97.0%) than using wheal diameter ≥ 5 mm alone as the sIgE detection criteria. The IDT false positive and sIgE detection rates decreased from 35% and 22.7% to 25.6% and 5.1%, respectively, when using a wheal diameter ≥ 10 mm or sIgE ≥ 0.70 kUa/L as the positive criteria.It was showed that IDT and sIgE detection were well correlated with each other in diagnosingArtemisia pollinosis, whereby both of them had the possibility of being false positive, but IDT had a higher false positive rate than sIgE detection. The IDT and sIgE detection false-positive rates can be decreased by increasing the positive criteria to a higher grading criterion.Sera from 50 weed pollen-induced allergic rhinitis patients were tested for specific serum IgE reactivity against allergenicArtemisia extracts (Artemisia vulgaris, Art v) and single Art v 1 or Art v 3 allergens [79]. Sera from 88% of the patients demonstrated a positive specific IgE reactivity to Art v, and of these, 82% were positive to Art v 1. The authors found that specific IgE reactivity towards the major mugwort allergen, Art v 1, was a good indicator for Art v sensitization.


## 10. Immunotherapy

### 10.1. Intradermal Immunotherapy

A one-year controlled trial for an immunotherapy was conducted in 50Artemisia sensitive hay fever patients (treatment group) [80]. From October 1985 to July 1986, all of the treatment group patients received regularArtemisia pollen allergen extract injections over one year, which totaled 30,000 protein nitrogen units (PNU). For these patients, the symptom score indices of the posttreatment 1986 pollination season were compared with those from the pretreatment 1985 season and also with the scores of a similar group of 30Artemisia sensitive patients treated only with symptomatic medications during the 1986 season (control group). The 1986 symptom scores for the treatment group were significantly improved, and the effective rate was 78%. An immunological study with the human basophil degranulation test (HBDT) showed a significant decrease in degranulation reactions after immunotherapy. Moreover, the decline in the HBDT positive rate in the treatment group was significantly greater in the patients with improved symptoms than the patients with unchanged symptoms. No difference was observed in basophil degranulation in those patients tested with a pollen-free plant extract, which was not applied in the immunotherapy. The results suggested that immunotherapy could induce basophil desensitization and that the induction might be allergen specific. Basophil desensitization may play an important role in immunotherapy mechanisms.


### 10.2. Oral Immunotherapy

In 1989, eighteen asymptomaticArtemisia pollen asthma patients with normal pulmonary functions were selected for a double-blinded oral immunotherapy trial [81]. Each patient had a positiveArtemisia pollen extract skin test and also had a positive bronchial challenge response to the same extract. The patients were randomly assigned to an active treatment or a placebo group and received intensive oral administration ofArtemisia pollen extract over a 50-day course. The nine patients who received the active treatment ingested a cumulative dose of 396,652 PNU and showed a significant decrease in serum-specific IgE antibodies (P≤0.05) and a significant reduction in bronchial sensitivity to the same extract (P≤0.01). The changes in these two variables correlated well. The nine patients who received the placebo showed no significant changes in serum-specific IgE or bronchial sensitivity to theArtemisia pollen extract. Follow-ups for two cases with the same extract showed that the reductions in serum-specific IgE as well as bronchial sensitivity induced by oral immunotherapy were maintained for 3 months.Clinically, sublingual immunotherapy (SLIT) that uses allergen extracts effectively alleviates allergic rhinitis and asthma symptoms. Ma et al. [82] hypothesized that the oral administration of a high dose of allergen extracts imitates SLIT and may prevent IgE-related responses in allergic diseases. In this study, they investigated the effects of the oral administration of mugwort (Artemisia) pollen (MP) allergen extracts on allergen-induced inflammation and airway hyperresponsiveness (AHR) in an allergic mouse model. After the administration of MP drops containing Art v 1 and Art v 4 extracts derived from MP specifically in MP-sensitized mice, the effects of the MP drops on AHR, inflammatory cell accumulation, cytokine production in the bronchoalveolar lavage fluid and lung tissue, and serum IgE and IgG levels were investigated. The results indicated that the MP drops not only prevented AHR in response to methacholine in a dose-dependent manner but also significantly reduced the total serum and allergen-specific IgE levels. All of the maximal effects were achieved at a dose of 100 μg/(kgd) and were comparable to the effects of dexamethasone at a dose of 0.5 mg/(kgd). Furthermore, the oral administration of the MP drops dose dependently elevated allergen-specific serum IgG2a levels, reduced total and allergen-specific IgE levels, and normalized the imbalance between the Th1 cytokine IL-12 and the Th2 cytokines IL-4 and IL-5. Finally, the oral administration of the MP drops significantly reduced goblet cell hyperplasia and eosinophilia in the MP-sensitized allergic mouse model. These sets of data suggest that the MP drops effectively improve specific allergen-induced inflammation and AHR in MP-sensitized and MP-challenged mice and provide the rationale for the clinical use of MP drops in specific allergen-induced asthma. Currently, a Stage I clinical SLIT trial forArtemisia annuaL. was permitted by the Chinese Food and Drug Administration for one Chinese pharmaceutical company (http://www.sfda.gov.cn/WS01/CL0001/).


## 10.1. Intradermal Immunotherapy

A one-year controlled trial for an immunotherapy was conducted in 50Artemisia sensitive hay fever patients (treatment group) [80]. From October 1985 to July 1986, all of the treatment group patients received regularArtemisia pollen allergen extract injections over one year, which totaled 30,000 protein nitrogen units (PNU). For these patients, the symptom score indices of the posttreatment 1986 pollination season were compared with those from the pretreatment 1985 season and also with the scores of a similar group of 30Artemisia sensitive patients treated only with symptomatic medications during the 1986 season (control group). The 1986 symptom scores for the treatment group were significantly improved, and the effective rate was 78%. An immunological study with the human basophil degranulation test (HBDT) showed a significant decrease in degranulation reactions after immunotherapy. Moreover, the decline in the HBDT positive rate in the treatment group was significantly greater in the patients with improved symptoms than the patients with unchanged symptoms. No difference was observed in basophil degranulation in those patients tested with a pollen-free plant extract, which was not applied in the immunotherapy. The results suggested that immunotherapy could induce basophil desensitization and that the induction might be allergen specific. Basophil desensitization may play an important role in immunotherapy mechanisms.


## 10.2. Oral Immunotherapy

In 1989, eighteen asymptomaticArtemisia pollen asthma patients with normal pulmonary functions were selected for a double-blinded oral immunotherapy trial [81]. Each patient had a positiveArtemisia pollen extract skin test and also had a positive bronchial challenge response to the same extract. The patients were randomly assigned to an active treatment or a placebo group and received intensive oral administration ofArtemisia pollen extract over a 50-day course. The nine patients who received the active treatment ingested a cumulative dose of 396,652 PNU and showed a significant decrease in serum-specific IgE antibodies (P≤0.05) and a significant reduction in bronchial sensitivity to the same extract (P≤0.01). The changes in these two variables correlated well. The nine patients who received the placebo showed no significant changes in serum-specific IgE or bronchial sensitivity to theArtemisia pollen extract. Follow-ups for two cases with the same extract showed that the reductions in serum-specific IgE as well as bronchial sensitivity induced by oral immunotherapy were maintained for 3 months.Clinically, sublingual immunotherapy (SLIT) that uses allergen extracts effectively alleviates allergic rhinitis and asthma symptoms. Ma et al. [82] hypothesized that the oral administration of a high dose of allergen extracts imitates SLIT and may prevent IgE-related responses in allergic diseases. In this study, they investigated the effects of the oral administration of mugwort (Artemisia) pollen (MP) allergen extracts on allergen-induced inflammation and airway hyperresponsiveness (AHR) in an allergic mouse model. After the administration of MP drops containing Art v 1 and Art v 4 extracts derived from MP specifically in MP-sensitized mice, the effects of the MP drops on AHR, inflammatory cell accumulation, cytokine production in the bronchoalveolar lavage fluid and lung tissue, and serum IgE and IgG levels were investigated. The results indicated that the MP drops not only prevented AHR in response to methacholine in a dose-dependent manner but also significantly reduced the total serum and allergen-specific IgE levels. All of the maximal effects were achieved at a dose of 100 μg/(kgd) and were comparable to the effects of dexamethasone at a dose of 0.5 mg/(kgd). Furthermore, the oral administration of the MP drops dose dependently elevated allergen-specific serum IgG2a levels, reduced total and allergen-specific IgE levels, and normalized the imbalance between the Th1 cytokine IL-12 and the Th2 cytokines IL-4 and IL-5. Finally, the oral administration of the MP drops significantly reduced goblet cell hyperplasia and eosinophilia in the MP-sensitized allergic mouse model. These sets of data suggest that the MP drops effectively improve specific allergen-induced inflammation and AHR in MP-sensitized and MP-challenged mice and provide the rationale for the clinical use of MP drops in specific allergen-induced asthma. Currently, a Stage I clinical SLIT trial forArtemisia annuaL. was permitted by the Chinese Food and Drug Administration for one Chinese pharmaceutical company (http://www.sfda.gov.cn/WS01/CL0001/).


## 11. Summary

Artemisia pollen is a major important outdoor allergen in China. It has been verified as an allergen by nasal challenge and bronchial provocation tests, and these allergens have been shown to occur not only in its pollen but also in its leaves and stems. Two national allergenic pollen surveys have been conducted in China. The main allergenicArtemisia species in mainland China were recorded and described by color photos. Immunological changes fromArtemisia pollen-allergic subjects were studied, including Th1 and Th2 balance, basophils, HLA-DR, and ICAM-1.Artemisia pollen can trigger not only allergic rhinitis but also asthma alone or both of them. Almost half of the patients with autumnal pollen allergic rhinitis developed seasonal allergic asthma within 9 years. IDT and sIgE detection are well correlated with each other inArtemisia pollinosis diagnoses. Specific IgE reactivity towards the major mugwort allergen Art v 1 is a good indicator for Art v sensitization. In 1989, asymptomaticArtemisia pollen asthma patients were selected for a double-blinded oral immunotherapy trial. Recently, a Stage I clinical SLIT trial forArtemisia annuaL. was permitted by the Chinese Food and Drug Administration for one Chinese pharmaceutical company.Artemisia immunotherapy could induce the desensitization of basophils, and basophil desensitization may play an important role in immunotherapy mechanisms.



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*Source: 179426-2015-04-27.xml*