Epigenetic Regulation of Th2 Response in Asthma by Non-Coding RNAs

*Yanhua Niu, Chao Wang, Xiaoyan Dong and Nanbert Zhong*

### **Abstract**

Asthma is a common chronic inflammatory disease. Pathogenic mechanism underlying asthma is complex. The inflammatory response of asthma includes lymphocytes (T, B cells), ILC2, eosinophils and other types of immune and inflammatory cells. T CD4+ T helper 2 cells (Th2 cells) are thought to play a central role in regulating the phenotype of allergic asthma. Asthma is often closely associated with Th1/Th2 cell imbalance. Non-coding RNAs (ncRNAs) are non-protein coding RNA molecules in the transcriptome, mainly including microRNAs (miRNAs), long non-coding RNAs and circRNAs, etc., which are widely found in eukaryotic transcriptome and participate in the regulation of a variety of biological processes. ncRNAs are considered to function as modulators of the immune system. Their biological changes represent an important mechanism for the development of immune-mediated diseases. This chapter mainly discusses the epigenetic regulation of Th2 cells and their cytokines in asthma by non-coding RNAs. It helps us to better understand the pathogenesis of asthma and find potential asthma biomarkers.

**Keywords:** asthma, Th2, cytokines, non-coding RNAs

### **1. Introduction**

Asthma is a chronic airway inflammatory disease, associated with variable expiratory airflow limitation, clinically manifested as recurrent wheezing, shortness of breath, chest tightness, cough and other symptoms [1]. It has affected more than 300 million people worldwide and has become a major public health concern [2].

Non-coding RNAs (ncRNAs) are a class of non-coding RNA molecules widely found in eukaryotes and involved in a variety of biological regulatory processes. They have been extensively studied in human diseases [3–5]. NcRNAs mainly includes microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), etc.

The pathogenesis of asthma remains extremely complicated and the detailed mechanisms are not clarified. The most common phenotype is eosinophilic inflammation associated with Th2 response and concomitant atopic diseases. Asthma is often closely associated with Th1/Th2 cell imbalance. Th2 cells secrete Th2 cytokines, including interleukin-IL-4, IL-5, and IL-13, which amplify type 2 inflammation, while Th1 cells secrete Th1 cytokines [interferon IFN-γ, IL-2, lymphoid (LT)-α, and tumor necrosis factor TNF-α, which limit type 2 inflammation [6, 7].

The CD4+ T cells are major effector cells driving asthma-related inflammation and the skewing of T cells into Th2 cells can lead to imbalance of Th1-type and Th2-type cytokines, which promotes the onset and progression of asthma [8, 9]. Understanding the factors contributing to Th2 in asthma will provide important insights into the underlying pathogenesis of the disease. The skewing of T cells into Th2 cells causes an imbalance of Th1-type and Th2-type cytokines, which promotes the onset and progression of asthma. A number of studies have shown that ncRNAs may play an important role in Th2 cell-mediated inflammation in asthma. This chapter mainly discusses the epigenetic regulation of Th2 response in asthma by non-coding RNAs, in order to better understand the disease pathogenesis and find potential asthma biomarkers.

### **2. Regulation of microRNAs on Th2 in asthma**

MicroRNAs are a group of small nonprotein-coding RNAs that are 18–25 nucleotides in length. They act as transcriptional regulators involved in many complex human disorders and in biological processes including cell proliferation and apoptosis [10–12]. MiRNA expression profiles have also been described in some allergic conditions and asthma [13]. Previous studies have suggested that miRNAs are involved in the development of allergic diseases by affecting Th1/Th2 polarization, promoting chronic inflammation and tissue remodeling of epithelial cells, and activating innate immune cells [13]. Th2-mediated inflammation is the core of the pathogenesis of allergic asthma. Th2-dominated T lymphocytes regulate allergic diseases by secreting a variety of proinflammatory cytokines. Recent studies have shown that most of the miRNAs involved increase Th2 cytokine secretion, reduce Th1 cytokine secretion, promote T cell differentiation to Th2, or play a role in the proliferation and hypertrophy of bronchial smooth muscle cells [14–16]. There is no doubt that miRNA plays a role in the regulation of asthma inflammation. MiRNAs may regulate Th2 in asthma by affecting Th1/Th2 balance, secretion of Th2 cytokines and related signaling pathways.

### **2.1 Regulation of Th2 cytokines by miRNAs**

Th2-mediated inflammation is the core of the pathogenesis of allergic asthma. Typical cytokines involved in the Th2 response are IL-4, IL-5, and IL-13. Pua et al. [15] studied the miRNA related to Th2 cell differentiation and cytokine production by combining experimental and bioinformatics methods, and found that both miR-24 and miR-27 inhibited the production of IL-4 in T cells in vitro. Inhibition of the function of miR-145 suppresses house dust mites (HDM)-induced mucus hypersecretion in airway epithelial cells, eosinophilic inflammation, th2 cytokine production, and airway hyperresponsiveness as effectively as dexamethasone treatment. This study shows that miR-145 plays a key role in the occurrence and pathogenesis of allergic airway disease caused by house dust mites by inducing the release of IL-5 and IL-13 from Th2 cells [14]. Panganiban et al. found a variety of differentially expressed miRNAs in the serum of patients with asthma, and predicted that these miRNAs could regulate IL-5 and other TH2 mediators [17]. It was further confirmed that IL-5 was regulated by miRNA, and miR-1248 was identified as a positive regulator of IL-5 expression [17]. IL-10 levels are reduced in asthmatic patients, and the relative deficiency of IL-10 allows continued production of allergenic cytokines, such as IL-4 and IL-5, and other pro-inflammatory cytokines, including IL-1, TNF-α, and IL-6 [18]. Inhibition of miR-106a promotes IL-10 secretion and helps alleviate asthma symptoms by increasing Th2 response in a mouse

### *Epigenetic Regulation of Th2 Response in Asthma by Non-Coding RNAs DOI: http://dx.doi.org/10.5772/intechopen.97328*

model of asthma [19]. Simpson et al. demonstrated that the miR-17 ∼ 92 cluster, and specifically miR-19a, promotes Th2 cytokine production by simultaneously targeting inhibitors of the NF-κB, JAK–STAT, and PI (3)K pathways. Their data also suggest that upregulation of miR-19a in asthma airway T cells may be an indicator and cause of increased IL-13 production and may contribute to type 2 inflammation in asthma [20]. In ovalbumin (OVA)-induced asthma mice, miR-146a significantly inhibited inflammatory cell infiltration in bronchoalveolar lavage fluid (BALF) and reduced levels of OVA-specific IgE and T-helper 2 cell type cytokines (IL-5 and IL-13) [21]. MiR-146a may act as a novel therapeutic molecule to modulate the immune response of asthma. MiR-155 has been shown to be a key modulator of the immune system. MiR-155 may regulate Th2 inflammation by regulating Th2 cell differentiation and the secretion of IL-4, IL-5 and IL-13. These studies suggest that targeting miR-155 may be a novel therapeutic strategy for human diseases induced by the Th2 immune response, such as asthma [22, 23]. It has been found that let-7 microRNAs inhibit IL-13 expression and thereby modulate Th 2 inflammation in an IL-13-dependent mouse model of allergic airway inflammation [24]. In ovalbumin (OVA) -induced asthma mice, intranasal administration of miR-410 significantly reduced the expression of IL-4 and IL-13 and effectively inhibited airway inflammation in OVA-induced asthmatic mice. Therefore, targeting to increase the expression of miR-410 may be a promising approach for the treatment of allergic asthma [25]. In a mouse model of asthma induced by ovalbumin, the researchers tested the airway hyperresponsiveness, rt-pcr detection of miR - 135 a content in the lung tissue of mice, HE staining to evaluate the pathological changes of lung tissue and ELISA and immunohistochemical detection of bronchoalveolar lavage fluid (BALF) and lung tissue of the tumor necrosis factor (TNF) - alpha, interleukin (IL) - 6, IL - 5 and eosinophils chemokine expression. The results of this study showed that miR-135a decreased expression in asthmatic mice, and miR-135a reduced the levels of inflammatory cytokines TNF-α, IL-6, IL-5 and eosinophilic chemokines in the lung tissue of mice, thereby reducing airway inflammation. Further research in this study showed that miR-135a inhibited airway inflammation in asthmatic mice by regulating the JAK/STAT signaling pathway [26]. Previous studies in human, animal models, and cell culture have shown that the Th2 cytokine IL-13 is an important cause of airway epithelial abnormalities in asthma [27–29]. Kuperman et al. used miRNA microarray to analyze the bronchial epithelial cells of asthmatic patients and healthy control subjects, and found that the expression of miR-34/449 family members was decreased in asthmatic patients. IL-13-induced reduction of miR-34/449 in bronchial epithelial cells may lead to changes in epithelial differentiation common in asthma [30]. Zhang et al. investigated the role of miR-221-3p in airway eosinophilic inflammation in a mouse model of HDM-induced allergic airway inflammation, and showed that epithelial miR-221-3p expression was reduced in asthma. Airway overexpression of miR-221-3p induced the expression of IL-4, IL-5, and IL-13 mRNAs in the lungs of mice induced by HDM [31]. The expression of miR-26a, miR-146a, and miR-31 and cytokine levels of IL-5, IL-8, IL-12, and TNF-α were measured in lung tissue and bronchoalveolar lavage fluid of asthmatic mice and children with ovalbumin induced asthma. The results showed that miR-26a, miR-146a, and miR-31 were significantly elevated in asthma, and were involved in the progression of asthma by regulating the expression of inflammatory cytokines IL-5, IL-8, IL-12, and TNF-α [32]. The systems immunology approach (the Impact of Differential Expression Across Layers, a network-based algorithm to prioritize disease-relevant miRs based on the central role of their targets in the molecular interactome) was used to antagonize miRs (miR27b, miR206, miR106b, miR203, and miR23b) in vitro, which has significantly reduced cytokine production in Th2 cells. These results suggest that these miRNAs play an important role in the

Th2-driven immune response [33]. In conclusion, many miRNAs play an important role in asthma by regulating the secretion of Th2 cytokines. They may be new targets for the treatment of asthma in the future.

### **2.2 Regulation of Th1/Th2 balance by miRNAs**

Qui et al. detected the levels of Th1- and Th2-related cytokines by ELISA, performed microRNA microarray assay and analyzed the differentiation marker gene of T helper cells by qRT-PCR. The results indicated that an imbalance of Th1/ Th2 cells was present in the asthmatic patients; Runx3 expression is decreased in asthmatic patients; overexpression of Runx3 could restore the Th1/Th2 balance; miR-371, miR-138, miR-544, miR-145, and miR-214 could directly bind to the 3'-UTR of Runx3. All these findings suggest that these miRNAs may be involved in Th1/Th2 imbalance in asthma by regulating Runx3 [34]. One study used predictive algorithms dentified potential direct miR-21 targets among IL-13-regulated lung transcripts such as IL-12p35 mRNA that was decreased in IL-13 transgenic mice. MiR-21 was significantly elevated in ovalbumin-induced mice lungs, suggesting that miR-21 regulates Th1 to Th2 phenotypic transformation by decreasing the mouse IL-12p35 transcriptome [16]. Reduced levels of miR-29b were found in the lungs and spleens of OVA-induced asthmatic mice, and this miRNA indirectly affects the Th2 response by regulating the production of T-box transcription factors and IFN-γ in T helper cells [35]. Low expression of miR-29b in asthmatic lung can increase the production of IFN-γ and restore the balance of Th1/Th2 in asthmatic lung [36]. The researchers evaluated the relationship between miRNA levels in small extracellular vesicles (sEVs) from nasal washing and pulmonary function parameters in children with mild to moderate or severe asthma compared to healthy controls. The results showed that lower levels of miR-34a, miR-92b and miR-210 in children with sEVs in this study were associated with pulmonary function and airway obstruction. Subsequent functional pathway analysis showed reduced levels of miR-92b, miR-210, and miR-34a in epithelial-derived sEVs in asthma, and these miRNAs regulate Th2 polarization and dendritic cell maturation [37].

### **2.3 miRNAs regulation of Th2 differentiation via signaling pathways**

Inhibition of microRNA-126 (miR-126) has been shown to effectively inhibit Th2-driven airway inflammation, mucus hypersecretion, and airway hyperresponsiveness in a model of ovalbumin (OVA) -induced chronic asthma [38]. The blocking of miR-126 leads to the enhanced expression of POU domain 2 related factor 1, which activates the transcription factor PU1, that changes the function of Th2 cells by negatively regulating the expression of GATA3 [39]. In childhood asthma, miRNA-451a was found to inhibit Th2 cell differentiation by down-regulating protooncogene 1 (ETS1). This study reveals that miRNA-451a-ETS1 axis dysfunction is a novel molecular mechanism that underlies the pathogenesis of childhood asthma [40]. A study has shown that miR-1165-3p targets IL-13 and PPM1A to control Th2 differentiation and pulmonary inflammation in asthma. miR-1165-3p inhibits the Th2 response of allergy through the STAT and AKT signaling pathways by targeted inhibition of protein phosphatase, Mg 2+/Mn 2+ − dependent 1A (PPM1A), thus proving that miR-1165-3p and PPM1A may be effective targets for the prevention and treatment of allergic asthma and related diseases [41]. The miR-29c/B7-H3 axis plays an important role in asthmatic children by regulating Th2/Th17 cell differentiation, and may provide a new target for asthma treatment [42]. The role of Th2 mediated microRNAs in asthma are summarized in the **Table 1** (**Figure 1**).


### *Epigenetic Regulation of Th2 Response in Asthma by Non-Coding RNAs DOI: http://dx.doi.org/10.5772/intechopen.97328*


### **Table 1.**

*Regulation of Th2 in asthma by miRNAs.*

### **Figure 1.**

*Regulation of Th2 in asthma by miRNAs. Th1 and Th2 are in equilibrium. miR-34a, miR-92b and miR-210 regulate Th2 polarization. MiRNAs such as miR-371, miR-138, miR-544 and miR-145 affect Th1/Th2 balance of asthma by regulating Runx3. MiR-21 regulates Th1 and Th2 balance by regulating IL-12p35 transcripts. As shown in the figure, miR-24, miR-27, miR-410, let-7a, miR-145, miR-146a, miR-1248 and other miRNAs regulate the secretion of Th2 cytokines, such as IL-4, IL-5 and IL-13, through up-regulation or down-regulation in asthma, and affect the occurrence and development of asthma.*

### **3. lncRNA regulate Th2 response in asthma**

LncRNA refers to a class of RNA molecules with a length greater than 200 nucleotides which do not have the function of coding RNAs. LncRNAs are mainly involved in gene expression regulation at the transcription, post-transcription, translation and epigenetic levels, and are widely involved in various life processes such as cell proliferation, differentiation, apoptosis, migration, aging and metabolism [45, 46]. Abundant expressions of lncRNAs were found in T cell lineages,

*Epigenetic Regulation of Th2 Response in Asthma by Non-Coding RNAs DOI: http://dx.doi.org/10.5772/intechopen.97328*

suggesting that these transcripts play important roles in T cell development and differentiation [47]. Studies have found that some lncRNAs play important roles in the pathogenesis of asthma by regulating Th1/Th2 balance and Th2 inflammatory response [3, 48]. Understanding how lncRNAs alter gene expression to promote Th2 skewing may provide new insights into mechanisms and therapeutic targets for asthma.

### **3.1 Regulation of Th1/Th2 balance by lncRNAs**

The gene encoding lncRNA MALTA1, a highly conserved nuclear lncRNA, is located on chromosome 11 (11q13.1). MALTA1 is highly expressed in most cells [49]. Liang et al. [50] conducted a cohort study of 772 asthmatic patients and 441 healthy controls, and found that the expression of MALAT1 was up-regulated and the expression of miR-155 was down-regulated in the blood of asthmatic patients. MALAT1 expression was inversely associated with impaired lung function and the Th1 / Th2 ratio, suggesting that its role was to impairs lung function by promoting the Th2 response. That is, the up-regulated expression of MALAT1 can induce the production of Th2 cytokines and inhibit the release of Th1 cytokines. Further study of the experiment showed that MALAT1 sponging miR-155 could alter the Th1/Th2 balance within CD4+ T cells through cytotoxic T-lymphocyte antigen 4 (CTLA-4) dependent mechanism. This study highlights the novel role of lncRNA MALTA1 in the development of Th2 in asthma. Wei et al. found that lncRNA PVT1 expression was increased in ozone-induced mouse asthma models, and the lncRNA PVT1-miR-15a-5p axis promoted Th1/Th2 imbalance in CD4 + T cells by activating the PI3K-Akt- signaling pathway [51].

### **3.2 lncRNA regulate Th2-type inflammation in asthma**

Zhu et al. assessed expression of lncRNAs in peripheral blood samples of patients with eosinophilic asthma, neutrophilic asthma and healthy controls using RNA-sequencing. In this study, it was found that the expression of LNC\_000127 was increased in eosinophilic asthma, and knockdown of LNC\_000127 (refer to this article for details) reduced the expression of CCR8, CRLF2, and CD40L (Th2 inflammatory receptor). Targeting LNC\_000127 may effectively reduce Th2 inflammation in eosinophilic asthma [52]. It has been demonstrated that induced pluripotent stem cells (iPSCs)-mesenchymal stem cells (MSCs) can effectively inhibit airway allergic inflammation in mice, and significantly reduce the expression levels of immunoglobulin (Ig) E and Th2 cytokines [53]. Further studies by Wang et al. [54] found that lncRNA MM9lincrnaexon12105 + and AK089315 were up-regulated in a model of ova-induced asthma. These two lncRNAs may be the main therapeutic targets of induced pluripotent stem cell mesenchymal stem cells (iPSC-MSCs) and may be involved in the regulation of Th2 type inflammation in asthma. This study provides an important basis for the study of the potential mechanisms of airway allergic inflammation and iPSC-MSC immune regulation, and these abnormal lncRNAs may become potential targets of allergic inflammation and iPSC-MSC mediated immune regulation. Wang et al. [55] conducted next-generation sequencing analysis of lncRNA and mRNAs on CD4 + T cells from ovalbumin-induced acute asthma mice and control mice, constructed co-expression networks of lncRNA and mRNAs, and found that lncRNA Fantom3\_9230106C11 was decreased in Th2 cells. Further qRT-PCR verification showed that lncRNA Fantom3\_9230106C11 could regulate the differentiation of Th2 cells. This study provides a platform to elucidate the role of lncRNA in Th2 differentiation and the pathogenesis of asthma. The role of Th2-mediated lncRNA in asthma are summarized in the **Table 2** (**Figure 2**).


### **Table 2.**

*lncRNA regulate Th2 response in asthma.*

### **Figure 2.**

*lncRNA regulate Th2 response in asthma. MALAT1 sponging miR-155 could alter the Th1/Th2 balance within CD4+ T cells through CTLA-4 dependent mechanism. lncRNA PVT1-miR-15a-5p axis promoted Th1/Th2 imbalance in CD4 + T cells by activating the PI3K-Akt- signaling pathway. LNC\_000127, MM9lincrnaexon12105 + and AK089315 and lncRNA Fantom3\_9230106C11 primarily regulate the Th2-type inflammation.*

### **4. circRNAs regulate Th2 response in asthma**

CircRNAs compose a novel class of ncRNAs characterized by covalently closedloop structures [56]. CircRNAs typically act as molecular sponges to bind and inhibit the transcription or activity of microRNAs (miRNAs), thereby affecting downstream mRNA expression [57]. CircRNAs are involved in the pathogenesis of

### *Epigenetic Regulation of Th2 Response in Asthma by Non-Coding RNAs DOI: http://dx.doi.org/10.5772/intechopen.97328*

various diseases [58]. The role of circRNA in asthma regulation is still in its infancy, and there are relatively few studies on the role of circRNA in the pathogenesis of asthma, especially Th2 inflammation in asthma.

Huang et al. [59] confirmed the expression of hsa\_circ\_0002594 in CD4 + T cells in asthmatic patients and healthy subjects by quantitative real-time PCR (qRT-PCR) using circRNA microarray analysis (such as a student's *t* test, nonparametric tests, Spearman's rank-order correlation, Fisher's exact test, and the generation of receiver operating characteristic curves). Their data suggest that hsa\_circ\_0002594 is upregulated in CD4 + T cells of asthmatic patients, which may have potential value in the diagnosis and treatment of Th2-mediated allergic asthma. In a mouse model of HDM-induced asthma, the results revealed that the relative expression levels of circ\_0000629 and circ\_0000455 in the asthma group were significantly increased compared with those animals in the control group, whereas the expression levels of circ\_0000454 and circ\_0000723 were significantly decreased [60]. The circRNA-miRNA regulatory network indicated that two of the downregulated circRNAs (circ\_0001454 and circ\_0000723) targeted miR-146b and miR-214, and two of these upregulated circRNAs (circ\_0000455 and circ\_0000629) could target miR-29b and miR-15a [60]. The expression levels of inducible co-stimulator, a target gene of miR-29b, were also previously shown to be elevated in the lungs of asthmatic mice, and promoted Th2 cytokine production and eosinophilic inflammation [61]. Furthermore, vascular endothelial growth factor, which is a target gene of mir-15a, was shown to be overexpressed in cases of Th2-mediated lung inflammation, such as asthma, and induced an asthma-like phenotype [62]. By contrast, two of the downregulated circRNAs (circ\_0001454 and circ\_0000723) targeted miR-146b and miR-214, respectively, which were previously shown to be positively associated with asthma [34, 63]. Huang et al. found that hsa\_circ\_0005519 may induce IL-13 and IL-6 expression by regulating hsa-let-7a-5p in CD4+ T cells to affect asthma. And hsa\_circ\_0005519 may be a potential biomarker of asthma [64]. The role of Th2-mediated circRNAs in asthma are summarized in the **Table 3** (**Figure 3**).


### **Table 3.**

*circRNAs regulate Th2 response in asthma.*

### **Figure 3.**

*circRNAs regulate Th2 response in asthma. Hsa\_circ\_0005519 functions as an endogenous hsa-let-7a-5p sponge to regulate the hsa-let-7a-5p/IL-13/IL-6 pathway in CD4+ T cells. Two down-regulated circRNAs (circ\_0001454 and circ\_0000723) targeted miR-146b and miR-214, while two up-regulated circRNAs (circ\_0000455 and circ\_0000629) targeted miR-29b and miR-15a. These four circRNAs regulate TH2 cytokine production by targeting miRNA.*

### **5. Summary**

NcRNAs display a wide range of functions, and each ncRNA has its own characteristics. This chapter mainly summarized the regulation of Th2 differentiation and immune response in asthma and experimental models of disease.

The role of miRNA in regulating Th2 cell-mediated inflammation in asthma is mainly reflected in several aspects: regulating Th1/Th2 balance, influencing cytokine secretion and regulating the activation state of T cells. The pathway of regulation can be that a single miRNA regulates one or more mRNAs, or multiple miRNAs of one or more gene clusters synergistically act on one or more mRNAs to exert biological effects. LncRNA plays a similar role to miRNA in regulating Th2 cell-mediated inflammation in asthma, affecting its activation, transformation and cytokine secretion. Most of the existing studies only analyzed the expression profile of lncRNA and identified the differentially expressed lncRNA molecules, but did not conduct in-depth study on its precise molecular mechanism. CircRNAs may play important roles in Th2 cells differentiation and, thus, play regulatory roles in Th2 cell-mediated inflammation in asthma. They can act as competitive endogenous RNAs (ceRNAs, which can regulate each other by competitively binding common microRNA response elements) of miRNAs to exert their biological effects, but the specific mechanism needs to be further studied.

In conclusion, miRNA, lncRNA and circRNA play important roles in regulation of Th2 cell function in asthma. However, the exact molecular mechanism of ncRNA in the regulation of TH2 cell function in asthma remains to be determined. Therefore, how to find out functional ncRNAs and elucidate their precise functions present the difficulties and challenges in the study of ncRNAs in this field. In future, more and more ncRNAs involved in the pathogenesis of asthma will be discovered, and the role of ncRNAs in the inflammatory process mediated by Th2 cells will be revealed. This will provide new details in the pathogenesis of asthma, and will help to develop new biomarkers and molecular targets for the diagnosis, classification, and treatment of asthma.

*Epigenetic Regulation of Th2 Response in Asthma by Non-Coding RNAs DOI: http://dx.doi.org/10.5772/intechopen.97328*

### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Yanhua Niu1 , Chao Wang1 , Xiaoyan Dong1 \* and Nanbert Zhong2 \*

1 Department of Pulmonary, Shanghai Children's Hospital, Shanghai Jiaotong University, Shanghai, China

2 New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA

\*Address all correspondence to: dong\_x\_y0305@126.com and dongxy@shchildren.com.cn

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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### **Chapter 5**

## Asthma Phenotypes and Current Biological Treatments

*Aşkın Gülşen*

### **Abstract**

Asthma is a heterogeneous disease characterized by bronchial hyperreactivity, chronic airway inflammation, and reversible airflow obstruction, and it affects individuals in all age groups. In recent years, the concept of intrinsic and extrinsic asthma as per the former classification has been replaced by endotypic and phenotypic definitions. However, the two main asthma endotypes described and have simplified its classification. These endotypes, "Th2-high" and "Th2-low", are based on various measurements obtained for different biological materials, including blood, bronchial and sputum samples. The definitions of asthma is useful for targeted and individualized treatments, estimating the treatment response and prognosis. In the field of respiratory medicine, biological drugs (BDs) have shown rapid evolution and positive developments in the last 10 years, particularly for the treatment of asthma, interstitial lung disease, and lung cancer. However, because of the increasing number of BDs and associated studies, it has become very difficult to update treatment guidelines on a regular basis. BDs are used for patients with difficult-to-treat, moderate to severe, and/or uncontrolled allergic asthma. Here we present a review of current asthma phenotypes and the role, efficacy, and side effects of BDs used for the treatment of these conditions.

**Keywords:** Asthma, phenotype, endotype, biological treatment, biologics

### **1. Introduction**

Asthma is a heterogeneous disease characterized by bronchial hyperreactivity, chronic airway inflammation, and reversible airflow obstruction, and it affects individuals in all age groups [1]. In recent years, studies on endotype and phenotype have intensified, and many different types have been identified. Symptom control is generally achieved with the use of inhaled corticosteroids (ICSs), although biological drugs (BDs) are used for patients with difficult-to-treat, moderate to severe, and/or uncontrolled allergic asthma [1], as these patient groups largely benefit from BD therapies. BDs, also known as biologics, encompass a number of agents that are rapidly growing and expanding their range of use. These drugs generally act on cell surface receptors or by interacting with a specific cytokine and are produced either directly from living sources (animal, human or microorganism) or by synthesizing from different cell cultures [2]. Currently, they are widely used in the fields of oncology, rheumatology, dermatology, and organ transplantation, and their indications include organ-specific cancers, psoriasis, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, chronic urticaria, multiple sclerosis, and transplants [3]. In the field of respiratory medicine, biologics have shown rapid

evolution and positive developments in the last 10 years, particularly for the treatment of severe uncontrolled asthma, interstitial lung disease, and lung cancer. In this review, we will evaluate the current updates of asthma phenotypes and the role, efficacy, and side effects of BDs used for the treatment of these conditions.

### **2. Endotypes and phenotypes of asthma**

The concept of intrinsic and extrinsic asthma as per the former classification has been replaced by endotypic and phenotypic definitions. However, a lack of clear classification system leads to a confusion and limitation in treatment. The current Global Initiative for Asthma (GINA) 2020 guideline mentions phenotypic differences in allergic asthma, nonallergic asthma, late-onset asthma, asthma with fixed airflow limitation, and asthma with obesity [1]. Although this guideline does not provide much details on asthma phenotyping, it mentions that further studies are necessary. Following the introduction of the phenotype concept, in 2006 Simpson et al. [4] conducted a study to fully characterize asthma based on the airway inflammatory type. The authors performed induced sputum analysis and divided the patients into the following four subgroups according to the dominant inflammatory cell type: a. neutrophilic, where neutrophils are >61% and the total cell count is >10 million cells/g; b. eosinophilic, where eosinophils are >1.9–3%; c. mixed granulocytic, where there is an increase in both neutrophils and eosinophils; and d. paucigranulocytic, where both neutrophils and eosinophils are within the normal range [4]. It is known that this classification of airway inflammation in asthma is important in predicting the clinical significance and response to BDs. Moreover, the authors reported that the rate of eosinophils in induced sputum is homogeneous and reproducible for eosinophilic asthma and heterogeneous for the other non-eosinophilic types of disease, and that further classification can be based on the presence of neutrophils [4].

However, a study involving 726 patients from the Severe Asthma Research Program (SARP) cohort was performed, and five main groups were identified [5] as follows: group 1, early-onset atopic asthma, control with two or fewer controlling drugs, normal lung function; group 2, early-onset atopic asthma, preserved lung function [65%; forced expiratory volume in 1 s (FEV1), >80% predicted], control with three or more controlling drugs (29% patients); group 3, late-onset nonatopic asthma, moderate decrease in FEV1, frequent oral corticosteroid (OCS) and ICS use for the treatment of exacerbations; group 4, early-onset atopic asthma with severely compromised pulmonary function (57% of the mean FEV1); and group 5, late-onset asthma, most severe airflow limitation (43% of the mean FEV1), less atopic patients with varying degrees of susceptibility to bronchodilator therapy. Then, subgroup analysis was performed as an extension of the same study, and the importance of eosinophil (≥2%) and neutrophil (≥40%) percentages in the sputum was emphasized [6]. From these findings, it was understood that asthma is a very heterogeneous disease with inflammatory and noninflammatory mechanisms. Considering the role of Type 2 T-helper cell (Th2) lymphocytes in eosinophilic airway inflammation, clinical studies have been inclined toward this topic. However, the two main asthma endotypes described in recent years have simplified its classification [7–9]. These endotypes, "Th2-high" and "Th2-low", are based on various measurements obtained for different biological materials, including blood, and bronchial, and sputum samples [10]. The Th2-high type is generally characterized by increased eosinophils in the patient's sputum and respiratory tract, while the Th2-low type is characterized by increased neutrophils or by the presence of a paucigranulocytic pattern [10]. The Th2-high patient group can be identified by some biomarkers, particularly an elevated blood eosinophil count of >300 cells/mL, and these patients have shown a good response to treatment with BDs [10]. There are no defined biomarkers for the Th2-low endotype, so this phenotype is often identified by the absence of Th2-high biomarkers. Moreover, these patients do not respond well to steroids [10].

Currently, the serum immunglobulin (Ig)-E concentration and the number of peripheral blood eosinophilis are generally used to determine the response of patients with BD treatment [7, 9]. A combination of Th2 biomarkers such as interleukin (IL)-4, IL-5, and IL-13 is also considered to be a credible predictor of peripheral blood eosinophilia and eosinophilic inflammation [11]. Several other biomarkers that can be used include the following: **a.)** periostin, which plays a role in late-onset asthma and determines eosinophilic inflammation; **b.)** eotaxin-2, which determines eosinophilic inflammation; **c.)** L-arginine and leptin, which are associated with obesity-related asthma; **d.)** Chlamydia pneumonia antibodies (IgG, IgA, and IgE), which are associated with severe and obstructive asthma; **e.)** *Staphylococcus aureus* enterotoxin-IgE, which is associated with severe asthma, hospitalizations, OCS use, and lower FEV1; and f.) thymic stromal lymphopoietin (TSLP), which may play a role in sputum eosinophil elevation in smokers with asthma, thus helping in identification of this patient group [12]. Other investigations that help to improve endotyping include the measurements of the fraction of exhaled nitric oxide (FeNO) and skin prick tests [7]. The levels of allergen-specific antibodies may be considered clinically important in patients with asthma and atopy even if they are not used for endotyping. The World Asthma Phenotypes (WASP) study was initiated in 2016 and conducted in five countries; the results are awaited [13]. The aim of this study was to evaluate and compare detailed biomarker and clinical information, the distribution of disease phenotypes, and the risk factors and characteristics for each phenotype, including clinical severity.

In summary, the definition of asthma phenotypes and endotypes is useful for estimating the treatment response and prognosis. This approach has resulted in targeted and individualized treatments for patients (**Figure 1**).

### **2.1 Th2-high endotype**

The asthma phenotypes that can be included in this group include aspirinassociated asthma, allergic bronchopulmonary mycosis (ABPM), earlyonset (preschool wheezer) asthma, adult-onset asthma, late-onset severe hypereosinophilic asthma, and IgE-mediated occupational asthma (**Table 1**). These phenotypes can be classified under the Th2-high endotype because of the presence of significant allergic symptoms and eosinophilic inflammation.

Patients with aspirin-related or aspirin-sensitive asthma often present at polyclinics with nasal polyposis and severe rhinosinusitis [7]. The most important biomarkers are urinary leukotriene and blood eosinophils, although periostin may also be elevated [14]. The ABPM phenotype includes patients with adult-onset, severe asthma attacks and increased mucus production [7], and blood eosinophil counts, high IgE levels, high FeNO values, allergen-specific IgE, and skin prick tests can be used for identification [14]. Preschool wheezers are children with a family history of asthma who experience more than three episodes per year and often exhibit blood eosinophilia (>4%) and aeroallergen-specific IgE positivity [14]. The adult-onset allergic asthma phenotype includes patients having asthma since childhood, with symptoms of allergen-related rhinitis, positive skin prick tests, high IgE levels, and high FeNO values [7, 14]. The severe late-onset hypereosinophilic asthma phenotype includes nonatopic patients with severe exacerbations and peripheral blood eosinophilia [7, 14]. Patients with IgE-mediated occupational asthma, wherein asthma symptoms develop after the start of a new occupation or job, may also be included in

### **Figure 1.**

*Asthma phenotypes and current targets for biological treatment. Th2, T-helper type 2 cell; IL, interleukin; IgE, immunoglobulin E; TSLP, tymic stromal lymphopoietin; ACO, Asthma COPD overlap.*


*5-LO, 5-lipoxygenase; LT, leukotriene recepter antagonist; GK, Glucocorticoid; IgE,Immunglobulin E; FeNO, Fraction of exhaled nitric oxide in ppb; IL, Interleukin.*

### **Table 1.**

*Possible Th2-high Endotypes of asthma.*

this group. Specific inhalation challenge and peak expiratory flow measurement are required to diagnose these patients, along with high IgE levels, high allergen-specific IgE levels, high FeNO values, and sputum eosinophilia [15].

### **2.2 Th2-low endotype**

This group includes asthma-COPD overlap (ACO; fixed obstruction) syndrome, late-onset nonatopic asthma, steroid-resistant or neutrophilic asthma, obesity related asthma, perimenstrual asthma, and non-IgE-mediated occupational asthma. Phenotypes induced by external factors, including exercise-induced asthma, cold-induced or cross-country skiers asthma, stress-induced asthma, and psychological asthma, may also be included in this group (**Table 2**). However, this classification needs to be improved by further research.

According to the current GINA guideline, the term ACOS is used for patients with chronic respiratory symptoms, exposure to a risk factor such as smoking, and a postbronchodilatator FEV1/forced vital capacity (FVC) of <0.7 [1]. Although the latter is not a well-known biomarker, the condition can be easily identified by using a questionnaire [1]. Late-onset nonatopic asthma generally affects women and adults.


*ACO, Asthma-COPD-Overlap; LABA, long-acting beta agonist; LAMA, long-acting muscarinic antagonist; ICS, inhaled corticosteroids; FEV1, forced expiratory volume in 1 s; FVC, orced vital capacity; See Table 1 legend for expansion of other abbreviation.*

### **Table 2.**

*Possible Th2-low Endotypes of asthma.*

Patients do not respond well to glucocorticoids and require high-dose ICSs [12]. This phenotype is similar to the obesity-associated phenotype. Although there is no biomarker, the absence of an increase in the sputum eosinophil count or FeNO is considered an indicator [16]. Patients with steroid-resistant asthma do not respond well to glucocorticosteroids and are mostly adults. Their FEV1 is considerably lower, with more air trapping, and there is an increased association with respiratory infections, obesity, smoking, and air pollution [8]. Increased sputum neutrophil counts and IL-17 levels can be used as biomarkers [7, 8]. Obesity-related asthma is thought to occur because of high-fat diet-related systemic inflammation, and L-arginine and leptin can be used as biomarkers [12]. Premenstrual or catamenial asthma is characterized by the deterioration of asthma symptoms in the premenstrual phase, and the role of hormone levels and systemic inflammation in these patients remains unknown [1]. Asthma in cross-country skiers or cold-induced asthma is characterized by mild to moderate symptoms and often triggered by exercise and cold. It is also associated with respiratory tract infection [14, 17]. Increased leukotriene (LT) E4 in urine may be used as a biomarker [14]. Exercise-induced asthma develops because of increased catecholamines during exercise, resulting in increased airway resistance [17]. Histamine and prostaglandin release reportedly play a role [17], but there is no specific biomarker. In asthma induced by stress or psychological factors, central nervous system activation by psychological stress, followed by the release of stress hormones (glucocorticoids, epinephrine, and norepinephrine) and immunological changes, may cause asthma exacerbation [18]. Although there is evidence regarding the critical role of psychological stress in the development and exacerbation of allergic asthma, this phenotype requires further research [18].

### **3. Asthma treatment and targets for biological drugs**

A personalized approach with specific and targeted therapies for the cytokines constituting the inflammation cascade are of great benefit in the treatment of asthma, particularly the difficult-to-treat phenotypes [1, 14]. The pathophysiology of asthma has conventionally been mediated by Th2 lymphocytes, which induce the stimulation of eosinophils by IL-3, IL-5, and granulocyte–macrophage colony-stimulating factor (GM-CSF); basophils by IL-3; and mast cells by IL-4 and IL-9; alternatively, they cause direct mucosal damage via IL-4/IL-13 after antigen presentation [7–9]. Both IL-4 and IL-13 play a role in the activation of eosinophils, IgE synthesis, and, consequently, mucus secretion and airway remodeling [10]. However, they share the same receptor and signal pathways. All these cytokines also stimulate B-cells, causing the release of IgE. Currently approved targets for BD treatment in asthma include IgE, IL-4/IL-13, and IL-5, with uncontrolled or difficult-to-treat asthma requiring step 4 treatment as per the GINA guideline being the main indication [1]. In this group of patients, symptom control cannot be achieved despite maximum treatment [long-acting beta agonists (LABAs), tiotropium, high-dose ICSs, leukotriene antagonists, or theophylline with OCSs].

### **4. Classification for biologics**

Biologics are divided into three common classes: monoclonal antibodies (mAbs), fusion proteins, and cytokines [2]. These drugs may be fully humanized mAbs or chimeric (human + murine mix) or fully murine/mouse antibodies [2, 19]. Diverse side effects with varying severities have been reported according to the level of humanization [3, 19]. Widely accepted nomenclature systems for biologics include the

*Asthma Phenotypes and Current Biological Treatments DOI: http://dx.doi.org/10.5772/intechopen.97376*

USAN (the United States' Adopted Names) and INN (World Health Organization's International Nonproprietary Names) [2, 20]. Currently approved mAbs target IgE antibodies, cell surface molecules, soluble mediators, cytokines, viral proteins, and tumor antigens [2, 20]. Examples of these drugs include omalizumab (anti-IgE), rituximab (anti-CD20), infliximab [anti-tumor necrosis factor alpha (TNFα)], mepolizumab (anti-IL-5), and cetuximab (anti-epidermal growth factor receptor). Examples for fusion proteins; etanercept (anti-TNFα-RII), anakinra (anti-IL-1 receptor), and ritanercept (anti-IL-1β) are examples. The cytokine group includes recombinant cytokines such as interferon-α, interferon-β, GM-CSF, and IL-2.

### **5. Overview of biologics used for asthma treatment**

Biologics have been used for the treatment of asthma since 2003. In the United States, omalizumab was the first drug approved for the treatment of severe and uncontrolled asthma [20]. Subsequently, several drugs targeting IgE, IL-5, IL-4, IL-5, IL-9, IL-13, IL-17, and TSLP were developed for the treatment of this patient group (**Table 3**). Details about these drugs are provided below.

### **5.1 Anti-IgE**

a.**Omalizumab** (Xolair®) is a humanized mAb and the first drug to be approved by the Food and Drug Administration (FDA) for the treatment of severe uncontrolled asthma [21]. The mechanism of action involves selective binding to IgE antibodies, reduction of free IgE levels, and inhibition of inflammatory mediator release via the inhibition of mast cell degranulation.

The PERSIST study, a "real-life" study, demonstrated that 12-month treatment with omalizumab can significantly improve the lung function and quality of life and minimize the rate of exacerbation [22]. The APEX II multicenter observational study demonstrated a clinical response rate to omalizumab at week 16 to be 82.4%. [23]. When the pre- and post-treatment periods were compared, a decrease in the daily OCS dose and number of exacerbations requiring hospitalization was observed. Moreover, pulmonary function test findings and the quality of life of patients were significantly improved. In a newly published study by Vennera et al., 60% patients who received omalizumab treatment for 6 years showed that the drug maintained its positive effect for at least 4 years after treatment discontinuation [24]. On the basis of clinical evidence, the response to omalizumab treatment is routinely evaluated after 16 weeks of treatment [25]; this evaluation is accepted as the most meaningful measurement and indication of permanent treatment response in the world.

In pre- and postmarketing studies, the risk of anaphylaxis was reported to be 0.1%–-0.2% [26]. It was found that 61% reactions occurred within 2 h after one of the first three doses, while 14% occurred within 30 min after a fourth or subsequent dose [27]. In another study, 3.4%, 2.2%, and 0% participants reported injection site reactions, hypersensitivity reactions (HSR), and anaphylaxis, respectively [28].

b.**Quilizumab** is a humanized mAb against the M1 major segment of membranebound IgE, and it causes memory depletion of B-cells and inhibits IgE production [29]. The primary indication is uncontrolled allergic asthma and chronic spontaneous urticaria. In a study by Harris et al., it was demonstrated that


**Table 3.**

*Administration.*

*Overview of biological agents used in asthma.*

quilizumab was well tolerated by patients and reduced the IgE levels (serum total and allergen-specific) by 30–40% [30]. However, there was no beneficial effect with regard to asthma exacerbations, lung function, and patientreported symptom measures. At 36 weeks, the asthma exacerbation rate decreased by 19.6% relative to that in the placebo group, although this was not a statistically significant result. Significant clinical efficacy benefit has not been demonstrated in studies of various biomarker subgroups (serum IgE, blood eosinophils, exhaled NO, and periostin). The safety of the drug was evaluated in the same study, and injection site reactions (mostly pain) were reported in 6.9% patients [30]. Currently, phase III studies of this drug are in progress.

c.**Ligelizumab** is an investigational humanized mAb that binds to IgE with a higher affinity than does omalizumab. In a 2016 study of patients with mild allergic asthma, it was found that inhaled and skin allergen responses were 3-fold and 16-fold greater with ligelizumab than with omalizumab and placebo, respectively [31]. These findings suggest the effectiveness of this drug in asthma treatment; phase III studies are currently ongoing.

### **5.2 Anti-IL-5**

a.**Mepolizumab** (Nucala®) is a humanized mAb that binds to IL-5, selectively inhibits eosinophilic inflammation, and reduces both sputum and the number of eosinophils in the blood [32]. After receiving approval for the treatment of eosinophilic and severe asthma in Europe in December 2015, it was approved for the treatment of eosinophilic granulomatosis with polyangiitis and Churg– Strauss syndrome in December 2017.

In one study, subcutaneous administration of mepolizumab 100 mg every 4 days significantly lowered the rate of asthma exacerbations and the daily dose of OCSs in patients dependent on OCSs for asthma control [33]. In another study, mepolizumab was found to be at least as effective as omalizumab, and no significant difference was found between the tolerability profiles of the two treatments [34]. The most commonly reported adverse events in the Dose Ranging Efficiency and Safety with Mepolizumab in Severe Asthma (DREAM) study were nonallergic reactions associated with infusion [35]. In addition, Lugogo et al. [36] observed HSRs in <1% patients, injection site reactions in 4%, and infusion/injection reactions (nonallergic) in 1%. None of the recent studies has reported the occurrence of anaphylaxis as a side effect [35, 36].

b.**Reslizumab** (Cinqaero®) is a humanized mAb that binds to IL-5 and is used as an adjunctive drug in the treatment of severe and uncontrolled eosinophilic asthma [37]. The drug inhibits the activation, differentiation, and growth of eosinophils by inhibiting the binding of IL-5 to eosinophils. Unlike other drugs, it is intravenously administered at a dose of 3 mg/kg every 4 weeks.

In a subgroup analysis by Corren et al., the efficacy of resolizumab for an improvement in respiratory function, Asthma Control Questionnaire (ACQ ) scores, and recovery inhaler use were evaluated for patients with a blood eosinophil count of >400 cells/μL [38]. Therefore, the blood eosinophil count is a useful pre-treatment biomarker in predicting patients' response to therapy and for the appropriate patient selection. In addition, two phase III studies reported that reslizumab administration improves lung function and controls asthma and related symptoms in patients with severe, uncontrolled, eosinophilic (≥400 cells/μL) asthma [38, 39]. Murphy et al. [40] demonstrated the long-term clinical effects and reported HSRs (<1%), drug rash (<1%), and very rare local infusion-related adverse events (e.g., pain at the site of injection; <1%) during the follow-up period, with no documented case of anaphylaxis [40].

c.**Benralizumab** (Fasenra®) is the newest biologics in the family of humanized mAbs, and it is being developed for the treatment of eosinophilic and allergic asthma [41]. Its acts by binding to the α-subunit of the IL-5 receptor (IL5Rα) on eosinophils and basophils.

In the SIROCCO [42] and CALIMA [43] trials, both phase III trials, benralizumab significantly lowered the annual exacerbation rate in patients with uncontrolled asthma (despite high-dose ICS plus LABA treatment) and a blood eosinophil count of >300 cells/μL. The safety of the drug was also tested, and it was found to be well tolerated. Following these promising data, it was approved for use in Europe in the beginning of 2018. The most commonly reported side effect is mild to moderate nasopharyngitis [44]. FDA labels report a HSR (rash, urticaria) rate of 3% for patients receiving benralizumab and placebo therapy [41]. In these labels, the rate of injection site reactions was 2.2% for patients treated with benralizumab and 1.9% for those treated with placebo, with two cases of anaphylaxis [41]. Post-marketing recording and notification of side effects are currently ongoing.

### **5.3 Anti-IL-4/13**


### **5.4 Anti-IL-13**


### **5.5 Anti-IL-17**

**Secukinumab and Brodalumab** are monoclonal antibodies that target IL-17A and IL-17RA signaling, respectively. A phase II trial of the efficacy and safety of secukinumab treatment for asthma has been completed (NCT01478360), and the results are expected. On the other hand, a phase II trial of brodalumab (NCT01902290) was terminated because of the lack of efficacy in a predetermined intermediate analysis. Both drugs are approved and presently used for the treatment of moderate to severe plaque psoriasis.

### **5.6 Anti-IL-9**

**Enokizumab (Medi-528)**, which is a mAb against IL-9, is defined as a T-cell and mast cell growth factor [54]. It was initially tested in animal models of asthma and was shown to alleviate the disease [54]. Subsequently, a double-blind, multicenter study involving 329 human adults was conducted [55], and the results revealed that the addition of this drug to existing anti-asthma drugs does not improve FEV1 values, decrease the asthma exacerbation rate, or improve ACQ scores. This observation was surprising, considering the very promising initial results. The main reason for this discrepancy is thought to be the heterogeneity of the study patients and the lack of differentiation between asthma subtypes [55].

### **5.7 Anti-epithelial cell-derived cytokine**

**Tezepelumab** is a human mAb specific for TSLP, which is an epithelial cytokine. TSLP is considered to play a critical role in the onset and progress of airway inflammation. In a study by Corren et al., 52-week treatment with this BD significantly decreased the asthma exacerbation rate, independent of the blood eosinophil count [56]. Moreover, the prebronchodilator FEV1 at 52 weeks was higher in all tezepelumab groups than in the placebo group (mean, 110–150 mL) [56]. This is a very promising drug for noneosinophilic, uncontrolled asthma, and phase III studies (NCT03927157, and NCT03347279) are currently ongoing.

### **5.8 Prostoglandin DP2 receptor antagonist**

**Fevipiprant and Timapiprant** is a promising biologics has been set for new biological treatments in allergic asthma. This target is prostaglandin D2 (PGD2) which acts through the DP2 receptor, also known as chemoattractant receptorhomologous molecule expressed on Th2 cells (CRTh2). DP2 is a G-proteindependent receptor that mediates activation and migration of Th2 cells and eosinophils at the center of allergic and inflammatory processes.

Fevipiprant is a powerful, reversible and highly selective DP2 receptor antagonist that can be used orally, targeting PGD2 directly [57]. In phase 2 studies performed in patients with severe uncontrolled eosinophilic asthma, the rate of sputum eosinophils decreased, 160–207 ml increase in FEV1 level and Asthma Control Questionnaire scores was obtained [58]. Phase III studies (NCT02555683 and NCT02563067) was completed and the results are expected. If positive results are obtained in these studies, it can be thought that this oral treatment would be an alternative to the biological treatments and would be easier to access.

Timapiprant (OC000459), which also affected the same receptor, showed 95 ml FEV1 increase in mild to moderate allergic asthma compared to placebo, and in the post hoc analysis, 220 ml increase was reported in FEV1 compared to placebo when atopic eosinophilic uncontrolled asthma subjects were selected [59]. No serious drug-related side effects were reported in the same study.

### **6. Conclusion**

In summary, BDs play an important role in the treatment of many lung diseases. Recent advances in our knowledge of asthma pathologies, the role of cytokines,

allergen-directed immune responses, and disease phenotyping have resulted in the identification of numerous potential and specific targets for BDs. Monoclonal antibodies targeting IgE, IL-5 and IL-4/IL-13 have demonstrated significant improvements in asthma control such as reduce asthma exacerbations and improve lung functions [60]. In addition, long-term benefits such as reduced need for oral corticosteroids and control medications, reduction in asthma symptoms, improving quality of life, and reduced loss of work capacity have been demonstrated [7–9]. For the future, there is a need for new biomarkers to identify asthma patients with Th2-low endotype and thus new BDs that affect inflammatory pathways [60].

On the other hand, anti-IL-9 and anti-IL-17 treatments showed no positive results in terms of clinical benefits [55]. Meanwhile, anti-TSLP and anti-PGD2 treatment has shown very promising results, and the results of phase III studies are awaited. However, because of the increasing number of BDs and associated studies, it has become very difficult to update treatment guidelines on a regular basis; this issue and personalized treatment options needs to be resolved in future. However, after the endotypes and phenotypes are classified, investigation of the effects of these drugs may yield different results.

### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Aşkın Gülşen Department of Pneumology, University of Lübeck, Germany

\*Address all correspondence to: askingulsen@hotmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Asthma Phenotypes and Current Biological Treatments DOI: http://dx.doi.org/10.5772/intechopen.97376*

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### **Chapter 6**

## Anaphylactic Reactions in Radiology Procedures

*Callen Kwamboka Onyambu, Angeline Anyona Aywak, Sarah Kemunto Osiemo and Timothy Musila Mutala*

### **Abstract**

Reactions to contrast agents are uncommon but range from mild urticaria to life threatening anaphylactic reactions. Majority of these reactions occur due to intravenous administration of iodinated contrast media. Acute reactions to MRI gadolinium-based contrast are much less common but they do occur and thus have to be managed. Usual presentations include urticaria, nausea, vomiting, angioedema, bronchospasm, laryngospasm and systemic hypotension. Majority of these reactions occur within the first twenty minutes after administration of contrast. Therefore, their recognition and prompt treatment are critical for good patient outcome. Attendant to this the radiology department must be adequately prepared to handle these emergencies as and when they do occur. This means an up to date emergency tray must be checked regularly before the start of the procedure, ensure there is epinephrine, antihistamines, beta-2-agonists metered dose inhalers, IV fluids, and ready supply of oxygen. Close collaboration of radiology staff with the hospital emergency response team is critical since severe reactions will need the intervention of this team.

**Keywords:** anaphylaxis, iodinated contrast, bronchospasm, hypotension, diagnosis, treatment

### **1. Introduction**

Contrast media is a substance that is used to enhance the differentiation of tissues within the body in medical imaging. They are administered either intravenously, intraarterially, orally or into body cavities, majority being administered intravenously. Over the past few years there has been an increase in the number of radiographic examinations that use contrast media for better lesion characterization, more so in CT and MRI examinations [1]. Although contrast media has become progressively safer over time, especially with the use of low osmolar contrast media (LOCM), anaphylactic reactions still do occur. It is estimated that 0.6% of iodinated and 0.12% of gadolinium contrast cause anaphylactic reactions [2–4]. Reactions to contrast media range from mild reactions to life threatening severe reactions. Most acute reactions occur within 1 hour of contrast media administration, with majority occurring within the first 20 minutes. Therefore, it is important to be aware of these reactions, to monitor the patient closely in this period and to manage the reactions when they do occur [5].

There are two main types of iodinated contrast comprising high osmolar (HOCM) or ionic contrast that dissociates in solution to form particles and low


### **Table 1.**

*Types of iodine based contrast media and osmolarity.*

osmolar or non-ionic that does not dissociate in solution. Contrast media osmolality is determined by the number of particles formed in solution. Ionic contrast media dissociates into osmotically active ions in solution and therefore have a higher osmolality. Non-ionic agents do not dissociate to ions when dissolved in solution and hence have a lower osmolality. In recent years there has been a shift to using the LOCM because of associated fewer reactions therefore making contrast administration safer. Nevertheless, acute anaphylactic reactions can still occur unpredictably and therefore must be recognized and managed promptly. Some of the commonly used iodine-based contrast agents and their osmolality are listed in **Table 1** above.

### **2. Gadolinium based contrast**

Gadolinium based MRI contrast agents have been shown to be safe for intravenous administration, and actually a better safety profile than iodinated contrast for CT and other radiographic examinations. However acute reactions do occur and include urticaria, nausea and vomiting, and rarely anaphylaxis. In a study of 141,623 doses of MRI contrast administered Jae-woo et al. identified 0.079% immediate hypersensitivity reactions including urticaria, angioedema, bronchospasm and anaphylaxis and one fatality giving a mortality rate of 0.007% [6].

### **3. Presentation and management of contrast reactions**

### **3.1 Clinical presentation**

Reactions can be categorized as mild, moderate and severe as well as immediate and delayed. Mild reactions are usually self-limiting and require just supportive treatment, whereas moderate to severe reactions require prompt treatment. Delayed reactions such as abdominal pains, joint pains, fever and chills, diarrhea, headache, rashes and dizziness may be seen within two weeks from the date of contrast administration. Renal toxicity is also a commonly encountered side effect of contrast reactions manifesting as impaired renal function within two weeks of contrast administration.

**Table 2** below shows the different types of reactions seen.

### *Anaphylactic Reactions in Radiology Procedures DOI: http://dx.doi.org/10.5772/intechopen.95784*


### **Table 2.**

*Classification of contrast media reactions.*

**Figure 1.** *Patient evaluation algorithm.*

Anaphylactic reaction usually occurs within one hour of contrast administration, with majority occurring within the first 20 minutes. This is a life-threatening reaction and manifests with hypotension, bronchospasm/laryngeal oedema and circulatory collapse. Patient evaluation algorithm is as outlined in **Figure 1** above.

### **4. Anaphylactic reactions to contrast media**

Although contrast side effects are infrequent, the knowledge of their presentation, their relationship with pre existing conditions and their management is required to ensure optimal patient care [2, 7]. Non ionic agents are iso-osmolar or low osmolar in nature and have fewer adverse effects [8, 9].

Majority of contrast reactions occur unpredictably and severe reactions may occur even when there has been a previous uneventful examination.

Risk factors that increase the likelihood of occurrence of adverse reactions [10–12] include:


A detailed history should be obtained and pre medication administered prior to contrast use to reduce the risk of reaction occurrence.

Adverse reactions to contrast can be divided into organ specific and non organ specific or general reactions. They can also be classified into acute and delayed based on the timing after contrast administration.

Acute hypersensitivity reactions are those that develop within 1 hour of contrast administration and can classified into allergic-like and physiologic [13]. Allergiclike reactions are largely dose and concentration independent. They do not require prior sensitization or Ig-E and are thus called idiosyncratic /anaphylactoid reactions. They occur via direct mast cell stimulations or via activation of complement by immune complexes [14]. These are the most frequent type of adverse reactions and may have serious, occasionally fatal, complications.

Physiologic reactions are those that are dose and concentration dependent are thus called non idiosyncratic reactions. They are due to direct chemotoxic or osmotoxic effects of the contrast media [15].

### *Anaphylactic Reactions in Radiology Procedures DOI: http://dx.doi.org/10.5772/intechopen.95784*

These acute reactions can be further subclassified into into 3 categories based on severity-mild, moderate and severe [11]. Mild reactions are those that are self limiting. The mild allergic-like reactions include limited urticaria, pruritus, cutaneous edema, nasal congestion while the physiologic reactions include limited nausea and vomiting, transient flushing, headache, dizziness, anxiety and vasovagal reactions that resolve spontaneously [16]. Moderate reactions are those that are progressive and more pronounced and require medical management [17, 18]. The moderate allergic-like reactions include diffuse urticaria/pruritus, diffuse erythema with normal vital signs, facial edema, throat tightness, wheezing and bronchospasms. While the moderate physiological reactions include protracted vomiting, hypertensive urgency, vasovagal reactions that require treatment and respond to it [13]. Severe reactions are those that are potentially life threatening with impending death if not managed properly [2]. The severe allergic-like reactions include diffuse edema with dyspnea, diffuse erythema with hypotension, laryngeal edema with stridor, bronchospasms with hypoxia and anaphylactic shock. The severe physiologic reactions include vasovagal reactions resistant to treatment, convulsions, arrhythmia and hypertensive emergency [13]. The end result of severe allergic like and physiologic reactions is CPA which is a medical emergency and prompt and proper management using the BLS protocol and drugs including epinephrine, vasopressors, antihistamines and inhaled B-agonists is necessary to save lives.

Contrast induced acute kidney injury and nephropathy can also occur following contrast administration [19]. Risk factors include co morbidities like diabetes mellitus, dehydration, cardiac disease, hypertension and multiple iodinated contrast media doses in less than 24 hours. Baseline serum creatinine +/− glomerular filtration rate should be availed before injection of contrast media in at risk patients [13]. Contrast media administration in such patients can be done with caution by: reduced dose of contrast media, hydration and use of iso-osmolar agents.

### **5. Management of acute contrast media reactions**

Management of acute contrast begins with discontinuation of injection if not completed [13, 20]. General principals of BLS and ACLS should apply in case of cardiorespiratory arrest.

Summary of the management of contrast reactions is as outlined in **Table 3** below.

### **6. Premedication of at risk patients**

Premedication of patients who have a higher risk of acute allergic like reactions should be considered to reduce the chance of reaction occurrence [18]. For elective premedication oral prednisolone and diphenhydramine are used. For emergency premedication I.V methyl prednisolone sodium succinate or dexamethasone sodium sulfate. I.V diphenhydramine can be used instead of steroids in emergency cases [13].

### **7. Reaction rebound prevention**

Intravenous corticosteroids play a role in preventing short term recurrence of an allergic like reactions. They may also be administered to patients having severe allergic like manifestations prior to transport to an emergency unit. They are however not useful in the acute treatment of any reaction.




**Table 3.**

*Management of contrast reactions.*

### **7.1 Radiology department preparedness to manage anaphylactic reactions to contrast media**

The hospital administration in liaison with the heads of the radiology department and the radiology contrast committee should set up and publish an institutional policy and procedure manual on contrast media administration.

The purpose of this manual is:


iv.To ensure that patients due to receive intravenous contrast media have appropriate laboratory tests done and reviewed by the radiologist to determine their suitability for the procedure.

Guidelines for administration on intravenous contrast:


### **7.2 Radiology department emergency trolley**

All imaging sections in the radiology department must be equipped with the emergency equipment and medication required to monitor and manage a patient in cardiopulmonary arrest and more specifically a patient undergoing a severe reaction to contrast media.

Majority of the emergency equipment and medication are part of the standard crash cart/ emergency trolley; therefore, it is upon the administration of the radiology department to decide whether a dedicated contrast reaction kit is necessary. This will depend on the size of the imaging department, patient numbers and budget allocations.

The basic equipment required to monitor patients experiencing an adverse reaction to contrast media include:


Equipment and supplies for managing patients in an acute adverse reaction include:


Basic medication required in case of a contrast media reactions include:

i.Epinephrine


Additional medication and supplies include:


In view that cardiopulmonary arrest and adverse reactions to contrast media in the radiology department are rare, it is imperative that periodic stock checks are done to ensure the equipment and medications stocked for the management of these emergencies are within the recommended validity period.

### **7.3 Hospital emergency response team**

When faced with a severe reaction to contrast media in which the patient's condition warrants implementation of basic life support and advanced cardiac life support protocols, it is imperative that the hospital emergency response team be alerted to assist in initiation of these lifesaving protocols.

Modern radiology departments are fitted with an emergency bell that alerts the emergency response team to respond to an emergency in each imaging section. All radiology staff must be made aware of the location of these bells to activate them when needed.

In the event that such a system is not in place, the phone number of an internal/ external emergency response unit should be clearly posted in each imaging section.

### **7.4 Training**

Despite the rare occurrence of contrast media reactions, they may carry substantial morbidity and mortality and thus require immediate intervention by the attending staff. These staff must therefore be equipped with the knowledge and skills to initiate effective cardiopulmonary resuscitation in order to manage these emergencies as they await the arrival of the emergency response team.

All clinical staff should receive life support training upon employment and thereafter attend at least three yearly refresher course as recommended by the American heart association.

Continuous medical education on contrast media reactions and their management should be held frequently to ensure these vital knowledge and skills are up to date.

Advanced radiology life support ™ is a course that uses concepts from basic life support and advanced cardiac life support to radiology clinical staff on recognizing and managing life threatening emergencies occurring in the imaging department.

This training covers:


*Anaphylactic Reactions in Radiology Procedures DOI: http://dx.doi.org/10.5772/intechopen.95784*

Advanced radiology life support ™ has been successful in United states of America and Canada in training of radiologists, radiology technicians and nurses in the management of contrast media reactions and cardiopulmonary arrest in the radiology department. Accreditation is by the Mayo clinic of medicine and Science.

This training is available online in form interactive videos, therefore imaging departments should allocate a budget for purchase of this training for each of its clinical staff members.

### **Author details**

Callen Kwamboka Onyambu1 \*, Angeline Anyona Aywak1 , Sarah Kemunto Osiemo2 and Timothy Musila Mutala1

1 Department of Diagnostic Imaging and Radiation Medicine, University of Nairobi, Nairobi, Kenya

2 Kenyatta University Hospital, Nairobi, Kenya

\*Address all correspondence to: callen.onyambu@uonbi.ac.ke

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

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[2] Singh J, Daftary A. Iodinated contrast media and their adverse reactions. Journal of Nuclear Medicine Technology. 2008.

[3] Wang C.L., Cohan R.H., Ellis J.H., Caoili E.M., Wang G., Francis I.R. Frequency, outcome, and appropriateness of treatment of nonionic iodinated contrast media reactions. Am J Roentgenol. 2008;

[4] Gaeta TJ, Clark S, Pelletier AJ, Camargo CA. National study of US emergency department visits for acute allergic reactions, 1993 to 2004. Ann Allergy, Asthma Immunol. 2007;

[5] Osiem SK, Onyamb CK, Aywa AA. Knowledge and practices of cardiopulmonary arrest and anaphylactic reactions in the radiology department. South African J Radiol. 2020;

[6] Jung JW, Kang HR, Kim MH, Lee W, Min KU, Han MH, et al. Immediate hypersensitivity reaction to gadoliniumbased MR contrast media. Radiology. 2012;

[7] Park HK, Kang MG, Yang MS, Jung JW, Cho SH, Kang HR. Epidemiology of drug-induced anaphylaxis in a tertiary hospital in Korea. Allergol Int. 2017;

[8] Katzberg RW, Haller C. Contrastinduced nephrotoxicity: Clinical landscape. Kidney Int. 2006;

[9] Katzberg RW. Urography into the 21st century: New contrast media, renal handling, imaging characteristics, and nephrotoxicity. Radiology. 1997.

[10] Cohan RH, Ellis JH. Iodinated contrast material in uroradiology: Choice of agent and management of complications. Urol Clin North Am. 1997;

[11] Tublin ME, Murphy ME, Tessler FN. Current concepts in contrast mediainduced nephropathy. American Journal of Roentgenology. 1998.

[12] Mamoulakis C, Tsarouhas K, Fragkiadoulaki I, Heretis I, Wilks MF, Spandidos DA, et al. Contrastinduced nephropathy: Basic concepts, pathophysiological implications and prevention strategies. Pharmacology and Therapeutics. 2017.

[13] ACR Committee on drugs and contrast Media. ACR Contrast Manual v10.3. American College of Radiology. 2018.

[14] Almén T. The etiology of contrast medium reactions. Invest Radiol. 1994;

[15] Katzberg RW, Lamba R. Contrast-Induced Nephropathy after Intravenous Administration: Fact or Fiction? Radiologic Clinics of North America. 2009.

[16] Böhm I, Heverhagen JT, Klose KJ. Classification of acute and delayed contrast media-induced reactions: Proposal of a three-step system. Contrast Media Mol Imaging. 2012;

[17] J.M. EM, S. MB, R. MB, R. VC, A. A-L. Clinical characteristics of adverse reaction to iodinated contrast media. Allergy Eur J Allergy Clin Immunol. 2013;

[18] Dispenza MC, Ditto AM. Adverse Reactions to Contrast Media. In: Drug Allergy Testing. 2018.

[19] Hossain MA, Costanzo E, Cosentino J, Patel C, Qaisar H, Singh V, *Anaphylactic Reactions in Radiology Procedures DOI: http://dx.doi.org/10.5772/intechopen.95784*

et al. Contrast-induced nephropathy: Pathophysiology, risk factors, and prevention. Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia. 2018.

[20] Neumar RW, Shuster M, Callaway CW, Gent LM, Atkins DL, Bhanji F, et al. Part 1: Executive summary: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2015;

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