Allergic Rhinitis and Pollinosis

Number of patients

3068

4933

2060

1787

No complications

1320 (43.0%)

2976 (60.3%)

784 (38.1%)

623 (34.9%)

Complication

–

1174 (23.8%)

675 (32.8%)

714 (40.0%)

1174 (38.3%)

–

862 (41.8%)

728 (40.7%)

675 (22.0%)

862 (17.5%)

–

426 (23.8%)

714 (23.3%)

728 (14.8%)

426 (20.7%)

–

Epidemiological survey of 19,461 high school students in Japan. The table shows the number and percentage of cases complicated by other allergic diseases (Tokunaga T et al. [3], modified table)

AD atopic dermatitis, AR allergic rhinitis, BA bronchial asthma, FA food allergy

Kurukulaaratchy RJ et al. conducted a cohort study identifying the heterogeneity of young adult rhinitis by cluster analysis. They divided rhinitis into four clusters (Table 27.2) [6], among which clusters 1 (moderate childhood-onset rhinitis) and 3 (severe earliest-onset rhinitis with asthma) tended to complicate AD. The Swedish Dampness in Buildings and Health Study [7] found that the risk factors for the development of bronchial asthma and AR were (1) severity of eczema in infants, (2) lower age at eczema development, and (3) retention of eczema symptoms. Early childhood eczema was strongly associated with the development of both bronchial asthma (odds ratio [OR], 3.07; 95% confidence interval [CI], 1.79–5.27) and AR (OR, 2.63; 95% CI, 1.85–3.73). This study also found that those with early-onset eczema, moderate-to-severe eczema, and persistent eczema had the highest odds of developing bronchial asthma and AR. Carlsten et al. [8] also showed that only early-onset persistent eczema was associated with all atopy-related phenotypes. Early-onset persistent eczema was associated with pediatric allergist-diagnosed bronchial asthma (OR, 7.48; 95% CI, 2.53–22.2), AR (OR, 3.47; 95% CI, 1.34–8.99), and food allergy (OR, 13.4; 95% CI, 2.94–61.4). This study was the first to provide clear evidence of an atopic march from AD to food allergy. There is a notable relation between early-onset rhinitis and severe AD. Children with moderate-to-severe AD have a 50% risk of developing asthma and a 75% risk of developing AR [9, 10].

Table 27.2

Heterogeneity of young adult rhinitis

	Cluster	BA	Atopy	Eczema	Total IgE	BDR	BHR	Perennial rhinitis
1	Moderate childhood-onset rhinitis	+	+++	+++	++	+	+	++
2	Mild adolescent-onset rhinitis	+	+	++	+	+	+	+
3	Severe earliest-onset rhinitis with asthma	+++	+++	+++	++	+++	+++	+++
4	Moderate childhood-onset male rhinitis with asthma	++	++	+	+++	++	+	++

Four clusters divided by seven factors. +, mild or low; ++, moderate; +++, severe or high (Kurukulaaratchy RJ et al. [6], modified table)

BA bronchial asthma, BDR bronchodilator reversibility, BHR bronchial hyperresponsiveness

It is well known that the impairment of epithelial barrier function by eczema or AD in infants causes the consequent bronchial asthma and AR. In vivo studies have shown that percutaneous allergen sensitization causes the symptoms of bronchial asthma and AR in mice [11, 12]. The mechanism of the induction of type 2 immune responses by percutaneous sensitization remains unclear. According to a study in a mouse model [13], thymic stromal lymphopoietin—which is produced by skin epithelial cells exposed to an allergen—activates basophils. Activated basophils localize to regional lymph nodes, and they induce naïve T cells to become Th2 cells as antigen-presenting cells (APCs) producing IL-4 [14]. Skin sensitization precedes airway sensitization to the same allergen and is one of the strongest predictors of the development of childhood asthma and allergic rhinitis [15]. Together, these findings suggest that interventions to improve barrier function, which is likely to minimize the ingress of allergens, could be an important measure to control the onset of the atopic march.

27.2 Genomic Factors

Genome-wide association studies (GWASs) have revealed genes associated with the development of allergic diseases [16]. Among these, filaggrin is an important gene involved in the development of both AD and AR [17]. Furthermore, the loci of chromosomes 11q13, 2q12, 16p13.3, and 17q21.32 were found to be associated with AD and other allergic diseases. These loci include genes involved in epithelial barrier function, innate immunity, regulatory T (Treg) cells, and the metabolic pathway of vitamin D, as well as the interleukin gene family. Among these genes, IL1RL1, HLA, OR10A3-NLRP10, GLB1, IL-13, and C11orf30 were reported to be associated with AR [18].

The locus 11q13 was first reported by a GWAS in AD [19]. Subsequent GWASs showed that this locus is associated with bronchial asthma [20], eosinophilic esophagitis [21], and AR [22]. Interestingly, this locus is associated with not only the development of symptoms but also allergen sensitization [23]. The peaks of a single nucleotide polymorphisms (SNPs) associated with these allergic diseases exist between genes C11orf30 and LRRC32. However, which gene is associated with these diseases has not been investigated in detail. LRRC32 is expressed on the cell surface of Treg cells, and it acts as a latent receptor of TGF-β [24], which may be associated with the pathophysiology of allergy. The genes in loci associated with allergic diseases include the genes encoding epithelial cell-derived cytokines. The locus 2q12 includes IL1RL1, which is one of the candidate genes underlying allergic diseases. This locus was first reported by a GWAS of bronchial asthma [25]. This locus was shown to be associated with AD, peripheral eosinophilia, and allergen sensitization. IL1RL1 and IL1RAP consist of a heterodimeric receptor of interleukin-33 (IL-33). IL-33, which is released by epithelial cell damage, affects type 2 innate lymphoid cells and mast cells and induces them to release Th2 cytokines. Sakashita M et al. reported that serum levels of IL-33 were significantly higher in patients with Japanese cedar pollinosis (JCP) than in control individuals, and polymorphisms of IL-33 were associated with JCP [26]. These genes identified by various GWASs may contribute to the mechanism of allergic disease development, but there is no evidence that these genes affect the relationship between AD and AR thus far.

27.3 Risk Factors and Protective Factors

Many risk factors and some protective factors have been identified for atopic diseases. Most of these determine the development of bronchial asthma. However, factors related to AD or AR have not been explored and reported in great detail.

The epidemiological survey of high school students in Japan showed the factors involved in the onset and remission of allergic diseases (Fig. 27.1) [3]. Family history of the same disease had the highest association with the development and remission of allergic symptoms. The genetic factors underlying AD and AR are described in Sect. 27.2 (genomic factors). Constipation was found to be associated with the development of AD and AR. In this survey, the prevalence of constipation was significantly higher in female participants (male subjects, 9.2%; female subjects, 35.3%). Although multivariate analysis showed the risk of development of AD and AR to be higher in male individuals, the prevalence of AD and AR was higher in female individuals. These results suggest that constipation is closely associated with the development of AD and AR.

Fig. 27.1

(a) Analysis of factors involved in the onset of allergic diseases. (b) Analysis of factors involved in the remission of allergic diseases. Propensity score analysis using the inverse probability weighting method was performed. Error bars represent 95% confidence intervals (Tokunaga T et al. [3], modified figure). *, p < 0.05; **, p < 0.01; ***, p < 0.001. AD atopic dermatitis, AR allergic rhinitis, BA bronchial asthma

Regular intake of lactic acid bacteria was not linked to the development of allergic diseases, but it was responsible for the remission of AD. Intestinal microbiota may affect the development of allergic diseases. The anti-allergic mechanism of microbiota is attributed mainly to facultative anaerobes inhabiting the ileum, predominantly Lactobacillus spp. They induce the type 1 immune response by APCs (i.e., dendritic cells and macrophages) [27]. Several studies have evaluated the effect of probiotics in allergic diseases, among which AD has been investigated the most. The findings of randomized double-blind placebo-controlled studies of probiotics in the treatment of AD are summarized in Table 27.3. Probiotics may be effective for the treatment of AD, but according to a Cochrane review, sufficient evidence of the effectiveness of probiotics in the treatment of AD is not available [28]. On the other hand, randomized double-blind placebo-controlled studies of probiotics in the treatment of AR have been performed by several groups (Table 27.4). A systematic review suggested that probiotic therapy might be useful in AR, but such a treatment is not yet recommended because of variations in the study conditions, including varied doses and intake periods, type and severity of the symptoms, and species and strains of the probiotics [29].

Table 27.3

Probiotics for the treatment of atopic dermatitis

Study	Age (years)	Lactobacillus probiotic	Result
Inoue Y et al. [35]	≥16	L. acidophilus strain L-92	Decreased SCORAD (p = 0.002)
Wang IJ et al. [36]	1–18	L. paracasei, L. fermentum, and their mixture	Decreased SCORAD (p < 0.001)
Han Y et al. [37]	0.5–13	L. plantarum CJLP133	Decreased SCORAD (p = 0.004)
Drago L et al. [38]	18–46	L. salivarius LS01	Decreased SCORAD (p < 0.001), improved DLQI (p = 0.021)
Moroi M et al. [39]	20–65	L. paracasei K71 (heat-killed)	Decreased skin severity score (p < 0.01)