Preface

Asthma is a chronic lung disease characterized by episodes of airway narrowing and obstruction, causing wheezing, coughing, chest tightness, and shortness of breath [1]. The National Institute of Allergy and Infectious Disease (NIAID) in the United States specifies why asthma research is its priority. Asthma significantly reduces the quality of life. In addition to high medical expenses, asthma has substantial effects on work/school attendance and performance. Patients with asthma exacerbation often require emergency room visits and/or hospitalization. NIAID is especially committed to reducing the burden of this disease and its complications by supporting targeted research aimed at understanding asthma mechanisms, developing new prevention and treatment strategies, and understanding the involvement of environmental factors and human genetics in asthma initiation, progression, and severity.

### **Asthma triggers**

Asthma is a Th2-driven systemic immunologic disease manifesting in lung pathology. Several factors bias the development of Th2 response to air pollution, traffic emissions, ozone, cigarette smoke, changes in the microbial environment, nutrition, and increased exposure to allergens [2]. NIAID supports research programs aimed at identifying the factors that contribute to asthma development and severity. It funds the Inner City Asthma Consortium (ICAC), a nationwide clinical network that conducts asthma research in nine US cities [3]. One of the studies from this Consortium determined the differences in clinical characteristics between easy-to-control and difficult-to-control asthma [4]. There was a relatively equal distribution of such asthma cases among the study participants, whereas around 22% of them fell into neither group. The study clearly points to allergen sensitizations as a major trigger of asthma exacerbations and the direct association of poorly controlled asthma with bronchodilator responsiveness, pulmonary physiology, rhinitis, and atopy. The more recent international study on the role of allergy in severe asthma by the Allergy and Asthma Severity EAACI Task Force was published in 2016 as a position document [4]. The document, in part, states that the proportion of severe asthma cases related to allergen exposure may be overestimated and other triggers such as fungal sensitization, smoking, and pollution contribute to severe asthma and must be considered during disease evaluation in patients.

The discussion by the international research expert group at the World Health Organization (WHO) meeting on the respiratory syncytial virus (RSV) and asthma was published in the journal Vaccine [5]. The main conclusions of the article are: (a) the casual association between lower respiratory tract infection with RSV and recurrent wheeze of early childhood in asthma is not fully established and requires further investigations; (b) there is no sufficient evidence that RSV monoclonal antibodies (mAbs) and potential future RSV vaccines will have a significant effect on asthma outcomes; and (c) there is a substantial public health threat from a severe acute RSV disease in young children, which requires the development of good clinical practice guidelines.

During the recent COVID-19 pandemic, taking into account that the SARS-CoV-2 virus primarily affects the respiratory system, reasonable concern was generated among health professionals on the viral effect on asthma patients, especially disease severity and exacerbation. One of the chapters in this book provides relevant information on this topic [6]. According to the International Primary Care Respiratory Group (IPCRG), which consists of 78 experts from 43 countries, patients are still struggling to differentiate their symptoms between asthma flare-ups and COVID-19 and might delay seeking care for either condition [7]. The IPCRG supports previous multiple observations concluding that asthma is not a risk factor for severe COVID-19, but patients taking oral corticosteroids may be at greater risk of severe COVID-19. The IPCRG recommendations include the use of protective equipment, lung function testing procedures, long-term use of oral steroids, and the application of biologics.

### **Asthma phenotypes and biologics**

Asthma is widely recognized as heterogeneous inflammatory lung disease. One of the chapters in this book is dedicated to asthma phenotypes and biologics [8]. It focuses on high and low Th2 endotypes and provides a detailed overview of current biologics, their safety, and effectiveness.

The recently published article by Conrad and associates [9] details the clinical characteristics of asthma clusters in adults and in children. The article also provides an approach to asthma diagnosis and management in children where a healthcare provider defines asthma severity and control according to the National Heart, Lung, and Blood Institute (NHLBI) guidelines based on symptom frequency and medication use. The presence of comorbidities and the results of pulmonary function tests are also incorporated into this systemic approach, which can be used in any given patient.

Another asthma classification proposed by the multi-institutional research team supported by the NHLBI's Severe Asthma Research Program is based on imaging cluster analysis and its association with known clinical parameters [10]. To identify the patient's clinical clusters, the authors developed lung tissue imaging-based clusters using multiple variables that reflect the airway and parenchymal pathologies. The observed structural and functional alterations were associated with the pathophysiology of asthma, which provided a meaningful association of airway structural pathologies with clinical metrics. Asthma clustering can be used as a basis for the development of novel and efficient immunotherapeutic measures to fight the disease.

Tay and Foster [11] defined four asthma groups based on the cellular composition of lung inflammatory infiltrates: (1) eosinophilic (T2), (2) neutrophilic (T1), (3) mixed eosinophilic/ neutrophilic, and (4) paucigranulocytic. The authors state that current treatments for asthma are non-specific and not often effective; therefore, there is a great need for the development and application of novel therapies. The wide range of new-generation biologics showed promising results as effective treatments for severe asthma. Those biologics specifically target the critical molecules of the Th2 immune response such as IgE, IL-4, IL-5, and IL-13. The authors also admit that biologics for non-Th2 asthma are difficult to develop and assess, as it is unclear what drives such asthma. Nevertheless, a chapter by Dr. Aşkın Gülşen [8] discusses IL-17-, IL-9-, TSLP-, and PGD2-directed therapies and their potential in the treatment of eosinophilic and non-eosinophilic asthma.

**V**

health burden.

**Summary**

discusses some of these novel findings.

Selected B7 and semaphorin molecules might provide new targets for biologics or serve as new biologics (reviewed in [12]). Another chapter in this book summarizes current knowledge concerning the roles of B7 family immunomodulatory ligands in asthma and analyzes the potential functions of emerging new B7-H4, B7-H5, and B7-H7 molecules. It also provides insight into the roles of neuroimmune semaphorins in allergy and asthma. The discussed data will help to design more specific and efficient novel therapies to fight these diseases, which represent a significant public

Several research groups examined the roles of selected miRNAs, lncRNAs, and circRNAs in Th2-mediated inflammation in asthma (reviewed [13]). Another chapter summarizes the most significant advances in RNA research over the past years focused on miRNA-19a, -106a, -145, -146a, -155, -214, and others. The chapter discusses the regulation of a Th1/Th2 balance by several lncRNAs such as MALTA1, LNC\_000127, PVT1, and others. The mechanistic interplay between miRNAs and lncRNAs and the effect of circRNAs on Th2 response in asthma showed that all studied RNAs play important regulatory roles in disease and need to be evaluated

Several mobile applications are currently available for monitoring and collecting patient data [14, 15]. One such advanced application useful for physicians and patients, kHealth: Knowledge-enabled Digital Healthcare Framework, is reported in this book [16]. This mobile app is aimed at monitoring and managing asthma symptoms, medication adherence, lung function, daily activity, sleep quality, and indoor and outdoor environmental triggers. Physicians can use kHealth technology for both in-person and telemedicine appointments and patients can use it to monitor, evaluate, and manage their asthma symptoms and treatments continuously.

There have been many advances in our understanding of asthma genetics and immunologic mechanisms over the past several decades. Many scientific advances have been made in defining the distinct asthma phenotypes, which require personalized treatment strategies with available therapeutics. The identification of novel biologics can potentially lead to the development of better therapeutics. This book

**Svetlana P. Chapoval, MD, Ph.D.**

Department of Microbiology and Immunology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine,

Assistant Professor,

Baltimore, Maryland, USA Founder, SemaPlex LLC, Ellicott City, Maryland, USA

further as potential druggable targets for therapeutic intervention.

Selected B7 and semaphorin molecules might provide new targets for biologics or serve as new biologics (reviewed in [12]). Another chapter in this book summarizes current knowledge concerning the roles of B7 family immunomodulatory ligands in asthma and analyzes the potential functions of emerging new B7-H4, B7-H5, and B7-H7 molecules. It also provides insight into the roles of neuroimmune semaphorins in allergy and asthma. The discussed data will help to design more specific and efficient novel therapies to fight these diseases, which represent a significant public health burden.

Several research groups examined the roles of selected miRNAs, lncRNAs, and circRNAs in Th2-mediated inflammation in asthma (reviewed [13]). Another chapter summarizes the most significant advances in RNA research over the past years focused on miRNA-19a, -106a, -145, -146a, -155, -214, and others. The chapter discusses the regulation of a Th1/Th2 balance by several lncRNAs such as MALTA1, LNC\_000127, PVT1, and others. The mechanistic interplay between miRNAs and lncRNAs and the effect of circRNAs on Th2 response in asthma showed that all studied RNAs play important regulatory roles in disease and need to be evaluated further as potential druggable targets for therapeutic intervention.

Several mobile applications are currently available for monitoring and collecting patient data [14, 15]. One such advanced application useful for physicians and patients, kHealth: Knowledge-enabled Digital Healthcare Framework, is reported in this book [16]. This mobile app is aimed at monitoring and managing asthma symptoms, medication adherence, lung function, daily activity, sleep quality, and indoor and outdoor environmental triggers. Physicians can use kHealth technology for both in-person and telemedicine appointments and patients can use it to monitor, evaluate, and manage their asthma symptoms and treatments continuously.

### **Summary**

There have been many advances in our understanding of asthma genetics and immunologic mechanisms over the past several decades. Many scientific advances have been made in defining the distinct asthma phenotypes, which require personalized treatment strategies with available therapeutics. The identification of novel biologics can potentially lead to the development of better therapeutics. This book discusses some of these novel findings.

> **Svetlana P. Chapoval, MD, Ph.D.** Assistant Professor, Department of Microbiology and Immunology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, USA

> > Founder, SemaPlex LLC, Ellicott City, Maryland, USA

### **References**

[1] https://www.niaid.nih.gov/ diseases-conditions/asthma

[2] Chapoval SP, David CS. Identification of antigenic epitopes on human allergens: studies with HLA transgenic mice. Environ Health Perspect. 2003 Feb;111(2):245-50.

[3] https://www.niaid.nih.gov/ news-events/niaid-sponsored-studyfinds-factors-influence-asthmaseverity-inner-city-children

[4] Pongracic JA, Krouse RZ, Babineau DC, Zoratti EM, Cohen RT, Wood RA, Khurana Hershey GK, Kercsmar CM, Gruchalla RS, Kattan M, Teach SJ, Johnson CC, Bacharier LB, Gern JE, Sigelman SM, Gergen PJ, Togias A, Visness CM, Busse WW, Liu AH. Distinguishing characteristics of difficult-to-control asthma in inner-city children and adolescents. J Allergy Clin Immunol. 2016 Oct;138(4):1030-1041.

[5] Driscoll AJ, Arshad SH, Bont L, Brunwasser SM, Cherian T, Englund JA,et al. Does respiratory syncytial virus lower respiratory illness in early life cause recurrent wheeze of early childhood and asthma? Critical review of the evidence and guidance for future studies from a World Health Organization-sponsored meeting. Vaccine. 2020 Mar 4;38(11):2435-2448.

[6] Uzan G. Asthma and COVID-19. In: P. DS, editor. Recent Advances in Asthma Research and Treatments [Working Title] [Internet]. London: IntechOpen; 2021 [cited 2022 Feb 15]. Available from: https://www. intechopen.com/online-first/75230 doi: 10.5772/intechopen.96211

[7] Bousquet J, Jutel M, Akdis CA, Klimek L, Pfaar O, Nadeau KC, et al. ARIA-EAACI statement on asthma and COVID-19 (June 2, 2020). Allergy. 2021 Mar;76(3):689-697.

[8] Gülşen A. Asthma Phenotypes and Current Biological Treatments. In: P. DS, editor. Recent Advances in Asthma Research and Treatments [Working Title] [Internet]. London: IntechOpen; 2021 [cited 2022 Feb 15]. Available from: https://www.intechopen.com/ online-first/76328 doi: 10.5772/ intechopen.97376

[9] Conrad LA, Cabana MD, Rastogi D. Defining pediatric asthma: phenotypes to endotypes and beyond. Pediatr Res. 2020 Nov 10:10.1038/ s41390-020-01231-6

[10] Choi S, Hoffman EA, Wenzel SE, Castro M, Fain S, Jarjour N, Schiebler ML, Chen K, Lin CL; National Heart, Lung and Blood Institute's Severe Asthma Research Program. Quantitative computed tomographic imaging-based clustering differentiates asthmatic subgroups with distinctive clinical phenotypes. J Allergy Clin Immunol. 2017 Sep;140(3):690-700.e8.

[11] Tay HL, Foster PS. Biologics or immunotherapeutics for asthma? Pharmacol Res. 2020 Aug;158:104782.

[12] Chapoval SP, Chapoval AI. Costimulation in Allergic Asthma: The Roles of B7 and Semaphorin Molecules. In: P. DS, editor. Recent Advances in Asthma Research and Treatments [Working Title] [Internet]. London: IntechOpen; 2022 [cited 2022 Feb 15]. Available from: https://www. intechopen.com/online-first/80428 doi: 10.5772/intechopen.102631

[13] Niu Y, Wang C, Dong X, Zhong N. Epigenetic Regulation of Th2 Response in Asthma by Non-Coding RNAs. In: P. DS, editor. Recent Advances in Asthma Research and Treatments

**VII**

[Working Title] [Internet]. London: IntechOpen; 2021 [cited 2022 Feb 15]. Available from: https://www. intechopen.com/online-first/76303 doi: 10.5772/intechopen.97328

[14] Himes BE, Leszinsky L, Walsh R, Hepner H, Wu AC. Mobile Health and Inhaler-Based Monitoring Devices for Asthma Management. J Allergy Clin Immunol Pract. 2019

Nov-Dec;7(8):2535-2543.

Jul;74(7):1292-1306.

[15] Sleurs K, Seys SF, Bousquet J, Fokkens WJ, Gorris S, Pugin B, Hellings PW. Mobile health tools for the management of chronic respiratory diseases. Allergy. 2019

[16] Jaimini U, Sheth A. Personalized Digital Phenotype Score, Healthcare Management and Intervention Strategies using Knowledge Enabled Digital Health Framework for Pediatric Asthma. In: P. DS, editor. Recent Advances in Asthma Research and Treatments [Working Title] [Internet]. London: IntechOpen; 2021 [cited 2022 Feb 15]. Available from: https://www. intechopen.com/online-first/76503 doi: 10.5772/intechopen.97430

[Working Title] [Internet]. London: IntechOpen; 2021 [cited 2022 Feb 15]. Available from: https://www. intechopen.com/online-first/76303 doi: 10.5772/intechopen.97328

[14] Himes BE, Leszinsky L, Walsh R, Hepner H, Wu AC. Mobile Health and Inhaler-Based Monitoring Devices for Asthma Management. J Allergy Clin Immunol Pract. 2019 Nov-Dec;7(8):2535-2543.

[15] Sleurs K, Seys SF, Bousquet J, Fokkens WJ, Gorris S, Pugin B, Hellings PW. Mobile health tools for the management of chronic respiratory diseases. Allergy. 2019 Jul;74(7):1292-1306.

[16] Jaimini U, Sheth A. Personalized Digital Phenotype Score, Healthcare Management and Intervention Strategies using Knowledge Enabled Digital Health Framework for Pediatric Asthma. In: P. DS, editor. Recent Advances in Asthma Research and Treatments [Working Title] [Internet]. London: IntechOpen; 2021 [cited 2022 Feb 15]. Available from: https://www. intechopen.com/online-first/76503 doi: 10.5772/intechopen.97430

### **Chapter 1**
