Chinese Society of Allergy Guidelines for Diagnosis and Treatment of Allergic Rhinitis

2.4.1 Bronchial asthma

AR is an independent risk factor for the onset of asthma, and 40% of AR patients have or will have asthma.30 As the upper and lower airway inflammatory responses are similar and interconnected in these individuals, this could be described as “one airway, one disease.” For AR patients, diagnosis for the coexisting asthma should be based on the patient's medical history, symptoms and lung function examination. Indeed, the 2004–2005 survey of AR patients in the 11 major cities in China showed that among all the subjects with self-reported AR, an average of 9.2% suffered from asthma31: Beijing (12.7%), Changchun (8.3%), Changsha (7.5%), Guangzhou (5.4%), Hangzhou (13.1%), Nanjing (9.2%), Shanghai (9.3%), Shenyang (8.8%), Urumqi (6.3%), Wuhan (4.3%) and Xi'an (9.6%). Similarly, in 2011, a survey consisting of total 47, 216 telephone interviews showed that the prevalence of asthma in the AR subpopulation was 28% (23).

2.4.2 Allergic conjunctivitis

Itchy/watery eyes, redness and other eye symptoms are the main symptom of AR patients with allergic conjunctivitis, especially seasonal AR patients, whose incidence could be as high as 85%.32 The AR survey during the year 2005-2011 showed that the incidence of eye symptoms in AR patients was 32%–59% based on medical history and clinical manifestation.26 It is not difficult to diagnose allergic conjunctivitis, but differential diagnosis for other common conjunctival lesions should be noticed.

2.4.3 Chronic rhinosinusitis

Allergic inflammation is a major factor related to chronic rhinosinusitis (CRS).33 The cross-sectional survey of 7 cities in China recently showed the prevalence of CRS ranging from 4.8% to 9.7%.34 Moreover, the prevalence of CRS was found to be 30% in AR patients and 23% in asthmatic patients, compared to just 6% and 7%, respectively, in subjects without AR or asthma. Similarly, larger surveys of subjects with self-reported AR from 11 and 18 major cities across China have demonstrated 13.3%31 and 10.1%, respectively, of the AR patients26 to have CRS. In another study, among all the 1,411 participants over 15 years old, 118 (8.4%) had self-reported CRS; patients with CRS had an increased prevalence of AR and chronic obstructive pulmonary disease compared to those without.35 Furthermore, the quality of life was significantly impaired in patients with CRS than in those without, with the quality of sleep being markedly impaired in CRS patients. Although this study did not assess the correlation between CRS severity and impairment of sleep, it is possible that the impairment in CRS patients with AR may indeed be correlated with the severity of CRS as shown in patients with AR.

2.4.4 Upper airway cough syndrome

AR and sinusitis are a common cause of chronic cough in children and adults.12, 36 Nasal secretions reflux from the nose and the throat directly or indirectly stimulate cough. Cough resulting from chronic sinusitis may thus be the main clinical manifestation of upper airway cough syndrome (UACS). A pilot study of 393 children with cough as a chief complaint in Chengdu has recently shown that 45.8% of the children suffered from AR. Similarly, a multicenter survey investigating causes of chronic cough in China found that UACS was most frequently associated with AR (63.4%).37

2.4.5 Otitis media

Secretory otitis media (SOM) is a nonsuppurative inflammatory disease. Middle ear effusion—which includes serous fluid and pulp-like mucus—and hearing loss are the main features, and AR is regarded as one of the possible risk factors inducing SOM in children.12 Indeed, one study from the UK found that the prevalence of AR in patients with chronic or recurrent OME ranged from 24% to 89%.38 Similarly, a study from Qingdao city in China has indicated that children with SOM have increased annual frequency of AR.

• 1) The type of allergen

  • a) SAR: the onset of symptoms is seasonal. Aeroallergens (pollen and fungi) are the most common allergens.

  • b) Perennial AR: the onset of symptoms is year-round. The allergens include dust mites, animal dander, tree pollen, etc.

• 2) The frequency of symptoms4, 10, 11, 80

  • a) Intermittent AR: <4 days/week or <4 weeks/year

  • b) Persistent AR: ≥4 days/week and ≥4 weeks/year

• 3) The severity of symptoms4, 10, 11, 80

  • a) Mild AR: the symptoms are not interfering with quality of the patient's lifestyle including daily life, work, study, etc.

  • b) Moderate-severe AR: the symptoms cause severe trouble in quality of the patient' life.

6.1.1 Genetics

AR, like other allergic diseases, is an inflammatory disease with a complex genetic component in the etiology of AR. Based on the European studies of twins, it was estimated that AR exhibited a heritability ranging between 33% and 91%.87, 88 In China, a genetic epidemiologic study involving 23,825 families from Jiangsu province reported that the average AR heritability of the first, the second, and third generations was 81.86%.89 Earlier studies using genome-wide linkage scans for AR in affected-sib-pair families from European and Japanese populations demonstrated that the chromosomes 1p31, 2q32, 3p24-p14, 4q32.2, and 9q22-q34 were likely to contain the candidate gene loci associated with the development of AR.90, 91, 92

With the rapid development of genotyping techniques, large population-based association strategies have been carried out more widely to investigate specific susceptibility genes for AR. Because of the important role in antigen presentation, the human leukocyte antigen (HLA) is known to be an important genetic susceptibility locus for a variety of allergic diseases. Moreover, several HLA alleles have been shown to be associated with AR in different ethnic groups. In an earlier study, Lin and colleagues93 first investigated the association between several HLA alleles (HLA-B27, RR of A31, A28, B12, and A33) and the genetic susceptibility of AR in a Chinese population. Subsequently, several studies have been performed in different ethnic groups from different parts of China (northeastern area,94 Beijing,95, 96, 97 Xinjiang98) and demonstrated a strong association between HLA class II alleles (DR and DQ) and AR. However, these studies have been limited by the complicated nature of the genotyping procedures employed and the small sample sizes (<100 AR patients) investigated. More recently, Zhao and colleagues99 have employed polymerase chain reaction sequence-based typing (PCR-SBT), a form of higher resolution HLA typing, to assess the HLA-II gene alleles associated with AR in HDM-sensitive Han Chinese subjects and control subjects. The authors reported that HLA-DQB1*06:01:01 and HLA-DRB1*08:03:02 were significantly increased in HDM-sensitive AR patients compared to healthy controls, suggesting that these alleles may confer a risk of AR in Han Chinese subjects sensitized to HDM.

Candidate gene studies have also implicated a number of several other susceptibility genes related to AR in Chinese subpopulations (Fig. 4). These include cytokines (IL13,100, 101 IL4,102 IL12B,103 IL17A,103, 104 17F,102 IL6,105 IL27106) cytokine receptors (IL23R,107 IL12RB1,108 and EBI3109) immunity pathway molecules (JAK1,110 FCRL3,111 TNFSF4,112 CTLA4,113 CD14,114 TNFA,115 PBX2,116 TAP1,117 TNFAIP3,118 FAM167A-BLK,112 GATA3,119 IRAK4,120 RORA,103 TGFB1,121 and FOXP3109), allergic airway inflammation and airway remodelling molecular genes (BDNF,122 CYP2R1,123 VDR,123 ACE,124, 125, 126 MRPL4,115 ADAM33127, 128), and others (rs4982958 at 14q11.2).129 Fig. 4 shows that Chinese subpopulations and other ethnic groups, including white European, Koreans and Japanese, share a large number of these genetic susceptibility loci.

Fig. 4
Susceptibility loci of AR in Chinese population studies. Some loci were reported only in Chinese populations (loci shown in black) or in both Chinese populations and other ethnic populations (loci shown in red).

• Click for larger image
• Download as PowerPoint slide

Loci on the chromosome 5q31-33 have been shown to be hotspots for AR susceptibility. These loci contain a cluster of cytokines and immune-related genes such as IL-13, IL-4, CD14, and IL-12B. Ying and colleagues101 conducted a meta-analysis involving Asian (China, Japan, and Korea) and Caucasian (Spain Germany and UK) subjects, and found that the functional single nucleotide polymorphism (SNP) rs20541 in the IL-13 gene was significantly associated with AR, particularly in Asians. However, inconsistent data from other studies suggest that rs20541 may explain little of the heritability of AR.130 Recently, Li and colleagues131 found that the DNA hypomethylation status of specific CpG islands located ~2 kb upstream of the IL-13 gene may be an independent risk factor for HDM-sensitive AR. Likewise, IL-4, another important Th2 cytokine gene, has multiple polymorphisms, including rs2243250, which regulates IL-4 gene expression and has been reported to be associated with AR in many ethnic groups (Chinese, Caucasian, and others).130 The best gene-environment interaction presented in allergy to date should be SNPs in the CD14 gene, which plays a critical role in the innate immune response to microbial invasion. However, the association between CD14 genotypes and AR was found to be controversial in different studies in the Chinese population.114 Except for HLA loci, chromosome 6 has several susceptible loci (TNFA, PBX, TAP1, IL17A, IL17F, and TNFAIP3) for AR. The study of Zhang and colleagues115 demonstrated a genotype-dependant association pattern with regard to the SNP rs1799964 in the TNFA gene vs AR development in a Chinese population.

Some allergic airway inflammation and airway remodelling molecular genes have been shown to be as important as immune-related genes for AR susceptibility. Jin and colleagues,122 have identified an association of a common functional SNP rs6265 in the brain-derived neurotrophic factor (BDNF) gene with AR risk and disease severity in 2 independent populations of Chinese patients with moderate-to-severe AR. A series of studies have focused on the correlation of the polymorphism based on the presence (insertion/deletion) of a non-sense DNA fragment in the angiotensin-converting enzyme (ACE) gene, exerting an anti-inflammatory effect by inactivating different proinflammatory peptides with and AR risk in different populations (also including Chinese populations).124, 125, 126 Similarly, the association of T1, T2, V4, and Q-1 polymorphisms in Disintegrin with the metalloproteinase 33 (ADAM33) gene encoded for a protein important for airway remodelling and AR have also been investigated in some Chinese studies.127, 128

To date, 3 genome-wide association studies (GWAS) have been performed specifically for the AR phenotype. Andiappan and colleagues132 first employed GWAS strategy in a cohort of 4,461 ethnic Chinese individuals in Singapore and demonstrated that SNPs in mitochondrial ribosomal protein L4 (MRPL4) and B-cell adaptor for phosphatidylinositol 3-kinase (BCAP) were suggestively associated with AR. A recent study in a Han Chinese population demonstrated that SNPs in the MRPL4 was strongly associated with the risk of AR.115 However, other association signals have not yet replicated in other populations.

Despite the overlapping genetic susceptibility to AR in the Chinese population and other ethnic populations, genetic heterogeneity also plays an important role in explaining the apparent discrepancy in the genetic studies between races.

Although remarkable progress has been made in the genetics of AR and allergy, several limitations of these studies remain to be overcome; in particular, the confounding effects of endophenotyping, sample size, unmapping variants, epigenetic effects, gene-gene/gene-environment interactions, and functional validation. Furthermore, Zhang and colleagues103 recently provided evidence that there are wide interactions among the crucial genes involved in the effector T-cell pathways and that the T helper 17 (Th17) pathway is a key player in developing susceptibility to AR. Therefore, future research should systematically integrate “overall data” from genomics, proteomics, epigenomics, and metabolomics to provide new insights into precision medical treatments for AR.

6.1.2 microRNA

Genetic regulation plays an undoubted role in the pathogenesis of AR. Because they function as endogenous inhibitors of translational processes, microRNA (miRNA/miR) is a class of short, noncoding RNAs that have emerged as important regulators of gene expression in the immune system.133 Altered miRNA expression profiles have been identified in AR. In this regard, 7 up-regulated and 10 down-regulated miRNAs were recently identified in activated bone marrow-derived mast cells following IgE-FcεRI cross-linking with antigen, suggesting that these miRNAs may exert considerable influence on core signalling pathways and biologic behaviors.134 Among these altered miRNAs, miR-21a-3p and miR-3113-5p were the most remarkably up-regulated and down-regulated miRNAs according to the bioinformatics algorithm.134 Some miRNAs can modify the messenger RNA (mRNA) and protein expression of the chemokines and transcription factors directly. The miRNA microarray chip analysis has shown that miR-224, miR-187, and miR-143 were down-regulated in AR patients,135 among which miR-143 has been shown to decrease the mRNA and protein expression levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), eotaxin, and mucin 5AC (MUC5AC) in IL-13-stimulated nasal epithelial cells through direct suppression of IL-13 receptor α1 chain (IL13Rα1).136 This is particularly relevant as IL-13 plays an important role in the pathogenesis of allergic inflammation. In addition, miR-135a can down-regulate the mRNA and protein expression levels of GATA- binding protein-3 and IL-4, and up-regulate the expression levels of T-bet and IFN-γ, thus correcting the Th1/Th2 imbalance in AR mice.137 The potential effects of miR-143 and miR-135a on signalling pathways in AR development are briefly illustrated in Fig. 5.

Fig. 5
The potential effects of miR-143 and miR-135a on signaling pathways. While miR-143 can inhibit the expression of GM-CSF, eotaxin, and MUC5AC by suppressing the IL13Rα1 signalling pathway, miR-135a can down-regulate the mRNA and protein expression levels of GATA-3 and IL-4 and up-regulate the expression levels of T-bet and IFN-γ, thereby correcting the Th1/Th2 imbalance.

• Click for larger image
• Download as PowerPoint slide

Some miRNAs could predict the onset of AR. Suojalehto and colleagues138 have reported that miR-205, miR-155, and miR-498 were up-regulated in the nasal mucosa of currently symptomatic AR, whereas let-7e was down-regulated in currently nonsymptomatic AR. Notably, Chen and colleagues139 found that miRNA-21 expression levels were significantly low in mononuclear leucocytes from cord blood samples with elevated cord blood IgE (CBIgE) and in monocytes from AR children, indicating that miRNA-21 may be an early predictor of AR and a possible therapeutic target for treating AR. However, further studies are needed reveal the full impact of miRNAs in the development of AR as well as to reveal their potential as therapeutic targets and noninvasive biomarkers in AR.

6.2.1 General concept

The symptoms of AR are a result of inhaled allergen-induced inflammation in the nasal mucosa, which is characterized by a Th2-dominated immune response associated with increased levels of serum IgE.140, 141

Similar to other allergic diseases, the immune response in AR begins with sensitization. When the nasal mucosa is exposed to allergens, the allergens are captured and processed by antigen-presenting cells (mainly dendritic cells) and presented to naïve T cells. Naïve T cells then differentiate into Th2 cells which produce IL-4, IL-5, and IL-13. The IL-4 and IL-13 cytokines, together with the ligation of matched co-stimulatory molecules in Th2 cells and B cells, promote B cell phenotype switching to produce allergen specific IgE. Thereafter, the allergen-specific IgE binds to its high-affinity receptors (FcεRI) on the surface of mast cells and basophils, causing sensitization of these 2 cell types (Fig. 6).142

Fig. 6
The process of allergen sensitization in AR. Following exposure of nasal mucosa to allergens, allergens are captured, taken up, and processed by dendritic cells (DCs). Subsequently, DCs are activate and, mature, and migrate to regional lymph nodes or to sites in the local mucosa, where they present allergen-derived peptides in the context of MHC class II molecules to naïve T cells. Naïve T cells then differentiate into Th2 cells, which produce IL-4 and IL-13 in the presence of early IL-4. In the presence of these Th2-derived cytokines, together with ligation of the suitable co-stimulatory molecules (CD40 ligand with CD40 and CD28 with CD80), B cells undergo immunoglobulin class-switch recombination to produce IgE antibodies. The locally and/or systemically diffused IgE binds to the high-affinity receptors (FcεRI) on mast cells and basophils (not shown), and results in sensitization of these cells (adapted from Galli and colleagues [142]).

• Click for larger image
• Download as PowerPoint slide

Re-exposure of sensitized individuals to the sensitizing allergens leads to a cascade of pathologic events, and subsequently the symptoms of AR. Allergic responsiveness can generally be divided into 2 phases: the immediate or early-phase and the late-phase responses.140

The early phase response occurs in sensitized individuals within minutes of allergen exposure, with mast cells and basophils being the best-known effector cells in this phase. Mast cells are abundant in the epithelial compartment of nasal mucosa in the sensitized individuals and can be easily activated upon re-exposure to the allergens. Cross-linking of the allergen-specific IgE-FcεRI complexes on the mast cell and basophil surfaces by specific allergen triggers secretion of 3 classes of biologic products: those stored in cytoplasmic granules, lipid-derived mediators, and newly synthesized cytokines, chemokines, and growth factors as well as other products.140 These mediators collectively result in vasodilation, increased vascular permeability, and mucus production, as well as stimulation of sensory nerves, which evoke the symptoms of nasal itching, rhinorrhea, sneezing and congestion (Fig. 7).142

Fig. 7
Early and late phase reactions in AR. (A) Early phase reaction: Ligation of allergen-specific IgE-FcεRI complexes by the corresponding allergen on mast cells activates mast cells to secrete preformed mediators (e.g. histamine and tryptase) and lipid-derived mediators (e.g. PGD2, LTB4 and PAF), which increase vascular permeability, mucus secretion, and blood vessel dilation. This results in watery rhinorrhea, mucosal edema, and nasal congestion. Stimulation of sensory nerves in the nose results in sneezing and sensations of nasal itch and congestion (adapted from Galli and colleagues [142]). (B) Late phase reaction: Ligation of IgE-FcεRI complexes by allergen on mast cells results in release of newly synthesized cytokines, chemokines and growth factors, which contribute to the late phase reaction. Mast cells promote the influx and activation of inflammatory leukocytes (such as neutrophils, eosinophils and T cells) by producing TNF-α, LTB4, IL-5, IL-8, and CCL2. T cells that recognize allergen-derived peptides also release products (e.g. IL-4, IL-13, and IL-9) and contribute to late-phase reactions. IL-4 and IL-13 released by Th2 cells can stimulate mast cells to produce more IgE and induce goblet cell hyperplasia, which results in excess mucus production. The recruited immune cells have some downstream effects. For example, elastase released by neutrophils promotes activation of matrix metalloproteinases and degradation of type III collagen. Basic proteins released by eosinophils can cause epithelial cell damage (adapted from Galli and colleagues [142]).

• Click for larger image
• Download as PowerPoint slide

Late-phase reaction typically develops at 2 to 6 hours after allergen exposure and is characterized by a prolongation of sneezing, rhinorrhea and a predominantly sustained nasal congestion. A variety of mediators and cells are involved in this phase. Some mast-cell products such as TNF-α, LTB4, IL-5, and IL-8/CXCL8 have the potential to recruit and activate other immune cells including monocytes, T cells, eosinophils and basophils. The released products of mast cells (e.g. histamine, LTB4, PGD2, and TNF-α) can also modulate the activity of dendritic cells, T cells and B cells, or influence structural cells (including vascular endothelial cells, epithelial cells and nerve cells). On the other hand, some mast cell products (e.g. IL-10 and TGF-β) have anti-inflammatory or immunosuppressive functions. The recruited immune cells, however, may lead to some tissue damage and remodelling, for example, eosinophil basic protein induces epithelial cells injury, and Th2 cytokines (IL-4, IL-5, and IL-9) provoke more IgE production, goblet cell hyperplasia, and excess mucus production (Fig. 7).142

In addition to the common pathophysiologic pathways detailed above, other mechanisms are also likely to be involved in AR. Although epithelial cells are important structural cells playing major roles in providing an effective barrier to entry of foreign particles, secretion of mucus, and removal of foreign agents by virtue of possessing cilia, increasing evidence shows that epithelial cells also have potent immunomodulatory activities through synthesizing and releasing cytokines and chemokines (e.g. CCL2, CCL20, GM-CSF, IL-1β, TSLP, IL-25, and IL-33).143 The epithelial cytokines and chemokines mediate the cross-talk between epithelial cells and immune cells,144 and thus bridge the innate and adaptive immunity in nasal tissues. Nasal epithelial cells in patients with AR may also play a role in antigen presentation through enhanced expression of HLA-DR and CD86.145 It has been proposed that diesel exhaust particles disrupt tight junctions and increase the paracellular permeability in RPMI 2,650 cells (a human nasal epithelial cell line) in vitro.146

Evidence from some recent studies suggests that regulatory T cells (Treg)147 and Th17 cells,148 type 2 innate lymphoid cells,149 miRNA,137, 150 follicular Th cells,151 and regulatory B cells151 may also play a role in AR. Indeed, apart from the well-documented classic immunopathologic mechanisms of AR, the following potential immunologic mechanisms may play key roles in AR.

1) Self-amplification mechanisms of mast cell activation

It has previously been advocated that at least 2 pathways exist in humans for mast cells to amplify their own activation-degranulation signals in an autocrine or paracrine manner,152 which may partially explain the phenomena that when a sensitized individual contacts allergen only once, the local allergic response in the involved tissue or organ may last for days or weeks. These pathways include the tryptase-protease-activated receptor (PAR)-2 pathway and the histamine-H1 receptor pathway (Fig. 8).

Fig. 8
Self-amplification mechanisms of mast cell degranulation. IL, interleukin; GM-CSF, granulocyte/macrophage colony-stimulating factor; PAR, protease activated receptor (adapted from He and colleagues [152]).

• Click for larger image
• Download as PowerPoint slide

Several self-amplification mechanisms of mast cell activation have been reported. For example, while IL-36 released from the mast cells153 can selectively induce retinaldehyde dehydrogenase-II release154 from mast cells, GM-CSF secreted from mast cells153, 155 is able to induce IL-4 release from mast cells.156 IL-4 secreted from mast cells157 can in turn amplify the classic Fc epsilonRI-dependent mast cell activation and release of cysteinyl leukotrienes,158 and in synergy with stem cell factor (SCF), IL-4 strongly enhances mast cell proliferation and shifts IgE-dependent cytokine production in mature human mast cells toward an increased release of Th2 cytokines IL-5, and IL-13.159

2) Self-amplification mechanisms of mast cell accumulation

The fundamental requirement for paracrine self-amplification mechanisms of mast cell activation is the presence of a relatively high density of mast cells in the involved tissues. It has long been recognized that the numbers of mast cells in allergic tissues such as lung160 and skin161 are dramatically increased, but the mechanisms through which mast cells are accumulated remain obscure. Generally speaking, mast cells can be accumulated by 2 mechanisms: (1) migration from adjacent tissues or from blood and (2) local generation in the tissue (Fig. 9).

Fig. 9
Self-amplification mechanisms of mast cell accumulation. IL, interleukin; pMC, pregenitor mast cell; MC, mast cell; SCF, stem cell factor; TNF, tumor necrosis factor; RANTES, regulated upon activation normal T cell expressed and secreted; MCP-1, monocyte chemotactic protein-1; PAF, platelet-activating factor (adapted from He and colleagues [152]).

• Click for larger image
• Download as PowerPoint slide

Numerous mast cell products have been found to be able to induce mast cell migration. Thus, while histamine has been shown to induce chemotaxis of mouse mast cells through histamine H4 receptor,162 PAF has been identified as a potent chemoattractant of both murine and human mast cells.163 Interactions of eotaxin, RANTES, and MCP-1 with CCR3 on basophils and mast cells are responsible for the recruitment of these cells.164 While IL-6165 and TNF166 stimulate migration of mast cells in the presence of laminin, IL-4 induces homotypic aggregation of human cord blood mononuclear progenitor cells (hCBMCs) in the presence of SCF and IL-6.167 SCF by itself is capable of inducing the migration of mast cells via its receptor c-Kit.168 Moreover, IL-29 has been found to be released from mast cells and is able to induce mast cell infiltration in mouse peritoneum by a CD18- and ICAM-1-dependent mechanism.169 Mast cells are found to express and release significantly higher concentration of IL-8 and expression of IL-8 receptors CXCR1 and CXCR2, through which IL-8 recruits mast cells.170

Little is known about whether mast cells can be generated in tissue, but a report that two-thirds of freshly dispersed mast cells from skin cultured with recombinant human SCF showed evidence of proliferation suggests that mast cells may have the ability to proliferate in skin tissue.171 Although there is a lack of direct evidence that mast cells can be derived from tissue stem cells, the finding that mast cells can be obtained from bone marrow and cord blood CD34172- or CD133- positive progenitor cells173 in the presence of IL-6 and SCF,174 strongly suggests that tissue stem cells could possibly be driven to differentiate into mast cells under inflammatory conditions.

4) Contribution of Tregs to AR

In recent years, Tregs have emerged as key cells involved during the sensitization phase of the pathogenesis of allergy.183 It is recognized that acquired immunity is controlled by Tregs that suppress responses of effector T cells. Tregs can be classified into natural Tregs (nTreg)184 including inducible costimulator (ICOS)(+) Tregs,185 inducible/adaptive Tregs (iTreg),186 IL-10-producing type 1 Tregs (Tr1 cells),187 CD8(+) Tregs188 and IL-17-producing Tregs.189 These cells share some common features including expression of Foxp3 (except for Tr1 cells) and secretion of inhibitory cytokine IL-10 and/or TGF-β (Table 5). It is apparent that Tregs are likely contribute to allergic disorders and play a crucial role in the treatment of allergy through their actions on suppression of effector T cells and inhibition of activation of mast cells and basophils. Thus, modulation of the functions of Tregs may provide a novel strategy for preventing and treating allergic diseases.

Table 5
Characteristics of subsets of Treg cell

• Click for larger image
• Click for full table
• Download as Excel file

There is increasing interest in the role of both nTreg and iTreg populations in preventing hypersensitive immune responses and the underlying sensitization to allergens. It was speculated as early as 2006 that Tregs may actively prevent Th2 responses to allergens occurring in healthy nonatopic individuals and that their functions may be impaired in allergic patients.190 It has been suggested that peripheral T-cell tolerance to environmental antigens is crucial for the avoidance of allergy and that aberrant activation of Th2 cells in allergy is secondary to impaired mechanisms of peripheral T-cell tolerance normally mediated by antigen-specific T-cell anergy, Tregs and the suppressive cytokines IL-10 and TGF-β. Therefore, the most appealing therapy for allergic diseases would be allergen-specific immunotherapy191 that reduces Th2 cytokine production and promotes induction of anergy, Treg, and suppressor cytokines.192

A study which investigated allergen-induced Th2, Th1 and Treg immune responses in peripheral blood mononuclear cells (PBMC), and their association with symptom improvement in AD patients after 3 years of AIT showed that both IL-4 expression and the IL-4/IFN-gamma ratio were decreased in patients with a good therapeutic outcome after 1 year of AIT, whereas the induced Treg and Th1 responses persisted over 3 years after AIT.193

6.2.2 Innate type 2 immune response

CD4+ Th2 cells play a significant role in AR. Indeed, type 2 cytokines produced by Th2 cells such as IL-4, IL-5 and IL-13 drive many features of allergic rhinitis. Group 2 innate lymphoid cells (ILC2s) are a newly recognized subset of the innate lymphoid cell family, which rapidly and dramatically produces IL-5 and IL-13 in response to IL-25 or IL-33194, 195, 196 and is likely to play a role in the etiology of AR (Fig. 10). ILC2s are morphologically similar to, but smaller than lymphocytes. ILC2s lack T-cell, B-cell, natural-killer cell or other cell lineage markers, but express the IL-7 receptor α-chain (CD127), c-Kit, Sca-1, etc.194, 195, 197, 198, 199 ILC2s produce dramatic amounts of IL-5 and IL-13, and some IL-4 in response to the Th2 cell-stimulating cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) produced by epithelial cells.200, 201, 202, 203, 204 The discovery of ILC2s puts forward a new challenge to the traditional opinions that T helper type 2 (Th2) cells play a dominant role in Th2-skewed allergic diseases. There may, however, be some interactions between ILC2 and Th2 cells via some cytokines as shown in Fig. 10. ILC2s may interact with T cells through both cytokine secretion and specific molecules on the cell surface. ILC2s may regulate T cell differentiation through antigen presentation via major histocompatibility complex (MHC) class II and through the production of IL-6. In turn, T cells support the maintenance and proliferation of ILCs through production of IL-2 and IL-9.205

Fig. 10
The role of ILC2 in AR. Type 2 responses are initiated by allergens that disrupt the epithelial barriers and induce secretion of IL-25, IL-33, and TSLP. IL-25 and IL-33 activate ILC2s to produce the type 2 cytokines IL-5 and IL-13. Epithelial cytokines also activate DCs to induce Th2 responses. Secretion of IL-5 by ILC2s leads to the recruitment and activation of mast cells and eosinophils. The activation of T cells further amplifies the secretion of type 2 cytokines, and the production of IL-4 and IL-13 by T cells leads to the production of IgE by B cells. Together, the responses triggered by secretion of type 2 cytokines from ILC2s and Th2 cells play an important role in inducing allergic inflammation.

• Click for larger image
• Download as PowerPoint slide

ILC2s have been reported to be involved in the pathology of both asthma and AR in animals and humans. Studies of adaptive immunodeficiency mice have demonstrated that influenza-,206 protease-,207 ryegrass-208 or mite-induced209 airway hyperreactivity or asthmatic inflammation is mediated via ILC2s. In addition, ILC2s have also been found to be increased in several allergic immune diseases in humans, such as AD,210, 211 active eosinophilic esophagitis212 and CRS with nasal polyps or eosinophilia.213, 214 Moreover, high ILC2 levels have been found in patients with even moderate-to-severe asthma,215 persistent airway eosinophilia215 or rhinovirus-induced asthma exacerbations.216 Importantly, increased peripheral ILC2s have been reported in AR patients during the grass pollen season217 or after the challenge with cat antigen.149

More recent evidence from a study in Chinese subjects has indicated that the percentage of ILC2s was significantly elevated in HDM-sensitized AR patients, compared to mugwort-sensitized AR patients and healthy controls, with no significant difference between the latter 2 groups.218 Importantly, peripheral ILC2 levels in HDM-sensitized AR patients were strongly correlated positively with the severity of the clinical VAS score and with the plasma levels of their functional cytokine IL-13.219 Moreover, stimulation with IL-25 and IL-33 induced significantly greater production of IL-5 and IL-13 in peripheral blood mononuclear cells (PBMCs) of HDM-sensitized AR patients than in those of mugwort-sensitized AR patients or healthy controls.218 The levels of IL-5 and IL-13 were also higher following stimulation with IL-25 and IL-33 compared to stimulation with DerP1 stimulation.219 Similarly, sorted ILC2s from AR patients produced large amounts of IL-5 and IL-13 after stimulation with IL-25 and IL-33. Furthermore, a prospective study has investigated the effects of glucocorticoid treatment on the levels and function of ILC2s in patients with asthma or asthma plus AR.220 The study showed high frequency of ILC2s in human PBMCs from both groups of patients with asthma or asthma plus AR, and demonstrated that ILC2 levels significantly decreased to normal levels 3 months after glucocorticoid treatment. Collectively, these findings suggest that sensitizing allergen type may be an important factor determining the functional profile and frequency of ILC2s in AR patients and that high levels of innate type 2 immune responses in AR may provide a potential strategy for mediating the immunopathogenesis and therapy of this disease.

6.3.1 Chemokines and receptors

Chemokines are a group of cytokines responsible for the activation of leukocytes, such as T/B lymphocytes, monocytes, neutrophils, eosinophils and basophils, which are associated with allergic inflammation. It is now generally accepted that several chemokines and their receptors play essential roles in the pathogenesis of AR.

Eotaxin is thought to be associated with allergic inflammation as it is involved in the recruitment and activation of eosinophils by chemotaxis after antigen challenge in AR patients.221 Eotaxin exists in 3 isoforms: eotaxin-1 (CCL11), eotaxin-2 (CCL24) and eotaxin-3 (CCL26). Eotaxin can accelerate basophilic cell degranulation, accumulate eosinophils, and then further induce an allergic reaction through the IgE-mast-cell-FεRI cascade.222 Regulated upon activation normal T cell expressed and secreted factor (RANTES/CCL5) is another chemokine closely associated with allergic inflammation and is found to be highly expressed in the epithelial and endothelial cells of the lower nasal mucosa in AR.223 RANTES contributes to eosinophil-mediated inflammatory responses in the earlier period of allergic reaction.224

Cytokines and chemokines produce marked effects via the receptors of chemokines. Among them, the most important eosinophil chemokine receptor is CCR3, which ligands with eotaxin-1, eotaxin-2, eotaxin-3, and RANTES to activate eosinophils to release granules.225, 226 Other receptors such as CCR4 and CCR8 expressed on eosinophils, mast cells and basophils are also associated with AR.227 Thus, this subset of chemokines and chemokine receptors are potentially important in modulating immune responses by amplifying Th2 cell responses in AR.

6.3.2 Nasal nitric oxide (NO) and gasotransmitters

The oxidant/antioxidant imbalance is also an important part of the pathogenesis of AR as allergens can stimulate the generation of reactive oxygen species, which can cause nasal mucosal epithelial damage. This induces inflammatory cells to release inflammatory mediators such as cytokines, chemokines and adhesion molecules, and lead to the development of further inflammation and damage. Additionally, some small gaseous molecules known as gasotransmitters have also been shown to play important roles in regulating the oxidation process in AR.228

The first gasotransmitter identified was nitric oxide (NO).229 An increasing body of evidence has indicated NO production to be increased in both perennial and seasonal AR,194 with many studies indicating nasally exhaled NO in humans to be generated mainly within the mucosal epithelium of the paranasal sinuses.230 Furthermore, increased local concentrations of NO in AR tend to increase Th2 cell-synthesized interleukins, including IL-4, IL-5, and IL-10, which promote the production of IgE and accumulation of eosinophils. NO also tends to increase edema and plasma exudation, and cause denudation and desquamation of the epithelial lining.231

Carbon monoxide (CO) and hydrogen sulfide (H2S) have also been identified as gasotransmitters, which participate in the resolution of allergy-induced airway inflammation.232 While exhaled CO has been implicated as a likely gasotransmitter in the development of asthma, its role in the development of AR is less clear, despite being generated in the nasal mucosa of AR.233 Similarly, the role of H2S in the pathogenesis of AR is also unclear. A previous study in humans has suggested that this gasotransmitter may have multiple functions in human nasal mucosa and contribute to the development of allergic symptoms such as rhinorrhea, sneezing and nasal stuffiness.234 However, other studies on the regulation of the endogenous H2S pathway in the nasal mucosa of an AR guinea pig model has suggested that H2S may exert anti-inflammatory as well as antioxidant effects in the nasal mucosa and therefore may serve a protective function in AR patients.235

6.3.3 Substance P

Substance P (SP) is a neuropeptide neurotransmitter that belongs to the tachykinin family of peptides, which can be released by C-nerve fibers in the nasal mucosa. It has been found to have a variety of proinflammatory and prosecretory effects in epithelial, glandular and vascular tissues in the nasal cavity and thus play an important role in neurogenic inflammation.236 The nasal mucosa is densely innervated by sensory nerve fibers that release SP, which leads to vascular permeability, plasma extravasation, glandular secretion and proinflammatory cell influx.237 Stimulation of the nasal mucosa by SP induces the release of histamine and thereby influences the physiologic and pathophysiologic nasal conditions, especially during allergic inflammatory processes. Using capsaicin as a blocking agent of SP experiments on AR animal models, Zhang and colleagues238 have shown that capsaicin could effectively deplete the concentration of SP in the nasal mucosa and thus relieve the various symptoms of AR in these animals. Intranasal administration of capsaicin in the treatment of patients with AR has also demonstrated to relieve clinical symptoms of AR and to markedly reduce the concentration of SP in the nasal secretions.239 These studies indicated that the therapeutic mechanism of capsaicin in AR was related to the blocking of axon reflex, via which stimulation of allergen on sensory nerve fibers may lead to the release of SP (Fig. 11).

Fig. 11
Stimulation of allergen on C fibers may lead to the release of substance P via axon reflex.

• Click for larger image
• Download as PowerPoint slide

There is some evidence that the expression of endogenous SP mRNA and peptide is significantly increased under IgE-activated conditions and that small hairpin RNA (shRNA)- mediated knockdown of endogenous SP can reduce the ability of IgE-activated mast cells to undergo degranulation.240 This finding suggests that endogenous SP plays an important role in mast cell antigen-mediated degranulation and thus enhances the progression of allergic inflammation.240 Indeed, it is notable that SP is expressed not only by neurons, but also in immune cells such as mast cells240 which release allergic mediators such as histamine,241 thereby exacerbating allergic symptoms. It is possible that widespread expression of SP in diverse cell types may indicate a multifunctional role for SP in a wide variety of physiologic and pathophysiologic conditions by activating a multitude of signalling pathways. Moreover, SP acts via neurokinin-1 receptors (NK-1R) to stimulate the release of inflammatory mediators including histamine and chemokines, which recruit inflammatory cells. Knockdown of NK-1R expression effectively inhibits NK-1R expression, and alleviates AR-related clinical symptoms and eosinophil inflammation in the nasal mucosal tissues of rats, suggesting that NK-1R may play an important role in the development of AR.242

6.4.1 Pollen

Pollens are important inhalant allergens as a cause of allergic disease. Pollen grains deposit on the nasal mucosa and release allergenic proteins to cause specific IgE and responses to pollen allergen, which are characterized by increased expression of Th2 cytokines. Allergic disease caused by pollen allergens is known as “pollinosis”. According to a study by Zhang and colleagues,20 the prevalence of pollen-related AR in China is 47.8%. The main airborne allergic pollens come from wind-pollinated plants rather than insect-pollinated plants and have their own characteristics to facilitate wind dispersion. These pollens are small (diameter 10–100 µm), light, and prolific with some conifer pollen developing air sacs to make it easy to become airborne. The allergic pollens also demonstrate seasonality and regionalism. The florescence of allergic plants is influenced by meteorological factors.

Tree and weed pollens are the main pollen allergens in China.243 Qiao and colleagues244 first collected the common airborne pollens and -plants in China and documented these as a compilation of “Airborne pollens and plants in China.” Most tree plants flower from March to May, and weed plants from July to October. The differences in the geography and climate result in the diversification of florescence in different regions of China. Artemisia, Humulus, and Amaranthaceae are the major weeds that cause late summer and fall seasonal pollinosis. The principal tree pollens in North China come from the cold-resistant trees such as Populus and Salix, whereas in South China the tree pollens are mainly from Broussonetia, Melia, and Casuarinatrees.243

A study conducted between November 2003 to October 2004 to investigate the general and seasonal distribution of airborne pollens and their relationship with pollinosis in 16 areas in 12 cities in Hubei province, Central China, identified 61 pollen genera within the 257, 520 pollen samples collected.245 The peak airborne pollen distribution occurred in 2 seasons each year, spring (March and April) and autumn (August to October), and pollinosis corresponded to the peak pollen distribution. Similarly, another study of airborne pollens performed in Beijing indicated that the summer-autumn pollen concentration peaked from August 20 to September 15, with the major pollens being Artemisia L, Chenopodium album, and Humulus scandens.246 There was a significant correlation between specific pollen concentration and the number of patients sensitized to a particular pollen as well as between pollen exposure and the onset of symptoms of AR.246

6.4.2 Traditional pollutants

In urban and suburban areas, industrial facilities and transportation-related emissions are major sources of air pollution. The main air pollutants include carbon oxides (CO_x), nitrogen oxides (NO_x), ozone (O₃), sulphur dioxide (SO₂), and PM—a complex mixture of chemicals and particles of which diesel exhaust particles (DEPs) are the largest single component.247

Increasing evidence shows that air pollution is associated with respiratory diseases, particularly AR. A study assessed the potential effects of PM10, SO₂, and NO₂ on outpatient visits caused by AR in Beijing during the period 2009–2010 and found strong associations between the daily concentrations of the 3 air pollutants and the daily number of outpatients for AR.248 Similarly, another study of 32,143 Taiwanese school children indicated that persistent exposure to NO_X, CO, and SO₂ may increase the prevalence of AR.249

Several molecular mechanisms underlying the effects of air pollution on allergic respiratory disease have been explored in animal and human studies. First, air pollution may enhance IgE production by stimulating B lymphocytes. Diaz-Sanchez and colleagues250 showed that exposure to DEPs significantly increased IgE levels in human nasal fluids by greatly increasing the number of IgE-secreting cells and by altering the expression of IgE mRNA isoforms. This suggests that DEP exposure in vivo induces both a quantitative increase in IgE production and a shift in the type of IgE produced. Secondly, air pollution may increase the levels of some proinflammatory cytokines. The study of Diaz-Sanchez and colleagues250 also showed that nasal challenge in healthy humans with 0.15 mg DEPs suspended in 200 µL of saline expressed the TH2-type cytokines IL-4, IL-5, IL-6, and IL-10 in their nasal mucosal cells 18-24 hours after exposure. Indeed, studies have demonstrated that DEPs may enhance the symptoms of allergic rhinitis by synergistic action with pollen resulting in increased production and secretion of inflammatory cytokines such as IL,4, IL-5, and IL-13251 as well as enhanced local IgE production accompanied by isotype switching from IgM or IgD to IgE antibody in nasal lavage cells.252 Moreover, nasal histamine levels after challenge with dust mite allergen in dust mite-sensitive subjects were increased 3-fold when DEPs were coadministered with the allergen.253 Thirdly, air pollution may enhance reactive oxygen species (ROS) production. ROS such as superoxide, hydrogen peroxide and hydroxyl radical react with proteins, lipids, and DNA, and then lead to cellular damage. Finally, air pollution may enhance the immune response to allergens by physically binding with them. For example, one study has demonstrated that incubation of DEPs with purified natural grass pollen allergen Lol p1 for 30 minutes resulted in the binding of Lol p1 to DEPs with sufficient strength, which could not be removed by different washing methods.254 However, by employing this mechanism, DEPs may be transported with allergens, such as pollen grain fragments, into human airways, where both agents may be deposited on the mucosa at the same location and the close proximity of the DEPs and allergens would facilitate synergistic immunologic responses and respiratory symptoms.255

6.6.1 Theories related to TCM

The origin of TCM can be traced back to remote antiquity. In its long course of development, TCM has gradually evolved into a unique and integrated system of medicine and an important part of Chinese culture. Huangdi Neijing (Huangdi's Canon of Medicine), the “Bible” for TCM published over 2000 years ago, is the earliest and greatest medical classic extant in China. The content of Huangdi Neijing covers the theories of yin-yang and Zangxiang. The theory of yin-yang permeates through all aspects of the theoretical system of TCM. Physiologically, the theory of yin-yang holds that the normal life activities of the human body result from the coordination between yin and yang in a unity of opposites, and pathologically TCM considers that the imbalance between yin and yang is one of the basic causes for the pathogenesis of disease. Based on this determination, right herbs are selected according to their yin or yang properties to rectify the imbalance of yin and yang, eventually achieving the purpose of curing the disease.

The theory of Zangxiang studies the physiologic and pathologic changes of viscera and their relationships. It plays an important role in the theoretical system of TCM and is significant in both expounding the physiology and pathology of the human body and guiding clinical practice. Viscera, which are the basis of the theory of Zangxiang, include the 5 Zang-organs: the heart, lungs, spleen, liver and kidneys. According to the theory of TCM, the lungs open into the nose. The main physiologic functions of the lung are to dominate Qi, control respiration, govern dispersing and descending activities, and regulate water passage. The fact that the nose is the pathway for respiration is why it is believed in TCM that the lung opens to the nose. The 5 Zang organs interact with each other in both the physiologic functions and the pathologic features.

Treatment based on syndrome differentiation is the basic principle guiding clinical diagnosis and treatment of disease. Syndrome is a pathologic generalization of a disease at a certain stage in the course of its development. Since syndrome includes the location, cause and nature of a disease as well as the relation between pathogenic factors and healthy Qi, it reveals the nature of disease more comprehensively and accurately. A patient's symptoms and signs collected with the 4 diagnostic methods are analyzed and generalized, and finally diagnosed with some syndrome or disease. Generally speaking, syndrome is a reflection of waning and waxing of yin and yang of Zangfu-organs or invasion of exogenous evils. Since physiologic functions of every Zang-fu organs are different, the reflections of pathology are different. The theory of physiology and pathology of Zang-fu organs is the theoretical basis of Visceral Syndrome Differentiation.

6.6.2 Syndrome differentiation

According to the theory of TCM, AR falls under the category of Biqiu. The etiology is based on the deficiency of a healthy-Qi, and external evils take advantage of a weak point. In terms of syndrome differentiation of solid and hollow viscera, AR is induced by the inconsistent function of the lungs, spleen and kidneys, especially because of the deficiency of the kidney-yang. According to the “Standards for the diagnosis and curative effect of Chinese medical symptom” issued by the State Administration of TCM in 1994266 and Chinese Otorhinolaryngology edited by Wang Shizhen,267 AR is divided into 4 types: kidney-yang deficiency, lung-Qi deficiency, spleen-Qi deficiency, and lung heat.

Kidney-yang deficiency.Kidney-yang deficiency and the lung's suffering from cold can lead to lung-Qi deficiency, which makes the body vulnerable to external evils and causes nasal itching and sneezing. The kidney fails to keep Qi and Qi descends to the top, causing frequent sneezing. Fading life gate fire and Qi transformation failure lead body fluids to ascend to the nose, which triggers constant rhinorrhea. Studies have shown that the kidney plays an important role in the regulation of cAMP/cGMP proportions.268, 269 Pharmacologic studies have found that yang-warming herbal medicinal formulae are instrumental in the IgE regulation system.270 Seasonal allergic diseases can be prevented by taking the medication in advance, effectively reducing seasonal allergic incidences.

Lung-Qi deficiency.The lung-Qi governs the lung and its opening at the nose. If the lung-Qi is deficient, there is insecurity of defense Qi, the lung will suffer from wind-cold evil invasion, and the lung fails to diffuse and descend, which causes stagnation of body fluids, leading to overflow rhinorrhea and Biqiu. Patients often have shortness of breath and fatigue, aversion to wind and cold, pale and fat tongue, thin and pale tongue coating, and weakened pulse. The Wind tends to move and change rapidly by nature, so does the symptoms of AR. The occurrence of lung-Qi deficiency is closely related to AR. Zhao Jiangyun and colleagues271 have shown that lung-Qi deficiency is related to lower than normal indicators of peripheral T-lymphocyte subpopulation, indicating lower cell immune function of patients, which affects the immune regulation of T cells. It has also been demonstrated that cAMP levels in plasma272 and nasal secretions273 are lower in patients with lung-Qi deficiency than in normal subjects. With a decreased cAMP and cAMP/cGMP ratio, the release of chemical medium is strengthened and accelerated, thus affecting the response of the nasal mucosa.

Spleen-Qi Deficiency.The spleen is the source of engendering transformation. A healthy spleen is full of Qi and blood, defending the body surface against the invasion of exogenous pathologic factors. When the spleen is deficient, there is no growth of Qi or blood, and leads to lung-Qi deficiency and malnutrition to the nose. Therefore, spleen-Qi deficiency also affects water transportation and regulation, and fluid retention invades nasal orifices, causing nasal mucosal edema and constant rhinorrhea. Moreover, a study has shown that patients suffering from lung-Qi deficiency and spleen-Qi deficiency have the highest level of serum IgE and a higher proportion of eosinophils in nasal secretions,274 suggesting that AR is more easily induced by spleen deficiency.

Lung heat.Apart from the above-mentioned syndrome differentiation typing, the lung-heat pattern for AR is generally considered one of the most common types.267, 275 As the lung suffers from heat evil, it fails to diffuse and descend, which causes stagnation of body fluids, leading to overflow rhinorrhea. Meanwhile, the heat invades nasal orifices, causing itching and constant sneezing.

7.1.1 Clinical history

Clinical history is essential for the accurate diagnosis of AR and for the assessment of its severity as well as its response to treatment. The interview begins with a thorough general medical history and should be followed up by questions more specific for allergy including environmental and occupational information. It is also common to collect information on personal and familial histories of patients with allergic disease.

The most frequent symptoms include sneezing, anterior rhinorrhea, bilateral nasal obstruction and nasal pruritus in patients with AR. In addition, most patients with pollen-induced rhinitis have eye symptoms. It is also important to distinguish between allergy and nonallergy symptoms.56 Subjective assessment of symptoms of AR is generally based on 4 nasal symptoms (sneezing, rhinorrhoea, nasal itching and nasal obstruction) and 2 ocular symptoms (ocular itching/grittiness/redness and ocular tearing).276 In China, VAS is most commonly used to quantify the above-mentioned assessments.276

7.1.2 Nasal examinations

In patients with AR, a nasal examination is necessary. Use of anterior rhinoscopy and nasal endoscopy is the widely used approaches, and nowadays the majority of hospitals in China have been equipped with an endoscopic examination system. Generally speaking, anterior rhinoscopy needs to be paired with the use of a speculum and mirror, and will provide the primary information. Nasal endoscopy is the next step, which is useful for patients with treatment failure or for excluding other conditions.

Nasal examination should describe: 1) the anatomical situation in the nose (e.g. the septum, the size of the inferior turbinate, and if possible the structures in the middle meatus); 2) the color of the mucosa; and 3) the amount and aspect of the mucus. An endoscopic image of nasal mucosa in a patient suffering from AR is exhibited in Fig. 12, demonstrating pale and edematous nasal mucosa, watery nasal discharge, and swollen inferior turbinates.

Fig. 12
A reprehensive endoscopic image of nasal mucosa suffering from AR.

• Click for larger image
• Download as PowerPoint slide

7.1.3 Skin tests

Skin tests are widely used to demonstrate an IgE-mediated allergic reaction in the skin. These tests represent a major diagnostic tool in the field of allergy. As there are many complexities in their performance and interpretation, it is recommended that they be carried out by trained health professionals.277

7.1.4 Serum specific IgE measurements

In contrast to the low predictive value of total serum IgE measurements in the diagnosis of allergic diseases, the measurement of allergen-specific IgE in serum is of importance. Furthermore, specific IgE measurements are not influenced by drugs or skin diseases.

7.1.5 Imaging

Computerized tomography (CT) is the principal radiologic investigation for most sinonasal disorders, but it is of limited use in the diagnosis of AR.298, 299, 300, 301, 302 CT scans should be carried out only in the following instances: to exclude other conditions, in patients who do not respond to treatment, and in patients with unilateral rhinitis.

7.1.6 Nasal provocation tests (NPTs)

NPTs elicit a response from the nasal mucosa by controlled and standardized exposure to allergens. Interpretation of nasal response includes symptom assessment and nasal patency evaluation. Rhinomanometry and acoustic rhinometry, 2 widely used complementary techniques, can evaluate nasal patency objectively.303 To date, NPTs are mostly used in research and seldom in clinical practice in China due to the lack of the registered drugs for NPTs. Additionally, they are important in the diagnosis of occupational AR and sometimes performed before immunotherapy for AR.304, 305

7.1.7 Fractional exhaled NO

Fractional exhaled NO (FeNO) can be used as a reproducible and noninvasive biomarker for asthma and other lower respiratory diseases.306, 307 The possible use of nasal NO measurements in the diagnosis and treatment of AR still needs to be further evaluated because of variable as well as contradictory findings of nasal NO concentrations in this disease.308, 309, 310 Likewise, nasal NO test was carried out in China in just recent years as there was not enough consistency in available data to obtain the range of normal value, which is necessary for the diagnosis of AR or other upper airway inflammatory diseases.311, 312, 313, 314

7.1.8 Diagnosis of AR in TCM

TCM employs unique methods for the diagnosis of AR, which are completely different from those employed in Western medicine. Looking, listening, questioning and feeling the pulse are the 4 main ways of diagnosing AR, by determining 4 types of syndromes for AR as detailed above in section (6.6.2) on “Syndrome Differentiation”.

7.2.1 Vasomotor Rhinitis

Vasomotor rhinitis, also known as nonallergic rhinitis and idiopathic rhinitis, is rhinitis with an unclear etiology, which may possibly be associated with neuroendocrine dysfunction.315, 316 The symptoms of vasomotor rhinitis, particularly sneezing and watery rhinorrhea, can be induced typically by cold air, irritant odors, tobacco smoke, alcohol, sports and emotional reaction.317 There is no unique finding with tests for sensitization to allergens and eosinophil granulocyte in nasal secretions.

7.2.2 Nonallergic rhinitis with eosinophilia syndrome (NARES)

NARES is a clinical syndrome characterized by hypereosinophilia. Patients may exhibit similar symptoms to AR, but more serious and often associated with olfactory dysfunction.318 Allergen sensitization tests and nasal provocation tests are negative. Hypereosinophilia is notable both in nasal discharge and blood, with the estimated standards showing >20% more eosinophils than granular cells and monocytes in the nasal discharge and >5% eosinophils in peripheral blood.317

7.2.3 Infectious rhinitis

Infectious rhinitis is caused by a viral or bacterial infection over a short course of 7–10 days and presents with similar symptoms compared to AR initially, accompanied by fever, headache, weakness and limb pain.319 Tests for sensitization to allergens and eosinophils in nasal secretions are negative, but high lymphocyte counts are noted after acute bacterial infection.320

7.2.4 Hormonal rhinitis

Hormonal rhinitis may typically presents nasal congestion and rhinorrhea caused by abnormal levels of endocrine hormones including sex hormones, thyroxine and pituitary hormones. Tests for sensitization to allergens and eosinophils in nasal secretions are negative.

7.2.5 Medicamentous rhinitis (Rhinitis medicamentosa)

Nasal congestion caused by long-term use of a decongestant nasal spray is the marked feature of medicamentous rhintis. Tests for sensitization to allergens and eosinophils in nasal secretions are negative.321

7.2.6 Aspirin intolerance triad

Rhinitis symptoms are accompanied with asthma and nasal polyps, perhaps with urticaria and angioedema provoked by acetylsalicylic or other analgesics. Nasal polyps with high recurrence and uncontrolled asthma are the challenges. Positive aspirin provocation test, identified history, hypereosinophilia and negative allergen sensitization test are the identified features.322

7.2.7 Cerebrospinal fluid rhinorrhea

Physicians should be alert to significant trauma history, watery rhinorrhea, and absence of itching and sneezing in the diagnosis of cerebrospinal fluid leaks.323, 324

Rarely, nasal symptoms similar to those of AR can also occur as a consequence of a foreign body325 or nasal tumor.326 A detailed history and examinations are the key to differential diagnosis of this condition.

7.3.1 Generic QOL questionnaire

Generic QOL questionnaires are used to measure physical, mental and psychosocial functions in all health conditions, and allow comparisons between different diseases and health populations. The most widely tested and used instrument for AR is Short-Form 36-item health survey questionnaire (SF-36), which provides summary scores in 2 domains: physical health and mental health.7 This questionnaire allows comparisons between different diseases and health populations, which makes them less suitable for measuring individual specific clinical outcomes.327 A Chinese version of SF-36 has been widely used in evaluation the QOL of adult AR and is especially suitable for comparison with other diseases. (The Chinese version of SF-36 is shown in Supporting information 1).

7.3.2 Disease-specific QOL questionnaires

Specific instruments have been designed for assessing problems patients experience from AR or conjunctivitis, and have the advantage of describing the disease-associated problems of the patients more accurately.7

1) Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ)

The RQLQ has been employed as a gold standard instrument of QOL in adult patients with both AR and rhinoconjunctivitis, and is widely used to assess the symptoms and effects of therapy.328 The RQLQ contains a list of 28 health-related items in 7 domains including sleep, non-hay fever symptoms, practical problems, nose symptoms, eye symptoms, activities and emotional function (Table 6). The RQLQ has also been adapted specifically for pediatric patients (PADQLQ)329 and adolescent patients330 according to health-related items and domains particularly relevant to these groups of patients (Table 6). The Chinese version of RQLQ is now available and can be acquired by authorization from Juniper (Shown in Supporting information 2). Currently, RQLQ is widely used in the clinic and for research purposes, especially to assess the effects of therapy including drug therapy and allergen immunotherapy.

Table 6
Different versions of RQLQ for different age groups

• Click for larger image
• Click for full table
• Download as Excel file

• 1) SCL-90 is one of the most famous psychologic measuring scales. It is sourced from the Cornell Medical Index and is widely used in psychiatric departments and psychologic counselling clinics. SCL-90 includes somatization, compulsion, interpersonal sensitivity, depression, anxiety, hostility, phobic disorder, paranoid personality and psychosis. Although Symptom Checklist-90 (SCL-90) can reflect the patient's mental health dimension relatively comprehensively, it is not a diagnostic tool, but just a type of screening checklist.

• 2) Self-rating Depression Scale (SDS) and Self-rating anxiety Scale (SAS) are specific screening checklists for assessing the patient's subjective feeling of depression and anxiety, respectively. In addition to early screening of patients suffering from depression and anxiety, these screens can also be used to observe changes in the degree of severity and development of the state of the illness during therapy.

• 3) State-Trait Anxiety Inventory (STAI) can not only directly reflect the level of the anxiety of patients, but also distinguish the state of anxiety from the consistent trait anxiety, thus offering the precise direction for further intervention and treatment.

• 4) Hospital Anxiety and Depression Scale (HADS) is suitable for rough screening of the tendency for depression and anxiety among general patients.

• 1) Minnesota Multiphasic Personality Inventory (MMPI) is as a diagnostic tool in psychiatry for assessing personality disorder and can fully reflect the degree of subjects' physical and mental dimensions as well as clinical symptoms. MMPI covers 2 parts: 4 validity scales and 10 clinical scales. The validity scales include Question (Q), Lie scale (L), Infrequency (F) and Correction (k), while the clinical scales involve Hypochondriasis (Hs), Depression (D), Hysteria (Hy), Psychopathic deviate (Pd), Masculinity/femininity (Mf), Paranoia (Pa), Psychasthenia (Pt), Schizophrenia (Sc), Hypomania (Ma) and Social introversion (Si).

• 2) Eysenck Personality Questionnaire (EPQ) is a type of simplified personality inventory test that has been categorized in terms of 3 personality dimensions, which involve introversion-extroversion, psychoticism and nervousness, and exert a great effect on the outcome of the treatment for long-term chronic diseases and tumors.

8.3.1 H₁-antihistamines

A large number of H₁-antihistamines have been available worldwide since 1942 when the antihistamines were introduced for clinical applications for the first time. Antihistamines act as inverse agonists that combine with and stabilize the inactive conformation of the H₁-receptor, shifting the equilibrium toward the inactive state. Antihistamines are functionally classified into 2 groups, first- or second-generation antihistamines, according to whether or not they enter the blood brain barrier (BBB) readily. First-generation antihistamines can cross the BBB readily and also have anticholinergic effects, which limits their use as a consequence of the side effects of sedation and mucosal dryness.342

1) Oral antihistamines

Oral antihistamines are effective against nasal symptoms, particularly rhinorrhea, sneezing and nasal itching, which are mainly mediated by histamine, but are less effective against nasal congestion.343 First-generation antihistamines often cause adverse effects such as sleepiness, impaired performance and dry mouth. In contrast, second-generation antihistamines are effective to some extent for nasal congestion aside from sneezing and watery rhinorrhea, and also cause less adverse side effects. Thus, in almost all situations, the use of oral second-generation antihistamines is proposed as first-line therapy for intermittent and persistent AR.7 Commonly used second-generation antihistamines include cetirizine, loratadine, levocetirizine and desloratadine. Some of these are marketed as OTC medications.

These agents have a rapid onset of action, occurring from 1 to 2 hours after oral administration. Most of them have duration of action of more than 24 hours, and patients can take them once daily. During regular daily dosing, little or no tolerance occurs towards their effects and they can also relieve some symptoms of eyes.344

The clinical effect for the control of nasal symptoms in trials of intermittent allergic rhinitis lasting 2 weeks and of persistent allergic rhinitis lasting 4 weeks has been extensively demonstrated; however, the sample- size has usually been small.345

The use of second-generation antihistamines prior to pollen exposure can improve nasal symptoms and activity impairment in pollinosis. Treatment is better on a regular basis than on as-needed basis for symptom relief.344

In contrast to first-generation antihistamines, second-generation antihistamines are relatively safe. The long-term safety of second-generation antihistamines, including cetirizine, levocetirizine, fexofenadine, loratadine and desloratadine, have been validated in randomized controlled trials (RCTs) lasting 6 to 18 months, in both adults and in children as young as 1 to 2 years old.342, 343, 346 Currently, numerous oral antihistamine products are available for use in Chinese AR patients (Table 7).

Table 7
Market share of the main oral antihistamine products used in China

• Click for larger image
• Click for full table
• Download as Excel file

2) Intranasal antihistamines

Intranasal antihistamines are also proposed as first-line therapy. The intranasal preparations are targeted delivery that can increase dosage to nasal tissues while decreasing systemic effects.347 Intranasal antihistamines have a more rapid onset of action than oral antihistamines, ranging from 15 to 30 minutes versus 150 minutes of average onset time. Due to the rapid onset of action and targeted delivery of intranasal formulations, they are especially useful in patients with episodic nasal symptoms or as a pretreatment before inhaled allergen exposure.348 However, because of washout from the nasal mucosa, intranasal formulations require administration at 6 to 12 hours intervals.

Intranasal antihistamines also have the advantage for the relief of nasal congestion, which is much more efficacious than oral preparations. Intranasal administration shows benefit even in patients who fail oral treatment. A recent meta-analysis has shown that the efficacy of intranasal antihistamines was superior to that of oral antihistamines with respect to total nasal symptom scores (TNSS), and there was no significant difference in TNSS between patients treated intranasal antihistamine and those treated with intranasal corticosteroids.349, 350, 351

Currently, only 4 intranasal antihistamine products (AZEP, MIN QI, LIVOSTIN and SHUNTUOMIN) are available for the treatment of AR patients in China, of which AZEP (azelastine hydrochloride) has the largest share of the Chinese market (Table 8). In a multicenter, randomized, double-blind, parallel-group trial, Han and colleagues352 have demonstrated that azelastine and levocabastine nasal sprays, which are commonly used worldwide for the treatment of AR, are comparably safe and effective in the treatment of Chinese patients with moderate-to-severe persistent AR.

Table 8
Intranasal antihistamine products available in China

• Click for larger image
• Click for full table
• Download as Excel file

The most common adverse events related to intranasal formulations use are local side effects such as epistaxis/nasal burning, poor taste, sedation, more frequent dosing and increased cost relative to oral formulations. Although the incidence of side effects is low, caution should be exercised at the initiation of intranasal antihistamines for signs of adverse events, and follow-up with a clinician is advised to assess response and side effects.

8.3.2 Leukotriene receptor antagonists

Leukotrienes are among the major mediators that are involved in the pathogenesis of AR and act by attracting eosinophils, increasing microvascular leakage and elevating mucous gland secretion.353 Leukotriene modifiers include leukotriene synthesis inhibitors and leukotriene receptor antagonist (LTRA). Singulair (Montelukast from MSD) is the patient's favourite choice of the LTRA products and occupies 11.7% of the total market in China (data taken from IMS CHPA (http://www.imshealth.com).

Montelukast works by blocking the leukotriene receptor and thus blocks the end organ response of leukotrienes. Montelukast has been shown to improve both allergen-induced nasal and ocular symptoms354 and early intervention with montelukast before pollen season significantly improves AR symptoms, compared to post-onset treatment with topical steroids only.355 Furthermore, LTRA is better suited for night-time symptoms and contributes to improvements in sleeping disorders.356

Compared to nonsedating antihistamines, LTRAs tend to provide more relief of nasal congestion. However, a meta-analysis by Xu and colleagues357 comparing the efficacy and safety of selective antihistamines and LTRAs for the treatment of seasonal AR, and a clinical trial by Liu and colleagues358 comparing the effect of treatment with montelukast or loratadine in patients with AR indicated that antihistamines and LTRAs had similar effects for seasonal AR. Indeed, a combined use of montelukast and loratadine has been suggested to provide the most effective treatment for seasonal AR and associated eye symptoms.353 Furthermore, the addition of an antihistamine to montelukast is reported to be equivalent to intranasal corticosteroids (INS).354 Montelukast in combination with intranasal steroids has also been shown to obtain faster improvement in TNSS,359 and in AR patients with steroid resistance LTRA can be used as an adjunct therapy.360

Montelukast 5 or 10 mg once daily has been reported to be a well-tolerated and safe therapeutic option for children. Alternative forms such as liquids or oral disintegrating tablets are available. Montelukast is pregnancy category B medication, allowing ease of administration to pregnant woman.

LTRAs constitute good therapeutic options in AR, with acknowledged underlying mechanisms,361 and are thus likely to provide greater benefits to AR patients in clinical practice in China.

8.3.3 Nasal corticosteroids

INS is the most efficacious anti-inflammatory medications available for the treatment of AR.362 The choice of INS in the treatment of AR is due to the attainment of high drug concentrations in the local mucosa, with a fairly small risk of systemic adverse effects.

INSs directly modulate the pathophysiology of AR, as they have been shown to significantly inhibit recruitment of basophils, eosinophils, neutrophils and mononuclear cells to nasal secretions in nasal allergen challenge models.363, 364, 365

One recent study has indicated that INS delivered 86% of metered dose to the nasal cavity, with approximately 60% of metered dose to the posterior nasal cavity.366 These delivery characteristics contributed to sustained nasal contact time, which improved the outcomes. For seasonal AR patients, inflammatory cells and cytokines within the nasal mucosa and secretions have been shown to be significantly reduced after use of INS.367, 368 Similarly, INSs tend to decrease the SP concentration in tears of patients with seasonal AR, which is correlated with the severity of ocular and nasal symptoms.369 The efficacy of INS appears after 3–5 hours of dosing, but maximum efficacy may develop over a period of up to 2 weeks.

INS has proved to be effective in improving all symptoms of AR.370 If nasal congestion is present or symptoms are frequent, INS is the most appropriate first-line treatment as it is more effective than any other treatment.371 INS is not only effective for all nasal symptoms, but also for ocular symptoms, including itching, tearing, redness and puffiness, with no significant difference compared to intranasal antihistamine.372

High drug concentrations of INSs can be achieved at receptor sites in the nasal mucosa, with a minimal risk of systemic adverse effects, in the treatment of AR. An efficient topical delivery system also ensures fewer systemic side effects and leads to a better treatment result, which benefits the AR patient significantly. INSs are well tolerated and the adverse effects are few in number. Safety and efficacy are proved for all INSs available by multiple studies, with the side effects being mild in severity and similar in incidence as for placebo.

Currently, only 2 clinical trials investigating the effects of INS in Chinese subjects have been published in international peer-review journals. Zhang and colleagues373 assessed the effect of mometasone furoate nasal spray 200 µg once daily in a multicenter open-label study involving 500 patients with moderate-to-severe AR. The authors reported that mometasone furoate nasal spray reduced symptoms and improved quality of life of the patients. Han and colleagues374 also assessed the effect and safety of fluticasone furoate nasal spray 110 µg once daily or placebo in a multicenter, randomized, double-blind, placebo-controlled, parallel-group study involving 363 adult and adolescent subjects with intermittent or persistent AR. The authors reported that fluticasone furoate nasal spray was safe and significantly more effective than placebo in improving nasal symptoms as well as in decreasing rhinoscopy score and activities of daily living (ADL) score in patients with intermittent or persistent AR. Currently, however, fluticasone furoate nasal spray is not in general clinical use in China.

Currently, there are 4 multinational corporation and 4 domestic corporation INS products in clinical use in China, of which the multinational corporation (MNC) INS have 85% of the market share, compared to only 15% of the market share for domestic INS. Nasonex continues to be the No. 1 product among China INS market. All data are from IMS China Hospital Pharmaceutical Analysis (CHPA) (http://www.imshealth.com). Table 9 exhibits the main characteristics of the INSs available in China.

Table 9
INSs available in China

• Click for larger image
• Click for full table
• Download as Excel file

8.3.4 Mast cell stabilizers

Mast cell stabilizers can stabilize the membrane of mast cells and basophils to prevent degranulation, thereby inhibiting the release of a variety of proinflammatory mediators, including histamine. The mast cell stabilizers are commonly used in clinical practice and include cromolyn sodium, tranilast, pemirolast potassium and so on. In China, tranilast is more widely used. These drugs partly relieve the symptoms of nasal itching, sneezing and rhinorrhea, but are not very effective in controlling nasal obstruction. In AR patients with allergic conjunctivitis, cromolyn sodium eye drops can improve ocular symptoms. Based on the mechanism of action of the mast cell stabilizers, these drugs can be used as prophylactic treatment. Indeed, patients with pollinosis (seasonal AR) are usually required to use mast cell stabilizers for about 2 weeks before the spread of pollen to reduce nose and eye symptoms.8, 375

Although mast cell stabilizers have good safety and tolerance, they belong to second-line drugs376 because they have some limitations such as slow onset and short action, and also because they may not be effective in the treatment of existing symptoms.

8.3.5 Nasal decongestants

Topical decongestants can constrict blood vessels in the nasal mucosa and improve nasal patency, thus relieving the symptom of nasal obstruction in patients with AR. In clinical therapy, the most frequently used nasal decongestants are ephedrine hydrochloride, pseudoephedrine hydrochloride, oxymetazoline hydrochloride, xylometazoline hydrochloride and so on. In China, the commonly used nasal decongestant is 0.05% oxymetazoline. It has been shown that the clinical concentration of 0.05% oxymetazoline has no obvious inhibitory effects on human nasal ciliary beat frequency in vitro377; however, it should be highlighted that the nasal decongestants relieve the symptom of nasal congestion only temporarily in AR patients. When used in conjunction with INS, decongestants can benefit AR patients with stuffy noses by improving even and effective distribution of the INS.4, 378

It has been pointed out that topical decongestants can cause rebound nasal congestion after continuous use for 5 days and drug-induced rhinitis after long-term use, and pose a risk to fluctuating blood pressure in elderly patients.379 As drugs belonging to a second-line therapy, nasal decongestants are generally not used continuously for more than 7 days.376 It is important to remember that a lower dose (half the concentration of the drug for adults) of nasal decongestant spray should be chosen for children.380

Oral decongestants could cause systemic side effects including hypertension, myocardial ischemia, arrhythmia and tachycardia, and are therefore not recommended for the treatment of AR patients.

8.3.6 Nasal anticholinergics

Intranasal anticholinergics can inhibit both watery secretion of nasal glands and vasodilatation of airway blood vessels. They are recommended as second-line drugs.376 Ipratropium bromide, a quaternary derivative of isopropyl noratropine, has proved to be effective in controlling watery nasal discharge of AR patients.7 Currently, however, there is no approved intranasal anticholinergic in the Chinese market.

Although systemic side effects of nasal anticholinergics are rare, care should nevertheless be exercised when these drugs are prescribed to patients suffering from prostatic hypertrophy or glaucoma.376

8.3.7 Nasal saline irrigation

Nasal saline irrigation (NSI) is a simple and inexpensive treatment for AR as well as other nasal disorders (e.g. CRS and atrophic rhinitis). Several studies have demonstrated NSI to be effective. In China, numerous types of irrigation equipment are available, and a patented product of nasal irrigation has recently been developed and extensively used by Beijing TongRen Hospital as shown in Fig. 13.

Fig. 13
Nasal irrigation equipment developed and patented by Beijing Tongren Hospital. (A) Nasal irrigator and salt package. (B) A patient performing nasal irrigation.

• Click for larger image
• Download as PowerPoint slide

The exact mechanism underlying the efficacy of NSI is not well understood, but at least 3 have been proposed. First, NSI has a direct cleaning effect. As the saline passes through the nasal cavity, it can humidify and remove obstructive mucus and crusts. This can likely improve the sense of breathing immediately. Secondly, NSI can remove or reduce the inflammatory mediators and allergenic proteins such as histamine, prostaglandins, leukotrienes, eosinophil-released major basic protein and pollen. Thirdly, NSI can restore impaired nasal mucociliary function. Improved mucociliary clearance with increased ciliary beat frequency has been shown in patients receiving nasal rinsing.381, 382, 383, 384, 385

Furthermore, NSI may improve the efficacy of topical medications, such as INS and intranasal antihistamines, via clearing excessive nasal secretions and decreasing pre-existing edema. It is crucial that NSI is proposed as a good adjunctive treatment option to maintain the effectiveness of other treatment, particularly in children and pregnant women.386

8.3.8 Chinese herbal medicines

Treatment based on syndrome differentiation, an important feature of TCM, is the basic principle guiding clinical diagnosis and treatment of disease. According to the theory of Zangxiang, the treatment of AR emphasizes syndrome differentiation. TCM in the treatment of “AR” involves “Toning” the kidney, thus benefiting the lung and invigorating the spleen simultaneously. The kidney can fully play the controlling and astringing role by nourishing kidney and invigorating yang, and therefore bring sneezing to a halt. The transportation and transformation function of the spleen is strengthened; therefore, the Qi and blood are vigorous. With adequate lung-Qi and firm interstitial striae, the body surface is protected from the invasion of exogenous pathologic factors such as wind evil. Therefore, AR can be effectively prevented.

The treatment of the kidney-yang deficiency involves warming yang and invigorating the kidney; commonly used formulas are Jin Gui Shen Qi Wan and You Gui Wan. Sun and colleagues387 adopted YouGui Soup to treat AR with kidney-yang deficiency and showed that YouGui treatment had a remarkable effectiveness on symptoms, and the total effective rate was 89.4%.

The treatment of lung-Qi deficiency involves warming the lung to dissipate cold. The common prescriptions are Xiao Qing Long decoction, Guizhi decoction and Yupingfeng granule, Cangerzi granule, etc. Lin and colleagues388 used the method of invigorating Qi to consolidate the exterior to treat AR, adjusting cyclic nucleotide levels in the body, inhibiting IgE and mast cell degranulation, and restoring blood flow in nasal mucosa. This suggests invigorating Qi and benefiting the lung in the treatment of lung-Qi deficiency have great effects on AR.

Treatment of spleen-Qi deficiency is replenishing Qi to invigorate the spleen. The commonly used prescriptions are decoction of 4 noble, Bu Zhong Yi Qi decoction, Shenling Baizhu decoction, etc. Qiu and colleagues389, 390 have shown that the onset of AR is closely related to spleen-Qi deficiency and that Bu Zhong Yi Qi decoction plays a role in the inhibition of cellular infiltration of acidophilic granulocytes and mastocytes in nasal mucosa in experimental spleen-Qi deficiency AR.

Treatment of lung heat is clearing lung-heat and relieving a stuffy nose. Xin Yi Qing Fei Yin is a commonly used prescription Zuwang Gan, a well-known Chinese otorhinolaryngology expert and one of the founders of modern otorhinolaryngology discipline in TCM, proposed that the treatment of lung-heat pattern AR is clearing away heat and desensitization and that Qingre Tuomin Decoction is the effective compound formulae for the pattern.391 The common Chinese herbs include: folium mori, peppermint, periostracum cicada, earthworm, beautiful sweetgum fruit, radix lithospermi, radix rubiae, Yerbadetajo Herb, etc.

Apart from the syndrome differentiation-oriented treatments for AR mentioned above, several randomized controlled clinical trials have investigated the efficacy and safety of Chinese herbal medicine (CHM) in Chinese patients with AR.392, 393, 394, 395, 396 Chan and colleagues392 reported that the Chinese herbal formulae (Cure-allergic-rhinitis Syrup [CS] and Yu-ping-feng San [YS]) were effective in reducing symptoms and enhancing the quality of life in AR patients with ‘yang- and/or Qi-deficiency’ body constitution. Similarly, Min and colleagues393 provided evidence that moxibustion in combination with a Chinese herbal preparation, comprising white mustard seed, euphorbia, corydalis tuber and ginger juice, was significantly more effective than loratadine in reducing symptoms and enhancing the quality of life in patients with AR. Another randomized controlled trial demonstrated that the Chinese herbal formula Shi-Bi-Lin was also significantly more effective than placebo in relieving symptoms of nasal blockage and improving quality of life in patients with PAR.394 Chui and colleagues395 compared the efficacy of a Chinese herbal nose drop preparation in patients with PAR and demonstrated that this preparation also significantly improved clinical symptom scores and several quality of life indices compared to placebo. A study by Hsu and colleagues396 investigated the effect of herbal point-patch treatment in AR patients and showed that acupoint herbal point-patches were an effective treatment for improvement in quality of life in AR. Besides studies in Chinese patients, some randomized trial also assessed the efficacy of CHM in Korean,397 Australian398, 399, 402 and German400 patients with AR. Although 2 meta-analysis of clinical trials on traditional CHM for the treatment of AR revealed that CHM interventions appeared to have beneficial effects in patients with AR,321, 402 some clinical trials subsequently provided conflicting data for the potential efficacy of CHM for AR399, 402 Particularly when the effect of CHM was assessed in combination with acupuncture for the treatment of SAR. While one study from Germany400 demonstrated that CHM combined with acupuncture significantly improved both symptoms and quality of life scores in SAR patients compared to acupuncture treatment alone, another study from Australia402 failed to show any significant differences in symptomatic relief or improvement in quality-of-life scores in SAR patients treated with CHM + acupuncture or acupuncture alone. While it is possible that the differences in the findings between these studies may attributed to a variety of inherent differences, the true potential of CHM as an effective therapy for AR needs to be assessed and confirmed by larger well-controlled multicenter trials in well-characterized patients treated for longer periods.

8.4.1 Mechanisms of immunotherapy

AIT represents a sole potentially curative and specific method of allergy treatment. AIT results in the restoration of immune tolerance toward the allergen of interest (Fig. 14). Numerous studies have shown that the mechanisms underlying AIT include desensitization effects (very early phase), modulation of effector cell responses and related antibody isotypes, modulation of migration of inflammatory cells (e.g. mast cells, basophils and eosinophils) and release of their mediators, and induction of Treg cells.403

Fig. 14
Allergen tolerance: changes in cells of allergic inflammation during allergen tolerance. AIT, allergen-specific immunotherapy; Breg, B regulatory cell; Treg, T regulatory cell.

• Click for larger image
• Download as PowerPoint slide

The desensitization effect of AIT is similar to rapid desensitization for hypersensitivity reactions to drugs.403, 404, 405, 406 In the very early phase, the suppression of mast cells and basophils might be affected by changes in other immune factors such as Treg cells and specific IgE levels.407 Following AIT, dendritic cells can induce T cells with a regulatory phenotype and function (Treg 1 [TR1] cells), which secrets IL-10. Such Treg cells inhibit subsequent inflammatory responses that might be important mediators of the beneficial action of AIT.408, 409, 410 Depletion and adoptive transfer of pulmonary plasmacytoid dendritic cells in a mouse model demonstrated that plasmacytoid dendritic cells played a central role in protection against sensitization to allergen and development of asthma.411 In addition, several clinical trials have shown that antigen presenting cells (APCs), including B cells, monocytes and macrophages, produce more IL-10 following AIT, which might lead to increased generation of IL-10-secreting TR1-like cells.412, 413

In allergic diseases, the activity of both allergen-specific IL-10-secreting TR1-like cells and CD4+CD25+ Treg cells is compromised, but can be ameliorated by AIT.412, 414, 415, 416, 417 Modulation of T-cell responses to allergen following AIT occurs in several ways. These include 1) increasing the allergen-induced ratio of Th1 cytokines to Th2 cytokines,418, 419 2) induction of epitope-specific T-cell anergy that can be blocked by neutralization of IL-10,422 3) generation of allergen-specific Treg cells that can suppress the responses of effector T cells following delivery of either whole allergen extracts or synthetic peptides that contain or consist of a T-cell epitope,416, 417 and 4) increasing the production of cytokines with regulatory activity. Induction of mRNA that encodes IL-10 and increased production of IL-10 protein have also been reported to occur in both the blood and the tissues following AIT.404, 416, 417, 421, 422, 423

When exposed to high concentrations of allergens, the levels of allergen-specific IgG4, IgG1 and IgA, but not specific IgE, are increased.416, 424 Allergen-specific IgG was found to prevent immediate allergic skin inflammation following AIT. IgG isotypes could compete with IgE for the same epitopes, resulting in the binding of allergen and were therefore termed blocking antibodies.425, 426, 427, 428, 429 Studies analyzing IgG isotypes induced by AIT have shown that the concentrations of IgG1 and particularly IgG4 were increased 10- to 100-fold following AIT, influencing the blocking activity on IgE-mediated responses.430, 431, 432, 433

8.4.2 Indications and contraindications

AIT is indicated in patients with AR/conjunctivitis and/or allergic asthma with the evidence of specific IgE antibodies to clinically relevant allergens434, 435 (Table 10). SPT is the preferred method of testing for specific IgE antibodies. In vitro allergen-specific IgE testing is a reasonable alternative to SPT.

Table 10
Indications for and contraindications to AIT

• Click for larger image
• Click for full table
• Download as Excel file

8.4.3 Routes of administration

AIT carries the risk of anaphylactic reactions and should therefore only be prescribed by physicians who are trained in the treatment of allergy and the use of immunotherapy.

8.4.4 Adverse reactions and management

1) Classification

The adverse reaction of specific allergen immunotherapy is classified as local reaction (LR) or systemic reaction (SR) according to its range and severity.

SCIT-related LR is defined as swelling, erythema or pruritus around the injection site (Fig. 15), involving 26%–82% of the patients and 0.7%–16% of the shots.450, 451, 452, 453 Chinese researchers have reported 62.9% of injections to be accompanied by LRs.454 Traditionally, SCIT-related LR can be differentiated as early local or late local reaction depending on whether the reaction happens within 30 minutes after injection.455 LRs seem to be just little bother or no bother to patients, and 96% of patients indicate that they would not discontinue the treatment because of local reactions.456

Fig. 15
SCIT-related local reaction.

• Click for larger image
• Download as PowerPoint slide

SLIT-related LR is defined as oral pruritus or swelling, gastrointestinal symptoms, dizziness, etc. The WAO has classified SLIT-related LRs as mild, moderate, severe, and unknown severity, according to the severity of symptoms, if patients require symptomatic treatment and discontinuation of SLIT is required. Most of the LRs tend to disappear after the initial dose and discontinuation because the side effects are almost always less than 5%.457 According to Chinese studies, 5.1% patients reported LRs with their treatment454; however, the rate appeared to be higher (7%–9.6%) in children with combined allergic rhinitis and asthma syndrome.458

SCIT-related SRs can range in severity from mild rhinitis or urticaria symptoms to life-threatening anaphylaxis. According to the WAO SCIT SR grading system, SCIT-related SRs are divided into 5 grades459 based on the organ involved and severity of the SR. The percentage of SR in conventional schedules is approximately 0.1%–0.2% per injection,459, 460 with fatal anaphylaxis reported at a rate of approximately 1 in 1–2.5 million injections.279, 280, 461 A recently completed multicenter study in China reported that SRs occurred in 0.47% of injections and that the occurrence of SRs was significantly higher in children than in adults.462 Risk factors for anaphylaxis include uncontrolled asthma, previous reactions to allergen immunotherapy, dosing errors, hypersensitivity, use of beta-blockers, dosing during the peak pollen season, inadequate waiting time after injections, epinephrine delayed or not given, and accelerated build-up regimens. Uncontrolled asthma is the most important risk factor therein,279, 280, 461, 463 thus making assessment of asthma severity especially important for the prevention of anaphylaxis.

Compared to SCIT-related SRs, SLIT-related SRs are rarer and occur at a rate of around 0.056% per dose administered.464 There is still no confirmed report of SLIT-related fatality.

2) Management

Premedication could be effective in decreasing LRs during allergen immunotherapy. Oral antihistamines have been demonstrated to be effective in preventing LRs in cluster465 and rush regimens,466 whereas leukotriene antagonists have been shown to be effective in rush protocols.467 However, routine dose adjustments for LRs are not supported by the current literature.453

Most of the SCIT-related SRs appear within 30 minutes after injection, although some SRs are biphasic and could occur during 2–48 hours after the injection is administered.468 However, the second phase reaction is generally mild and additional epinephrine is unnecessary in most cases. Prompt administration of epinephrine is vital when severe SRs occur469 as a lot of anaphylaxis-related fatalities are due to the delay of epinephrine use.

The specific management of adverse events is shown below (Table 11).376, 470

Table 11
The specific management of adverse events resulting from immunotherapy

• Click for larger image
• Click for full table
• Download as Excel file

8.5.1 Indications

1) Patients with persistent AR are dissatisfied with medical therapy for at least 2 years which consists of antihistamines, corticosteroid, leukotriene inhibitors and immunotherapy, and their symptoms significantly impact their quality of life. 2) The physician feels that surgical therapy may significantly improve symptoms and quality of life beyond what medical management has been able to accomplish.475

8.5.2 Contraindications

1) Patients have not ever been implemented medical therapy or immunotherapy. 2) Symptoms of concurrent asthma are not controlled. 3) Coagulation dysfunction of patients appears to be a tendency for bleeding. 4) Patients with poor health conditions hardly tolerate surgical procedures. 5) Patients with mental illness may be contraindicated to surgical treatment.376

8.5.3 The main procedures

2) Endoscopic vidian neurectomy

The 4 main symptoms that distress persistent AR patients are associated with dysfunction of the autonomic and sensory nerve imbalance in the nasal mucosa. The mechanism underlying neuronal-immune modulation is related to the symptoms of AR.483 The inhibition of parasympathetic nerve significantly relieves the symptoms of AR.484 Golding-Wood485 first developed transantral vidian neurectomy for treating vasomotor rhinitis and AR, with the transseptal and transpalatal approaches being reported a decade following Golding-Wood's report.475 However, none of these approaches offer entirely satisfactory outcomes, likely due to difficulties in nerve identification without magnification, risk of significant complications, including the palate fistula and damage to vision, and troublesome bleeding within a small surgical field.475 Recent advancements in endoscopic techniques of vidian neurectomy have made surgery safer and more effective (Fig. 16). Clinical studies reported that over 90% of patients with refractory AR were satisfied with surgical results during the 12 months follow-up period after endoscopic vidian neurectomy,486, 487 and approximately 65% of patients undergoing bilateral endoscopic vidian neurectomy categorized their symptoms as much improved at the end of the 3 to 6 years follow-up period.471, 482 Temporary dry eyes were reported in 23% to 72.9% of patients, and palatal numbness in 3% to 9%, which were resolved without any special treatment.471, 486, 487 No severe complications were noted in the studies.

Fig. 16
Vidian neurectomy diagram. (A) The area of incision and anatomical surroundings of interest in endoscopic vidian neurectomy. Yellow curved line indicates an incision; the oval, the location of sphenopalatine foramen; and the circle, the location of the pterygoid canal. (B) The yellow arrow indicates the horn-shaped pterygoid canal and nerve. E, indicates ethmoid sinus; IT, inferior turbinate; MT, middle turbinate; SS, sphenoid sinus; NS, nasal septum; PC, posterior choana.

• Click for larger image
• Download as PowerPoint slide

8.6.1 Acupuncture therapies on general acupoints to treat AR

Some Chinese acupuncturists have demonstrated that acupuncture works in the treatment of AR and achieves similar efficacy in moderate and severe AR as Western medicine. Acupuncture therapy is the safe and has no apparent adverse reactions.494 Indeed, a randomized controlled trial comparing the clinical efficacy and safety of acupuncture treatment with Western medicine in patients with moderate and severe persistent AR has recently concluded that acupuncture is not only a safe and effective intervention in these patients, but also the efficacy presents much more advantageous at its durability in the acupuncture group compared to the Western medicine group.495 An earlier study has also shown that penetration needling at various points has an obvious therapeutic effect on AR, which is even better than oral administration of Biyankang, a patented Chinese herbal medicine formulated for rhinitis.496 The basic acupoints for AR patients are Fengchi (GB 20), Yingxiang (LI 20), Feishu (BL 13) and Taiyuan (LU 9) for different causative factors.497 Acupuncture sometimes has a definite therapeutic effect on AR, especially with the anterior and posterior acupoint association method.498 The possible mechanisms underlying the efficacy of acupuncture treatment in AR are as follows: acupuncture may help improve the blood indices with an increased volume of blood flow and regulate the immunologic function of the human body which bring out therapeutic effects for AR.497 There is some evidence that acupuncture treatment can also reduce plasmatic level of IL-10 in chronic AR patients.499

8.6.2 Acupuncture therapies on special acupoints to treat AR

Acupuncture at 3 nasal points and the acupoints selected by syndrome differentiation have been shown to achieve a similar short-term efficacy on perennial AR compared to oral administration of loratadine.500 However, acupuncture therapy appears to be more advantageous for long-term efficacy compared to loratadine. A systematic review has recently indicated acupoint application for AR as follows: acupoints in lung and bladder meridians are mainly selected to assist exterior and resist the pathogenic Qi, and points in spleen and kidney meridians can treat AR fundamentally by joint use.501 Warm acupuncture in both summer and winter has been shown to improve the QOL of AR patients to a significantly greater extent than cetirizine, and this effect was also accompanied by a significantly greater decrease in serum IgE levels in acupuncture-treated patients, compared to cetirizine-treated patients.502 Jin's 3-needle therapy achieves superior efficacy on AR of lung-Qi deficiency and cold syndrome than administration of desloratadine oral suspension.503 The therapy of penetrating needling at head acupoints is safe for patients with PAR, and its effects can be found both in the short and long term.504 Compared to Western medication, the better efficacy of acupuncture and auricular pressing therapy in improvement of symptoms and signs of AR appear to be achieved by inhibition of the differentiation from Th cells to Th2 cells, adjustment of Th1/Th2 cells imbalance and reduction of IgE synthesis.505

In recent years, some acupuncturists have penetrated the needle at one special acupoint to reach the sphenopalatine ganglion (SPG) and get a definite effect (Fig. 17).506 It was concluded that SPG acupuncture could help improve nasal ventilation by increasing sympathetic nerve excitability in healthy volunteers. Two recent studies have also indicated that stimulation of the SPG by acupuncture can improve nasal symptoms and quality of life in nasal inflammatory diseases.507, 508 Thus, it is possible that acupuncture-stimulated neural regulation may offer an alternative form of therapy for the management of nasal inflammatory disease in the future.

Fig. 17
Acupuncture site. (A) Common acupuncture sites. (B) Site of sphenopalatine ganglion acupuncture for AR. (C) High- resolution CT scan 3-dimensional reconstruction of the sphenopalatine ganglion acupuncture site.

• Click for larger image
• Download as PowerPoint slide

8.6.3 Connected therapies on acupoints to treat AR

Application of the dog days plaster at Dazhui (GV 14), Feishu (BL 13), Pishu (BL 20) and Shenshu (BL 23) has been shown to achieve obvious effects with good safety for AR.509 In the same season, both acupoint sticking therapy in dog days and in non-dog days can improve the symptoms of AR, but the former is better than the latter.510 Sometimes, dog-days moxibustion could be considered an enhanced method for the prevention and treatment of PAR.511 A test involving plastered and blistered application of 10% Cantharides extracton Dazhui, Neiguan point has shown that its effectiveness rate was 88%.512 In particular, nasal allergen provocation test-induced-symptoms were significantly alleviated by the therapy, and there was a significant decrease in both the numbers of eosinophils and basophils in nasal secretion and serum total IgE levels. However, compared to acupoint plaster therapy, triple-strong stimulation therapy at Dazhui (GV 14) has been shown to achieve a superior effect on the prevention and treatment of AR in children, and has a good long-term effect in preventing recurrence.513 The medicinal vesiculation combined with quick cupping at Shenque (CV 8) has a better effect for AR with syndrome of yang deficiency than oral administration of loratadine and nasal spray of budesonide.514 Acupoint catgut embedding therapy combined with acupuncture-moxibustion therapy is also safe and effective in the treatment of AR and displays more advantages for the long-term efficacy.515 However, the effect of catgut implantation needs to be substantiated in high-quality studies and in larger sample sizes in the future.516 Acupoint autohemotherapy has also been shown to significantly relieve clinical symptoms of AR, and this effect is probably associated with an increase in serum IL-12 content and the promotion of IFN-γ synthesis.517 Point-injection plus TDP radiation is an ideal therapy with a short therapeutic course, with no adverse effect and reliable therapeutic effect for AR.518

To sum up, an increasing body of evidence indicates that acupuncture is a safe treatment option, and most of the acupuncture methods employed can improve AR symptoms of nasal itching, sneezing, rhinorrhea, and especially nasal stuffiness. Acupuncture at either general or special acupoints needs to be continued over several weeks to observe significant beneficial and stable effects on symptom improvement. Dog days plaster and acupoint catgut embedding therapy can provide long-term regulation for AR patients. SPG puncturing method is a new and unusual technique, with great potential for development.

9.1.1 Four-point scale:

9.1.2 VAS:

Patients grade their symptoms by putting a vertical line on a 0- to 10-cm line representing severity score from 0, ‘no symptoms’ to 10, ‘highest level of symptoms.’

• 1: Oral and/or topical H1-antihistamines (intranasal or intraocular)

• 2: INS

• 3: Oral corticosteroids

• 1: β₂-agonist

• 2: Inhaled corticosteroids