Costimulation in Allergic Asthma: The Roles of B7 and Semaphorin Molecules

*Svetlana P. Chapoval and Andrei I. Chapoval*

### **Abstract**

It is well established that allergic asthma is T cell-driven disease where CD4+ T cells of Th2 phenotype play a critical role in disease initiation and maintenance. There are several critical steps in the induction of Th2 type immune response to the allergen. The first critical step is the antigen processing and presentation of allergen-derived peptides in the context of specific major histocompatibility Class II (MHCII) molecules by antigen-presenting cells (APC). Recognition of this complex by T cell receptor (TCR) and interaction of costimulatory ligands with corresponding receptors represents the second step in T cell activation. As the third part of optimal T cell differentiation, proliferation, and expansion, several cytokines, integrins, and chemokines get involved in the fine-tuning of DC-T cell interaction and activation. Multiple recent evidences point to the selected members of B7 and semaphorin families as important checkpoints providing a fine-tuning regulation of immune response. In this book chapter, we discuss the properties of costimulatory molecules and address their roles in allergic asthma.

**Keywords:** asthma, immune response, costimulation, immune checkpoints, B7 family molecules, semaphorins

### **1. Introduction**

Allergic asthma is a Th2-driven, immunological chronic disease [1]. CD4+ T cells of Th2 phenotype secreting Th2 cytokines such as IL-4, IL-5, and IL-13 play a critical role in asthma initiation and propagation [2]. In this book chapter, we address the question of how different costimulatory molecules influence the allergic immune response which is central to asthma pathogenesis.

The initial step in the immune response is the antigen capture and processing by APC. APC subdivide into "professional" such as dendritic cells (DC), B cells, and macrophages, and "unprofessional" such as epithelial cells, fibroblasts, basophils, eosinophils, ILC2 (type 2 innate lymphoid cells), which normally have other functions in tissues and do not act as APC [3–5]. Antigenic epitopes derived from a captured allergen are presented to T cells in the context of specific MHC (human leukocyte antigen, HLA, for human cells) molecules [1]. This is the first signal for T cell activation, whereas a second signal is derived from costimulation where specific costimulatory molecules on APC interact with their receptors on T cells (**Figure 1**) [6]. The first

### **Figure 1.**

*The two-signal model of the T-cell activation. (a) Functions of the immune checkpoint molecules (IChMs) are completely dependent on the first signal because the interaction of the receptor (Co-R) on T-cells with the ligand (Co-L) on APCs (the second signal) do not result in an activation of T-cells without the first signal. (b) T-cell activation has not occurred in the absence of the second signal. In several cases, the absence of the second signal leads to T-cell tolerance and anergy. (c) the correct activation of T-lymphocytes occurs after the TCR interaction with the MHC-presented peptide (Ag) (the first signal) and after the interaction of a ligand of the B7 family (Co-L) with its receptor (Co-R) (the second signal). A synergism of the two signals results in an optimal activation of T-cells.*

signal alone does not lead to the immune response to allergen (**Figure 1**), it rather induces T cell unresponsiveness or "anergy" [6, 7].

The members of the B7 family are the most characterized immunomodulatory ligands that bind to receptors on lymphocytes. They can act as costimulators or inhibitors/checkpoints. Currently, there are eleven known representatives of the B7 family, namely: B7–1 (CD80), B7–2 (CD86), B7-H1 (PD-L1, CD274), B7-DC (PDCD1LG2, PD-L2, CD273), B7-H2 (B7RP1, ICOS-L, CD275), B7-H3 (CD276), B7-H4 (B7x, B7S1, Vtcn1), B7-H5 (VISTA, Platelet receptor Gi24, SISP1), B7-H6 (NCR3LG1), B7-H7 (HHLA2), and ILDR2 (the synonyms of IChM names of the B7 family are given in parentheses) [7, 8]. Two molecules of B7 family proteins [9], B7–1 and B7–2, are the best characterized costimulators [7, 8]. Their ligation of CD28 expressed on T cells leads to T cell activation whereas interaction with cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) functions as an inhibitory signal.

Multiple recent reports pointed to selected semaphorin family [10, 11] members acting as checkpoints in the immune response regulating optimal T cell activation and cytokine production [10, 12]. Semaphorins alone are unable to induce or suppress T cell activation regulated by a combination of signals 1 and 2 but can significantly potentiate or downregulate it [10, 12]. Moreover, their involvement in asthmatic disease development has been supported by several recent publications (reviewed in [13–15] establishing them as potential immunomodulatory targets.

The goal of this book chapter is to discuss the roles of these molecules in asthma and provide the ground for their therapeutic use in disease prevention, management, or treatment.

### **2. B7 family members in asthma**

### **2.1 B7: 1 and B7: 2**

Asthma is Th2 cell-driven disease with Th2 type cytokines such as IL-4, IL-5, and IL-13 driving the disease pathology [2]. The effect of costimulation in asthma has been a subject of several decades' of research. The differential role of two B7 family members in allergic response has been extensively studied and described in multiple articles published in the late 1990-s (16–19, reviewed in 20, 21). The work by Freeman et al. [16] questioned the functional necessity of two known at that time B7 family members. Using the *in vitro* cell cultures and distinct transfectants, they reported that both B7–1 and B7–2 effectively and equally costimulate T cells to produce IL-2 and IFNγ, however, B7–2 was more efficient in costimulation of IL-4 production with cell priming and especially with a repetitive cell stimulation, whereas B7–1 was efficient for GM-CSF production. Similarly, anti-B7–2 mAb significantly reduced the induction of IL-4 mRNA in a primary human allogeneic MLR whereas anti-B7–1 mAb failed to do so. The work by Van Neerven [17] addressed the same question as the discussed above research but in different experimental settings, namely the stimulation of human PBMC obtained from allergic and non-allergic persons *in vitro* with house dust mite allergen (HDM) in the presence or absence of B7–1 or B7–2 blocking Abs, or CTLA-Ig. CTLA4-Ig was efficient in inhibiting allergen-induced cell proliferation and cytokine production. The proliferation of CTLA4-Ig-treated cells was partially restored by stimulating them with anti-CD28 mAb which indicated that CTLA4-Ig inhibits the interaction of CD28 with both, CD80 and CD86. Interestingly, anti-CD86 mAb inhibited the HDMinduced cell proliferation similarly to CTLA4-Ig but with less degree of inhibition. However, the addition of anti-CD80 blocking mAb to the anti- CD86 mAb treated cells resulted in identical inhibition as with CTLA4-Ig. This report suggested that the costimulation inactivation could be efficient in the downregulation of allergendependent Th2 responses in asthmatic patients (**Figure 2**). The research by Larche et al. [18] used allergen stimulation of human PBMC and cells obtained by alveolar lavages to examine B7–1 and B7–2 dependence of T cell immune response. While allergen-induced PBMC proliferation and cytokine production were inhibited by the use of CTLA4-Ig and anti-B7–2 Ab in cell cultures, anti-B7–1 Ab showed no effect. Moreover, HDM-induced broncho-alveolar lavage (BAL) T cell proliferation was also B7–2 but not B7–1 dependent. This study further supported the notion that T cell costimulation-targeted therapy could be beneficial in asthma management. The study by Jaffar et al. [19] stimulated with HDM allergen the explants from endobronchial mucosal biopsies obtained from asthmatic patients. Although this study did not address the requirement of individual B7–1 or B7–2 molecules in anti-allergic T cell response, it clearly demonstrated the requirement of B7/CD28 costimulation in IL-5 and IL-13 production using a novel tool for asthma research, the bronchial explant system. Moreover, they were the first to demonstrate a significant difference in cytokine profile in bronchial explants between asthmatic and non-asthmatic lungs.

### **2.2 B7-H1 (PD-L1) and B7-DC (PD-L2)**

The B7 homolog 1 (B7-H1) shares the same inducible PD-1 receptor on T cells with B7-DC (reviewed in 20, 21). While B7-H1 is constitutively expressed on monocytes and is downregulated with cell activation, B7-DC expression is induced by cell activation (reviewed in 7, 8, 20). Functionally, it was speculated that PDL-1

### **Figure 2.**

*Role of costimulation in T cell immune response and asthma. a. B7–1 and B7–2 interaction with CTLA-4 contributes to suppressive activity of allergen-specific Treg cells whereas their interaction with CD28 costimulates Th1 and Th2 responses. b. ICOS-L – ICOS interaction regulates Th2 effector cell function; it is efficient in stimulation of IL-4 and IL-10 production but not IFN*γ*. It regulates Th2 cell infiltration into lungs, promotes B cell differentiation and IgE production, contributes to AHR. This pathway also regulates IL-10 production in Treg cells. c. PD-L1 interaction with PD-1 receptor play a protective role in allergic asthma as it was reported to drive a differentiation of Treg cells and to downregulate contact hypersensitivity reaction. On the other hand, the use of neutralizing anti-PD-1 ab in vivo decreased eosinophilic lung infiltration but increased AHR and lung neutrophilia. d. PD-L2 interaction with PD-1 receptor downregulates allergic asthmatic response by suppressing Th2 cell activation, AHR, eosinophil infiltration, and IgE production. e. B7-H3 interaction with unknown receptor promotes Th2 and Th17 cell differentiation, lung infiltration by eosinophils, AHR, IL-4 and IL-17 production.*

may suppress Th1-mediated inflammation and PDL-2 may suppress Th2-mediated inflammation (**Figure 2**) [20, 21]. The expression and regulation of PD-L1 and PD-L2 in asthma were analyzed using a segmental challenge of human lungs with allergen followed by BAL [22]. This study was initiated to clarify the importance of these costimulators in human asthma as previous reports using mouse models of the disease gave conflicting results [23–25]. The mouse lung expression levels of PD-L1 and PD-L2 were significantly upregulated by the OVA challenge [25]. However, the treatment of DC with CPG DNA, CD40L, GM-CSF, LPS, and IFN-γ led to the increased expression of PD-L2 on the cell surface whereas IL-4 and IL-13 induced the highest PD-L2 expression on DC among all mentioned above stimuli [25]. Interestingly, Th2 cytokines induce PD-L2 expression on DC but not B7–1 or B7–2

### *Costimulation in Allergic Asthma: The Roles of B7 and Semaphorin Molecules DOI: http://dx.doi.org/10.5772/intechopen.102631*

expression suggesting a regulatory role of this costimulatory in Th2 cell activation. *In vivo* treatment of mice with recombinant PD-L2-Fc resulted in a Th2-like inflammation in murine lungs. Such effect of PD-L2-Fc could be explained by a potential PD-L2-Fc blocking of the inhibitory interaction of cell-associated PD-L2 or PD-L1 with PD-1 or by a potential PD-L2-Fc interaction with a second receptor and enhancement of T cell activation via a PD-1-independent mechanism. This alternative yet unidentified receptor may dominate the inhibitory PD-1 receptor *in vivo*. The observed negative correlation between PD-1 expression by circulating CD4+ T cells and IgE concentrations in serum in asthma patients suggested a protective role of PD-L1 in allergic asthma [22]. However, there was an increase in blood and a decrease in BAL of PD-1+ CD4+ T cells after segmental bronchial challenge with the allergen [22]. The authors concluded that the up-regulation of PD-L1 and downregulation of PD-L2 on endobronchial DC subsets favor a Th2 inflammation in their human asthma model based on a segmental lung allergen challenge. They propose that modulating PD-1 ligand-mediated pathways by blocking PD-L1 or activating PD-L2 signaling could be a promising immunomodulatory approach in allergic asthma management. A more recent study has shown that in the *in vivo* experimental model of HDM-induced asthma anti-PD-L1 mAb completely abrogated eosinophil recruitment and PD-1/PD-L1 blockade by the use of neutralizing mAb to either PD-1 or PD-L1 led to the enhanced airway hyperreactivity (AHR) due to activation of Th17 cells and resulting increase of airway neutrophilia [26]. The authors identified the increased frequency of CD4 + IFNγ + and CD4 + IL-17A+ cells in PD-1-deficient (Pdcd1−/−) mice which directly correlated with higher levels of circulating IFNγ and IL-17A. This study goes in accord with previous research establishing allergic asthma as a mix Th2/Th17 response. Clinical observation in patients with chronic occupational asthma showed a persistent PD-L2 expressing mDC-mediated Th2 response that was partially PD-L2-dependent [27]. This suggests that other costimulators participate in Th2 activation in the asthmatic setting.

### **2.3 B7-H2 and ICOS**

Another pair of the B7 family ligand and its receptor involved in the regulation of T cell activation comprises of B7-H2 and ICOS (Inducible CO-Stimulator) (**Figure 2**). It was originally shown that the engagement of ICOS by B7-H2 on CD4+ T cells increased the production of Th1 (IFN-γ and TNFα) and Th2 (IL-4, IL-5, and IL-10) cytokines [28–30]. ICOS-deficient mice were unable to induce the allergenspecific IgE responses when compared to WT mice which demonstrated an important role of ICOS:B7-H2 interaction in the induction of IgE production [31]. It was shown recently that the injection of anti-B7-H2 mAb resulted in the reduction of inflammation and Th2 cytokines production in the mouse model of allergic asthma [32]. Moreover, blocking the ICOS:B7-H2 interaction on human ILC2s reduced AHR and lung inflammation in the experimental asthma model [33]. In addition, it was demonstrated that in contrast to wild-type counterparts, B7-H2 deficient mice did not develop AHR after OVA sensitization and challenge [34].

### **2.4 B7-H3 and other B7-H molecules**

To investigate the contribution of B7-H3 to the development of allergic asthma, mice were treated with antiB7-H3 blocking Ab during the course of OVA sensitization and challenges [35]. Anti-B7-H3 mAb treatment of mice at the experimental asthma induction phase (days 7–18 after allergen priming) suppressed allergic lung inflammation including eosinophilic infiltration, airway mucus hypersecretion, downregulated the number of B7-H3+ cells in the lung tissues as compared

with the immunoglobulin G (IgG) treated control group. In addition, anti-B7-H3 mAb inhibited IL-4 and IL-17 levels and increased the expression IFN-γ in BALF of allergen-treated mice. However, anti-B7-H3 mAb treatment did not show an inhibitory effect on any measured asthma parameters at the effector phase (days 21–27 after priming). Nevertheless, B7-H3 blockage can provide a novel therapeutic approach for allergic asthma especially if used in a combination with immunotherapies that work in the effector phase. Two years later the same group of scientists reported an association of asthma exacerbation with increased levels of B7-H3 expression in the peripheral blood of asthmatic children which was significantly decreased by the use of steroids [36]. Their further studies in an animal model of asthma showed that recombinant B7-H3 administration to the mouse lungs in the time-frame of allergen priming (days 0 to 14), but before challenge (days 21, 27), significantly upregulate all parameters of allergic response such as inflammatory cell infiltration to the lung tissues, Th1 and Th2 cytokine levels in BAL and plasma, allergen-specific IgE production, and Th2/Th17 cell proliferation and cytokine levels [37].

The roles of other B7 family members such as B7-H4, B7-H5, and B7-H7 in asthma have never been investigated. Conflicting data on B7-H7 costimulation results led to a proposed concept of dual functionality as it is in the case of B7–1/ B7–2 and CD28/CTLA-4. As an example, B7-H7 receptor CD28H could serve as an immunostimulatory receptor for T cell activation whereas KIR3DL3 could inhibit immune responses upon ligation of B7-H7 [38]. On the other hand, CD28H which is a CD28 homolog absent in mice but present in human serves as a functional receptor for B7-H5 [39]. B7-H5/CD28H interaction selectively costimulates human T-cell growth and cytokine production via an AKT-dependent signaling cascade. Interestingly, CD28H is constitutively expressed on all naïve T cells and its expression decreased with cell activation and is lost on terminally differentiated effector CD45RA + CCR7 − T cells [39]. Basically, the effector cytokine-producing CD4+ T helper cells and FoxP3+ CD4+ T reg cells lack CD28H expression. The authors associate such loss of expression for effector cells with repetitive cell stimulation. Moreover, the pattern on B7-H5 expression in peripheral tissue suggests that B7-H5/ CD28H interaction is critical for the co-stimulation of newly generated effector or effector/memory T cells at the periphery. B7-H6 was not detected in normal human tissues but was expressed on human tumor cells [40]. B7-H6 triggers NKp30 mediated activation of human NK cells [40]. In summary, the roles of B7-H4, B7-H5, B7-H6, and B7-H7 in allergic asthma are long overdue to be determined.

### **2.5 ILDR2 in the immune response**

Ildr2 (Ig-like domain-containing receptor 2), the gene encoding the murine ortholog (formerly designated "Lisch-like") was originally identified as a modifier of susceptibility to type 2 diabetes in obese mice [41]. Its expression level was associated with reduced β- cell number and reproduction and with persistent mild hypoinsulinemic hyperglycemia [41]. A new immunomodulatory function of this B7-like homolog protein has been recently reported by Hecht and associates [42]. They showed that the administration of a recombinant ILDR2-mFc protein to mice displayed a therapeutic effect in a model of rheumatoid arthritis. It induced an increase in the IgG1/IgG2a ratio which suggested a shift from the proinflammatory pro-rheumatic Th1 responses to anti-inflammatory Th2 responses. The ILDR2 upregulation was reported previously for DC cultures when they were stimulated to become DC2-like cell that promotes Th2 response [43]. Therefore, ILDR2 has a promoting effect on allergic diseases, however, it has never been investigated directly.

### **3. Neuroimmune semaphorins in asthma**

Several neuronal guidance proteins, known as semaphorin molecules, function in the immune system. This dual tissue performance has led to them being defined as "neuroimmune semaphorins" [44]. They have been shown to regulate T cell activation by serving as immune checkpoints (**Figure 3**) [12]. Neuroimmune semaphorins are either constitutively or inducibly expressed on immune cells. The T cell co-stimulatory action of neuroimmune semaphorins requires the presence of two signals: signal one provided by TCR/MHC engagement and signal two arises from B7/CD28 interaction. Thus, neuroimmune semaphorins serve as a "signal three" for immune cell activation by supporting their polarization, expansion, differentiation, and regulating the intensity of immune response. This book chapter summarizes the current knowledge on the structure and receptors for several neuroimmune semaphorins involved in the immune response and their role in allergic asthma.

### **3.1 Sema3A and Sema3E**

Sema3A, previously known as chick collapsin 1, SemD, or Sema III, was discovered in the 1990s. In the nervous system, it functions either as a repulsive agent for axonal outgrowth or an attractive agent for apical dendrite growth [45–48]. Sema3A is a glycoprotein with an Ig-like C2-type domain, a PSI (cysteine-rich module in extracellular portion) domain, and a Sema domain. Antipenko and associates [49] reported the crystal structure of Sema3A and identified a neuropilin (NRP) binding site and a potential plexin interaction site. Further studies demonstrated the physiologic receptors for Sema3A which consist of NRP/Plexin complexes where NRP1 serves as a ligand-binding receptor whereas Plexin A1 functions as a signaling receptor [50, 51]. The secreted 95 kDa forms of Sema3A can further undergo a proteolytic cleavage forming the 65 kDa forms [49], which have decreased activity toward neurons [52, 53]. The cryoEM of extracellular complex of Sema3A, PlexinA4, and NRP1 at 3.7Å resolution demonstrated a large symmetric 2:2:2 molecular assembly in which each subunit makes multiple interactions with others [54].

The immunomodulatory role of Sema3A in allergic asthma has been extensively studied by the laboratory of Dr. Vadasz at Technion, Israel [55–57]. When examining the serum levels of Sema3A in asthmatic patients with different stages of disease severity they have determined that Sema3A was significantly downregulated in both severe and moderate asthmatic patients when compared to that of healthy individuals [55]. Low levels of Sema3A correlated with asthma severity. Purified CD4 + T cells from asthmatic patients were incubated with recombinant human (rh) Sema3A protein for 24 h what led to a higher number of Treg cells as compared to similarly conditioned cell cultures from healthy controls [55]. Moreover, rhSema3A affected Treg cells directly by inducing a higher Foxp3 expression. Considering the results of these clinical studies and established downregulatory role of Treg cells in asthma, it is logical to conclude that Sema3A plays an inhibitory role in allergic disease in part by inducing and stabilizing Treg cells. Indeed, the low expression of Sema3A was noticed in the nasal epithelium in the animal model of allergic rhinitis as compared to control mice [58]. Re-introduction of recombinant Sema3A to the mouse nose alleviated sneezing and nasal rubbing symptoms in allergic mice. When rhSema3A was administered intraperitoneally to the mice treated with allergen, a downregulation of lung inflammatory response and angiogenesis was observed [56, 57]. However, the full understanding of the mechanisms of lung inflammation and angiogenesis suppression by Sema3A is still ill-defined.

### **Figure 3.**

*Neuroimmune semaphorins in T cell – DC crosstalk. a. Sema3A. Sema3A inhibits T cell activation. Low constitutive levels of Sema3A on DC are upregulated with cell activation. DC surface-expressed and soluble Sema3A inhibit T cell proliferation presumably acting through NRP-1. Sema3A inhibits DC activation and chemotaxis. Inducible T cell-expressed and soluble Sema3A use NRP-1 and NRP-2 as ligand-binding receptors and NRP-associated Plexin A1 and A2 as signaling receptors to regulate DC activation and chemotaxis. b. Sema3E. Sema3E regulates DC subsets. Higher numbers of CD11b + DC and lower numbers of CD103+ DC were detected in the lungs of Sema3E*−*/*− *mice at the steady-state condition and after allergen sensitization. The DC receptor involved in such Sema3E action is Plexin D1. c. Sema4A. Sema4A-mouse Tim2 (mTim2) or human ILT4 (hILT4) pathways costimulate T cells. Sema4A on DC directly binds mTim-2 or hILT4 on T cells. This leads to optimal T cell activation, proliferation and cytokine production. d. Sema4D. Distinct receptordependent effects of T cell-expressed Sema4D on DC functions. Sema4D costimulates T cells. Sema4D serves as an indirect costimulatory molecule for T cell activation. Sema4D on T cells stimulates DC to accelerate their activation and maturation. Stimulated DC, in their turn, enhance T cell activation. The main receptor for such Sema4D action is believed to be CD72. Sema4D costimulates DC. T cell-expressing and soluble Sema4D ligation of DC-expressing Plexin B1 and B2 receptors stimulates DC proinflammatory cytokine production and migration. e. Sema6D. Sema6D acts as indirect T cell costimulatory molecule. T cell expressed Sema6D activates DC through Plexin A1 receptor. Polyclonally- or Ag-stimulated T cells upregulate Sema6D expression. Sema6D stimulates T cell viability, proliferation and cytokine production on late stages of immune response. f. Sema7A. Sema7A in T cell-DC interaction. Indirect T cell stimulation by T cell expressed Sema7A ligation of Plexin C1 on DC.*

### *Costimulation in Allergic Asthma: The Roles of B7 and Semaphorin Molecules DOI: http://dx.doi.org/10.5772/intechopen.102631*

In summary, these experiments indicated that sema3A is a potential novel therapeutic agent for the treatment of bronchial asthma.

Sema3E (originally termed M-SemaH) was first identified in the metastatic cell lines using a differential display technique which allowed to identify 2 splice variants encoding the same 775 a.a. protein [59]. The protein consists of a putative signaling sequence in NH- terminus followed by a large semaphorin domain, a c2 immunoglobulin-like domain at the amino acids 595–659, approximately 20 residues serving as a transmembrane domain, and positively charged residues in the COOH-terminus [59]. Sema3E contains 13 conserved cysteine residues and 3 potential A'-glycosylation sites. The amino acid sequence of Sema3E was found to be 82% identical to the reported partial sequence of chick collapsin 5 and 44–48% to all other members of the subclass III of the family [59]. Also, the AU-rich motif (AUUUA) conferring protein instability has been defined.

The extensive work by Movassagh and associates from the laboratory of Dr. Gounni at the University of Manitoba, Canada [60] defined the effect of Sema3E deficiency in experimental mouse model of asthma. Such deficiency resulted in substantial airway eosinophilia in untreated Sema3E−/− mice whereas the numbers of alveolar macrophages, T, B, NK, and NKT cells were comparable to those in WT mice. Therefore, the absence of Sema3E predisposed mice to allergic inflammation. Indeed, repeated inhalational exposure to HDM increased many components of asthmatic response in Sema3E−/− mice. This increase involved peribronchial inflammation, AHR to methacholine challenges, goblet cell hyperplasia, collagen deposition, and Th2/Th17 cytokine levels. All these features of asthmatic response were significantly downregulated when recombinant Sema3E was administered to the allergen sensitized mice intranasally [61]. A higher frequency of CD11b + pulmonary DC, a Th2- promoting subtype of DC, was observed in Sema3E−/− mice in both, the steady-state and allergen sensitized conditions as compared to WT control animals. When adoptively transferred to naïve mice, these Sema3E−/− CD11b + DC were able to induce the highest allergic lung inflammatory response especially when the DC recipients were Sema3E−/− mice. While examining the generated bone marrow chimeric mice, the authors defined the contribution of Sema3E on bone marrow-derived inflammatory cells in allergen-induced lung pathology. This work aligns with their previous study demonstrating Sema3E-mediated inhibition of human ASM cell proliferation and migration and defining the signaling pathways involved in such effect [62]. Moreover, their recent study clearly demonstrated a suppressed Sema3E expression in human severe asthma using bronchial biopsy and lung tissue histology specimens [63]. These data suggest that Sema3E plays an important regulatory role in allergic asthma. Targeting this molecule could be a novel approach to treat allergic asthma.

### **3.2 Sema4A and Sema4D**

The Sema4A molecule is a 761 aa long glycoprotein of 150 kDa molecular weight with an NH2-terminal 32 aa signal peptide, a Sema domain, and an Ig domain of the C2 type (both 651 aa), a hydrophobic 21 aa transmembrane region, and a 57 aa cytoplasmic tail (Swissprot Accession # Q9H3S1). Its functions are the most complicated, diverse, and least studied. Sema4A has six known receptors (reviewed in 12). Sema4A exists in both membrane-bound and soluble forms [64, 65]. On the cell surface, it is expressed as a monomer and a dimer [65].

The role of Sema4A in asthma has been evaluated in the laboratory of Dr. Chapoval at the University of Maryland, USA [64, 66, 67]. It has been shown previously that lung-specific vascular endothelial growth factor (VEGF) expression induced asthma-like pathologies in the murine lungs [68, 69]. The experimental

models of OVA-induced and VEGF-mediated allergic airway inflammation were used to assess the changes in expression of immune semaphorins and their receptors in mouse lung tissues [64]. We reported Sema4A expression was detected on bronchial epithelial cells, smooth muscle cells, and accessory-like cells. Both external allergen and lung local VEGF upregulated the expression of Sema4A and its receptors in the lung tissue. Allergen treatment led to a detection of a whole Sema4A protein plus its dimer in the bronchoalveolar (BAL) fluids under inflammation which was not found in the control mouse group. *In vivo* allergic response which consisted of eosinophilic BAL and lung tissue infiltration, mucous cell hyperplasia, AHR to methacholine challenges, sera Ag-specific IgG1/IgG2b/IgE contents, and IL-13 levels in BAL, sera, and cell cultures, was significantly upregulated in Sema4A−/− mice as compared to similarly treated WT mice [66]. In our next study, we employed *in vivo* re-introduction of rhSema4A to Sema4A-deficient and sufficient mice before the allergen challenge which was sufficient to downregulate the number of BAL eosinophils and the levels of BAL cytokines such as IL-6, IL-17A and TNFα [67]. Moreover, using rhSema4A in a chronic model of allergen exposure, we showed that it retains a potent anti-inflammatory effect even when lung tissue damage and remodeling are established [67]. The observed *in vivo* critical regulatory effect of Sema4A in acute and chronic allergic responses suggests that Sema4Arelated pathways may be used for an immunotherapeutic asthma intervention.

A recent study by Lynch and associates [70] examined the role of Sema4A in respiratory syncytial virus (RSV)-induced bronchiolitis which is a predisposition for asthma. The authors used BDCA2-diphtheria toxin receptor (DTR) transgenic mice to induce the specific and reversible depletion of plasmacytoid DC (pDC) with intraperitoneal DT injections. They showed that pDC depletion in neonatal, but not adult, mice increased bronchiolitis severity and was sufficient to evoke an asthma-like phenotype upon viral challenge thus conforming that severe bronchiolitis in early life predisposes to subsequent asthma upon viral exposure. They also demonstrated that pDC from virus-infected mice expand Foxp3 + NRP1+ Treg cells and such expansion is effectively inhibited by the use of anti-Sema4A neutralizing Ab. Moreover, NRP1+ Treg cells transfer from infected to naïve mice prevents the recipients from viral bronchiolitis and subsequent asthma. This study further strengthens the importance of the Sema4A-mediated Treg cells expansion pathway and its important role in asthma protection and/or suppression.

Sema4D, also known as Cluster of Differentiation 100 (CD100), was the first semaphorin with defined expression and function in the immune system ([71, 72], reviewed in [12, 44, 73]). Several studies pointed to its critical regulatory role in the immune system ([74, 75], reviewed in [12, 44, 73, 76]). Sema4D consists of an NH2- terminal signal peptide, a sema domain, an Ig domain of the C2 type, a hydrophobic transmembrane region, and a cytoplasmic tail [71, 72]. The molecule's crystal modeling demonstrates the presence of a conserved seven-blade β-propeller structure [77] which is the structure of a conserved sema domain and is shared by all semaphorin family members. There is an 88% amino acid identity between human and murine Sema4D homologs [72]. Sema4D exists in both, membranebound and soluble forms, which are both biologically active [78, 79].

The recent report from Dr. Chapoval's laboratory at the University of Maryland has demonstrated an important regulatory role of Sema4D in asthma pathogenesis [80]. We exposed Sema4D-deficient and WT mice to OVA injections and challenges in the well-defined mouse model of OVA-induced experimental asthma. Sema4D-deficient mice demonstrated a significant decrease in eosinophilic airway infiltration after allergen challenge relative to WT mice. This reduced allergic inflammatory response was associated with decreased BAL Th2 and Th17 cytokine levels. The reduced T cell proliferation in OVA₃₂₃₋₃₃₉-restimulated Sema4D−/− cell

*Costimulation in Allergic Asthma: The Roles of B7 and Semaphorin Molecules DOI: http://dx.doi.org/10.5772/intechopen.102631*

cultures suggested lower T cell activation. Sema4D deficiency led to the increased number of Treg cells in mice after the allergen challenge. Surprisingly, Sema4D deficiency had no effect on airway hyperreactivity (AHR) to methacholine challenges in either acute or chronic experimental disease settings. Moreover, the lung DC number and activation were not affected by Sema4D deficiency. Our research data provided new insight into Sema4D biology and defined Sema4D as an important regulator of Th2-driven lung inflammation and as a potential target for disease immunotherapy.

### **3.3 Sema6D and Sema7A**

Molecular cloning, mapping, and functional analysis of Sema6D together with Sema6C have been carried out more recently if compared to other semaphorins with costimulatory properties ([81], reviewed in [12]). Amino acid sequence alignment analysis of human semaphorin (HSA)SEMA6C, rat Sema6C, and mouse Sema6C showed the existence of the class VI semaphorin characteristic of the extracellular domain and PSI domain, which differ from all known members of semaphorin family. Predicted structure (HSA)SEMA6D isoforms were compared with related semaphorin proteins. Five isoforms of SEMA6D have been isolated and the significance of the alternatively spliced variants was evaluated by RT-PCR and Northern blots. The expression of different isoforms was found to be regulated in a tissue- and development-dependent manner. Sema6D consists of a signal peptide, a PSI domain, a transmembrane segment, an Ig domain, and a sema domain. Sequence analysis has shown that the translated polypeptides are composed of a 1–21 aa signal peptide followed by a 59–477 aa sema domain, a 508–563 aa PSI domain, a transmembrane segment, and a long cytoplasmic region.

The role of Sema6D in asthma has never been investigated. Based on the published data claiming a costimulatory role of Sema6D in T cell activation, we assume it regulates a disease severity. Regulation of T cell activation by Sema6D was examined *in vitro* and *in vivo* [82]. Upon T cell activation, after an initial decrease in Sema6D mRNA expression, they observed its stable upregulation and, later, a protein expression on the surface of T cells. This upregulation was relevant to both anti-CD3/CD28-stimulated and Ag-stimulated T cells. Using Sema6D-Ig, the authors identified Plexin A1 on DC as a Sema6D receptor. Interestingly, when anti-Sema6D blocking Ab was added to the cell cultures, it affected T cell proliferation in late stages (4–6 days of culture) whereas in the early stages (2–4 days), T cell viability and proliferation, as well as cytokine (IL-2) production, were not different from those without Ab in the culture. Specific targeting of Sema6D decreased T cell activation *in vivo* in the OTII cell adoptive transfer model. In this model, OTII T cells were obtained from the aTCR-transgenic strain that contains rearranged TCR-Vα and -Vβ genes in the germline DNA encoding a TCR specific for chicken ovalbumin (OVA) peptide 323–339 bound to I-A molecules in a context of H-2b haplotype (CD45.2). These CD45.2 cells were adoptively transferred to congenic B6-Ly5.2/Cr (CD45.1) recipients. The splenocyte proliferation was assessed as an expansion of donor OTII T cells in the recipient mice and expressed as the percentage of TCR+ CD4+ CD45.2+ cells in the isolated splenocyte population. The donor cell numbers were significantly lower when the recipient (CD45.1) mice received Sema6D-Ig at the time of cell plus OVA protein injections. Interestingly, Sema6D-Ig treatment did not affect an early T cell activation (day 4) but significantly reduced CD45.2+ T cell expansion on day 7. It is still unclear, however, if Plexin A1 is the only functional receptor for Sema6D on DC.

It is well established that macrophage polarization is a result of and a contributor to asthma pathogenesis [83]. Macrophages consist of more than 70% of lung cells

and increased M2 macrophage polarization mirrored by increased Th2 response leads to further heightening of asthma pathology [83]. Macrophages and DCs expressed high levels of Sema6D [84]. Sema4D deficiency led to a downregulation of M2 polarization by bone marrow-derived macrophages accompanied by significant reductions in expression of Arg1, chitinase 3 like-1 (Chi3l1), Retnla, and Il10, as determined by qRT-PCR [84]. *In vivo*, Sema6D−/− mice demonstrated an exaggerated inflammatory response to LPS-induced sepsis accompanied by elevated levels of proinflammatory cytokines, including IL-12p40, TNF, and IL-6 as compared to WT mice. This study indirectly demonstrated the important role of Sema6D in asthma in part by regulation of macrophage polarization and activation.

The cDNA clone containing the entire coding sequence of the Sema7A gene and its molecular characteristics were first reported by Yamada and associates [85]. The human Sema7A cDNA clones were identified through the screening of a plasmid library generated from a leukemic T cell line. The 1998-base pairs of the cloned DNA's open reading frame encoded a 666 aa protein. This protein contained a 46 aa signal peptide and a 19 aa GPIanchor glycophosphatidylinositol linkage motif. The membrane-anchoring form of Sema7A was 602 aa long. The estimated molecular mass of the nonglycosylated form was 68 kDa. The authors located an "RGD (Arg-Gly-Asp) cell attachment sequence and the five potential N-linked glycosylation sites on the membrane-anchoring form". The expression of a native Sema7A form in transfected cells was confirmed by immunoprecipitation and flow cytometry analyses of cell transfectants. The Sema7A gene was identified on chromosome 15 (15q23–24) by radiation hybrid mapping. The 88.0% similarity at the nucleotide level was detected between murine and human Sema7A or 89.3% similarity at the amino acid level of corresponding proteins [86]. Both human and mouse SEMA7A contain a sevenbladed β-propeller semaphorin N- terminus domain, a plexin, semaphorin, and integrin domain (PSI), an immunoglobulin-like domain, and the characteristic for this particular semaphorin molecule GPI anchor in their C-terminus [87].

The extensive examination of a costimulatory function of Sema7A in T cell proliferation established this neuroimmune semaphorin as an inhibitor of T cell activation [88]. Sema7A−/− T cells demonstrated an enhanced proliferation upon Ag re-stimulation *in vitro*. However, no significant differences were observed in WT and Sema7A−/− DC maturation induced by various TLR ligands. Moreover, Sema7A deficiency in DC did not affect their ability to activate WT T cells. Furthermore, Sema7A−/− Treg cells were functional and actively comparably to WT Treg cells suppressed experimental colitis *in vivo*. This further points to a specific defect in the naive CD4 T cells associated with Sema7A deficiency. The proposed model of Sema7A function in T cell signaling is that Sema7A interacts with the components of the TCR complex and with a putative receptor on APCs which stabilizes TCR/CD3 complex and promotes inhibitory signals that limit T cell proliferation. The role of Sema7A in asthma has been reported in two recent publications [89, 90]. Sema7A was found to be expressed on the surface of circulating eosinophils and upregulated on bronchoalveolar lavage eosinophils obtained after segmental bronchoprovocation of asthmatic patients with allergen. Moreover, among all BAL cells, eosinophils were the predominant source of Sema7A. Among the members of the IL-5-family cytokines such as IL-3, IL-5, and GM-CSF, Sema7A protein on the surface of blood eosinophils was increased most by IL-3 exposure. The adherence of IL-3-activated eosinophils to the plate-bound receptor plexin C1 was doubled from the initial 30% in inactivated cells to 60% which proves the functional effect of Sema7A expressed on the eosinophil surface. Interestingly and relevant to asthma pathophysiology, a recombinant Sema7A induced alpha-smooth muscle actin production in human bronchial fibroblasts. These studies established semaphorin 7A as an important modulator of eosinophil profibrotic functions in the airway remodeling of patients

*Costimulation in Allergic Asthma: The Roles of B7 and Semaphorin Molecules DOI: http://dx.doi.org/10.5772/intechopen.102631*


### **Table 1.**

*Role of the B7 family members in asthma.*


### **Table 2.**

*Role of neuroimmune semaphorins in asthma.*

with chronic asthma. The interference with the described pathway holds the potential to modulate asthma inflammation in the future (**Tables 1** and **2**).

### **4. Conclusions**

Analysis of costimulatory molecules critically involved in asthma, a chronic respiratory Th2-driven disease, will help us to underline the immune mechanisms of disease development and progression. A complete understanding of these mechanisms will guide the development of novel therapeutic strategies to combat asthma and related allergies. Studies aimed to characterize the functions of several B7 family members and semaphorin family members in allergic asthma are either incomplete or ongoing. Further studies of the interplays between different individual costimulatory pathways should provide clearer insights into the disease pathology and guide the development of precise therapeutics.

### **Acknowledgements**

S.P.C is supported by SemaPlex LLC and by NIH/NIAID RO1 AI076736 and RO1 AI143845 grants where she is a co-investigator. A.I.C. is supported by the Ministry of Science and Higher Education of the Russian Federation grant No. FZMW-2020-0007.

### **Author details**

Svetlana P. Chapoval1,2,3,4\* and Andrei I. Chapoval5,6

1 Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA

2 Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA

3 Program in Oncology at the Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA

4 SemaPlex LLC, Ellicott City, MD, USA

5 Russian-American Anticancer Center, Altai State University, Barnaul, Russia

6 Center for Innovation in Medicine, Biodesign Institute, Arizona State University, Temple, AZ, USA

\*Address all correspondence to: schapoval@som.umaryland.edu

© 2022 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.

*Costimulation in Allergic Asthma: The Roles of B7 and Semaphorin Molecules DOI: http://dx.doi.org/10.5772/intechopen.102631*

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## **Chapter 2** Asthma and COVID-19

*Gulfidan Uzan*

### **Abstract**

Asthma is a heterogeneous disease developed against various stimuli (indoor and outdoor allergens, cigarette, air pollution, etc.), associated with airway hypersensitivity and characterized by chronic airway inflammation. COVID-19 is a disease caused by a coronavirus strain called Severe Acute Respiratory Syndromecoronavirus-2 (SARS-CoV-2). There may be some clinical confusions in proper diagnostics due to certain similarities of both diseases's symptoms such as, for example, a difficulty of breathing, cough, and shortness of breath. The current data on asthma being a risk factor for COVID-19 are controversial. It has been reported that asthma is not a risk factor for COVID-19 as the course of COVID-19 in patients with asthma is similar to that observed in the normal population. On the other hand, a current guidance from the World Health Organization (WHO) suggests that asthmatic patients can get more severe illness from COVID-19. Moreover, as with all respiratory tract infections, SARS-CoV-2 virus can certainly impair asthma control. However, recent studies suggest a potential beneficial effect of corticosteroids on SARS-CoV-2 infection as they suppress type II inflammation and restore anti-viral immunity. Prolonged use of a high dose of systemic steroids can increase susceptibility to infection and the occurrence of systemic side effects. However, patients with asthma should definitely continue their prescribed treatment with inhaler steroids and other additional medicines they use during SARS-CoV-2 infection. In asthmatic patients infected with SARS-CoV-2, the most significant risk factor is the loss of asthma control and subsequent presentation to healthcare centers due to the lack of asthma control. Therefore, the asthmatic patients using biological agents are recommended to continue their prescribed treatment such as omelizumab, mopelizumab and prolong the treatment intervals during the peak of infection.

**Keywords:** asthma, COVID-19, pandemic, asthma treatment, inflammation

### **1. Introduction**

COVID-19 is a disease caused by a novel *coronavirus strain* [1–10], which has been named by the *International Committee on Taxonomy of Viruses* (ICTV) as SARS-CoV-2. It has caused a severe viral pandemic worldwide since March 2020 [8, 11]. The virus was first reported in Wuhan, China. Its source is thought to be a live animal market, namely bats [12]. The transmission is via respiratory droplets [8, 9]. The mean incubation period is 2 to 7 days and the main symptoms include fatigue, shortness of breath, fever, coughing, loss of smell and taste, sore throat, muscle pain, headache, vomiting and diarrhea [2, 13]. The course of disease is highly variable. Comorbidities seen in infected individuals are important in terms of the healing time, going to intensive care, and affecting mortality. Among these

comorbidities, particular conditions such as hypertension, ischemic heart diseases, diabetes, and chronic obstructive pulmonary disease represent the most important risk factors for a severe course of disease [13, 14].

Asthma is one of the most common chronic respiratory tract diseases [15]. It is considered to affect approximately 300 million people across the world. Prevalence rates vary to a great extent, ranging from 1% to 18% in children and adults in different countries [16]. Asthma exacerbation is an important reason for emergency admission [15, 16]. It is defined by respiratory symptoms such as wheezing, shortness of breath, tightness in the chest and/or coughing and expiratory air flow limitation. These signs vary in in time. Usually, exacerbations are observed due to various factors like allergy or irritants, exercise, change of air or respiratory tract infections. Symptoms and airway limitation are frequently resolved with treatment or spontaneously and may be absent for weeks or months. On the other hand, such exacerbations may be life-threatening, i.e. the disease may have various clinical presentations and severities which are specific to each patient [16]. For an effective treatment and control of the disease, it is important to educate the patient and help to cooperate with the doctor. The education includes preparation of a written asthma action plan and medical evaluation at regular intervals. A written asthma action plan is a document prepared specifically for the patient by the doctor to show how to monitor his/her symptoms and respiratory functions at home, and it should be reviewed by the physician at regular intervals. This plan helps the patients recognize the aggravation of their asthma and use suitable treatment options [16]. This is very important for minimizing asthmatic patients' visits to healthcare centers during the pandemic and decreasing the risk of transmission [16, 17].

In pandemic the patients with asthma should be managed in two groups: the patients who have asthma but have not yet contracted COVID-19, and those who have asthma and have contracted COVID-19 [18]. COVID-19 and subsequent association between asthma and COVID-19 is a challenging clinical condition with more questions than answers. However, we can make some predictions based on the available data.

### **2. Management of a patient with asthma who has not contracted COVID-19**

The main objective for patients should be to avoid COVID-19 infection. At first, the patient should be informed that asthma does not pose an extra risk for contracting COVID-19 as well as leading to a severe course of disease [19, 20]. Social isolation and adherence to hygiene rules are the most important factors in prevention of disease transmission. Patients with asthma are recommended to remain isolated in their home environment, if possible. They should be instructed to self-monitor symptoms using a PEFmeter [21]. Thus, visits to healthcare centers should be kept at minimum. If patients do not have serious problems during this period, scheduled visits should be delayed as much as possible and physicians should be consulted by telephone, if necessary. In case of any increase in coughing and/or shortness of breath, first of all, it should be made sure that the bronchodilators are delivered at adequate doses and the bronchodilator device (nebulizer) is used correctly. The patients should be instructed by their physician about what to do when their asthma gets worse by means of a written action plan. Considering that an asthma patient who1 is on a control-visit may be a potential COVID-19 carrier, it is very important not to perform a respiratory function test unless it is extremely necessary. Otherwise, it is recommended to keep the room very well ventilated, provide the test technician with appropriate protective equipment, particularly an N95 mask, and perform the test in a negative pressure room, if possible [22].

### *Asthma and COVID-19 DOI: http://dx.doi.org/10.5772/intechopen.96211*

Approximately 80% of patients with asthma have allergic rhinitis and approximately 40% of patients with allergic rhinitis have allergic asthma. It is important to keep the symptoms of allergic rhinitis under control for control of asthma [22–24]. Patients with allergic rhinitis can also use their nasal steroids and antihistamines safely during this pandemic [23, 25]. During the quarantine, patients may have trouble gaining access to their medications due to outgoing restrictions and risk of contamination. In Turkey, the validity of the medication reports for patients with asthma has been extended from March 1st, 2020 by the Turkish Ministry of Health and Social Security Institution so that patients can obtain their medicines from pharmacies without prescription [8]. The validity of disability reports has been also automatically extended. If patients with allergic rhinitis do not use their drugs for symptom control especially during the pollen season, their sneezing will increase. The same also applies for patients allergic to house dust mites. Spring time poses a risk for asthma attacks in patients with pollen allergy while similarly prolonged isolation and quarantine is a risk factor for an attack and loss of asthma control in asthma patients allergic to house dust mites. If patients with pollen allergy follow the rules of isolation and avoid going out, their symptoms will be under control due to reduced contact with pollens. These patients should ventilate their rooms in the afternoon and, if they have to ventilate it in the morning, they should stay in another room. In patients with allergic rhinitis who use masks effectively when they go out, exposure to pollens will be reduced and thus their symptoms and the need for medications will also be decreased. Patients with allergic rhinitis sensitized to house dust mites are unfortunate during this period because of a prolonged stay in closed environments. Therefore, it is very important that they use their allergic rhinitis medications regularly and follow the measures to protect themselves from house dust mites. While hand disinfectants containing chlorhexidine are not effective in SARS-CoV-2 [26], they may also lead to asthma attacks in those allergic to this chemical [26]. Use of latex hand gloves for hand hygiene may also lead to asthma attacks in patients with latex allergy, therefore the washing hands with soap and water should be preferred [26].

As a result asthma patients who have not contracted COVID-19 should definitely continue their inhaler steroid treatments and additional prescribed medications, and should follow the protection and hygiene rules as much as possible even when they are clinically stable [8, 16]. Discontinuation of controlling medications leads to disease exacerbation, increases the risk of having an asthma attack and eventually poses a higher risk for SARS CoV-2 contamination by hospital admission. Doses of inhaler steroids should not be reduced even when asthma is under control. The disease may also be controlled with non-steroidal treatments in some patients with asthma. In these patients, other treatments should be continued without steroids or in combination with low dose steroids [18]. Systemic steroids should be used as short as possible in patients with severe asthma. Because in long-term use, susceptibility to infection and steroid side effects may occur [15, 18].

### **3. Management of a patient with asthma who has contracted COVID-19**

Pathophysiology of the coronaviruses (CoVs) and asthma comorbidity is complex and many aspects are unknown. In this book chapter we review the available literature on the pathogenesis of asthma and COVID-19.

Asthma is characterized by chronic airway inflammation [16], mainly a type 2 inflammation. Type 2 immunity involves helper T cells (Th 2), type 2 B cells, type 2 innate lymphoid cells, type 2 macrophages, IL-4 releasing natural killer (NK) and natural killer T (NKT) cells, basophils, eosinophils and mast cells [3, 4]. In general,

antiviral and allergic responses are two separate branches of immunity and interact in a comprehensive network of interactions. Type I IFNs are the family of antiviral cytokines that play an important and central role in this network. In asthma, release of type I IFNs from bronchial epithelial cells and plasmacytoid dendritic cells is disrupted [3, 4].

It is well known that eosinophils play a central role in allergic diseases including asthma [4]. The possible effects of eosinophils on CoV are also remarkable. Eosinophils have a potential role in enhancing viral clearance and antiviral host defense. Recombinant eosinophil-derived neurotoxin (a major eosinophil ribonuclease) is capable of reducing the infectivity of respiratory syncytial virus (RSV). In addition, eosinophils can be activated with ssRNA through triggering the TLR-7-MyD88 signaling pathway, which might result in RSV clearance and limitation of virus-induced lung dysfunction. The low prevalence of COVID-19 in asthma patients may be due to eosinophils' defense against the virus. Eosinopenia occurs in COVID-19, pathophysiology is unclear [27]. Blockade of eosinophil release from bone marrow during acute infection, decreased expression of chemokine receptors or direct eosinophil apoptosis may caused by type 1 IFNs may be responsible. There is little indication that eosinophils play a protective or aggravating role during SARS-CoV-2 infection. Eosinopenia, however, may be a prognostic indicator for more severe SARS-CoV-2 infection [27]. Additionally, it is not known whether eosinopenia is a consequence of impaired immunity or biologics intake. The role of eosinophils in the course of eosinophilic inflammation associated with SARS-CoV-2 infection and allergy needs to be investigated further [4].

In theory, asthma as a lung-targeted chronic disease should increase the vulnerability of lung tissue to COVID-19 infection and should lead to a worse course of COVID-19 and reduced anti-viral immune response. But, interestingly, it was reported that asthma produces a type 2 inflammatory cytokines (IL-4,-5 and − 13) and accumulation of eosinophils in the airways and their number increases systemically, what provides a protection against COVID-19 [4]. As with SARS and other seasonal coronaviruses, SARS-Cov-2 also uses the cellular receptors of angiotensin converting enzyme 2 (ACE2) to invade the cells. Upregulated ACE-2 expression increases the sensitivity of receptor-expressing cells to infection. However, ACE-2 expression in the respiratory tract epithelium is decreased in patients with asthma as compared to normal control subjects, and this protects from COVID-19 [4, 5, 28]. Allergic diseases do not predispose to COVID-19 and does not increase COVID-19 severity. Asthma also does not pose a risk to COVID-19, and there is no difference between asthma patients with and without COVID-19 in terms of hospital admission and severity of the course of disease [15, 28–30]. When patients with asthma contract COVID-19, they have a disease course similar to that of the normal population [15, 31]. But as with all viruses causing respiratory tract infections, SARS-CoV-2 is also a risk factor for asthma attacks and disrupts asthma control [16, 32]. Despite proper and adequate treatment bronchodilator therapy, patients with increased symptoms, additional symptoms and/or contact history should be admitted to the hospital and undergo appropriate examination and investigations.

Exacerbation of asthma and allergic rhinitis may also be confused with COVID-19 clinically [8, 23]. Dry coughs and shortness of breath may be seen asthma, allergic rhinitis and COVID-19. Seasonality of symptoms and history of symptom development in the presence of exposure to a certain allergic agent are quite helpful in the differential diagnosis of allergic rhinitis. Atopy test also supports the diagnosis. It is also very important to distinguish between an asthma attack and COVID-19 infection attack in a patient with a prior diagnosis of asthma as both display interfering symptoms such as shortness of breath and coughing. Therefore, differential diagnosis is extremely significant in the group of patients with such comorbidity.

### *Asthma and COVID-19 DOI: http://dx.doi.org/10.5772/intechopen.96211*

In addition to the clinical presentation, laboratory findings (such as eosinophil and lymphocyte count, C reactive protein, D Dimer) may also be beneficial in the differential diagnosis. While presence of lymphopenia and eosinopenia in hemogram may favor COVID-19 [8] increased eosinophil levels may indicate asthma. While an asthma patient presenting with symptoms such as coughing, shortness of breath, wheezing and stridor without any additional finding should be primarily evaluated for an asthma attack; considering that everybody may be infected in such a pandemic, extra care should be exercised regarding social isolation, distance and the use of personal protective equipment for the safety of both patient and healthcare personnel [8]. Asthmatic patients who develop weakness, loss of smell and taste should have chest X-ray and blood tests for COVID-19 [8].

### **4. Symptoms of asthma, COVID-19 and allergic rhinitis**

Corticosteroids hold a significant place in the treatment of asthma [2]. Highdose corticosteroids have been used α during the SARS and MERS outbreaks and in COVID-19 to suppress lung inflammation during critical illness of infected patients. Corticosteroids (inhaled or systemic) can inhibit production of the critical antiviral mediators type I and III interferons [3]). At the same time its suppress type 2 inflammation and their use in COVID-19-associated exacerbation may lead to the beneficial effect of secondary restoration of impaired antiviral immunity. However, clinical evidence of corticosteroid use in COVID-19 is still insufficient [3].

In patients with asthma who have contracted COVID-19, inhaled corticosteroid dose may be increased 4-fold depending on the severity of the disease or use of systemic administration of steroids is recommended [18, 30]. In patients with severe asthma, systemic steroid therapy should be used as short as possible, as in asthma patients without COVID-19.

Steroid therapy preferably should be taken in the form of metered-dose inhalers containing dry powder rather than nebulizers [5, 33]. Metered-dose inhalers are ideal devices thanks to their ease of use and low risk of viral transmission, but they may not be effective in cases of severe dyspnea, cognitive or neuromuscular disorders and respiratory failure with inadequate inspiratory strength [33]. Dry powder inhalers are able to reach the lungs in low inspiratory flow and do not require hand-breath coordination (squeezing the inhaler medication at the same time while breathing deeply). On the other hand, dry powder inhalers may lead to irritation in the airways and coughing, and a by creating aerolization potential viral transmission is also of question. It is contradictory whether the treatment with a nebulizer is risky in terms of viral transmission due to aerosolization [34]. As a result, a metered-dose inhalator with a valved reservoir or dry powder inhaler is preferred for reducing the auto-aerosolization and spread of the virus [35].

Leukotriene receptor antagonists with their beneficial anti-inflammatory and bronchodilator activities may also be added to the treatment of the patients with COVID-19 and asthma admitted to the hospital [5, 30, 36].

Azithromycin has been shown to be an effective treatment in decreasing the frequency of exacerbations and improving the quality of life in asthma patients whose condition cannot be controlled with standard treatment [31, 37]. Azithromycin decreases the risk of COVID-19-related severe outcomes by increasing the IFN production associated with a natural antiviral immunity in respiratory tract cells [37]. However, azithromycin is not recommended for prophylactic treatment of COVID-19 [37].

An asthma patient receiving allergen immunotherapy who is infected with COVID-19 or in contact with an infected person may continue to receive his/her treatment in the absence of any symptoms [38]. It has been reported that immune response to virus can be improved and cytokine storm can be prevented by this treatment [4, 30, 39]. But if there are any signs of respiratory tract infection, it is recommended to treat this infection [39].

Use of Anti-IgE, anti-IL-5/IL-5 alfa, anti-IL-4 alfa is not risky for patient with asthma who has contracted COVID-19, therefore such medications may be safely used to control asthma [30, 40]. Although patients using biologic agents are recommended to continue their treatment. During the period of COVID-19 peak, biological agent treatment is applied less frequently. Biological agent therapy continues as before when symptoms are improved or COVID-PCR becomes negative [22, 23]. Since patients with severe asthma may be at higher risk of severe COVID-19 infection, they should avoid any activities which may disrupt their asthma control and they should use their asthma therapies properly.

In conclusion, asthma does not represent a risk factor for COVID-19 and asthma does not adversely affect the course of COVID-19. However, it is extremely important to keep asthma under control particularly during the pandemic period. Patients with asthma should be recommended to continue to use inhaler steroids that keep their asthma under control along with other prescribed medications. Patients should be provided with a written emergency action plan because nowadays a visit to a healthcare center carries a risk for the SARS-CoV-2 infection. In order to prevent the risk of transmission of infection, training should be given on maintaining social isolation and distance, avoiding contact, hand hygiene and correct use of masks.

### **Author details**

Gulfidan Uzan

Department of Chest Disease, University of Health Science, Sultangazi Haseki Training and Research Hospital, Istanbul, Turkey

\*Address all correspondence to: gulfidan70@gmail.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.

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### **Chapter 3**
