Fast Facts: Asthma: Improve patient self-management and drug use, achieve asthma control

By J.A. Douglass and T.S.C. Hinks

Asthma is the world’s most common chronic respiratory condition, affecting over 350 million people worldwide and inflicting a heavy individual, social and economic burden of disease. In this rapidly changing field, a plethora of new inhaled therapies and devices have emerged, as well as a better understanding of disease phenotyping and biology. This fully updated fifth edition of 'Fast Facts: Asthma' discusses recent trends in an easy-reference format, while highlighting imminent new developments, to provide a valuable resource for general practitioners, specialist asthma nurses and others with a keen interest in improving the outcomes of the very many people living with asthma. Table of Contents: • Pathophysiology • Epidemiology, etiology and natural history • Diagnosis and classification • Asthma medications • Management principles • Severe and refractory asthma • Acute asthma attacks • Preventing asthma attacks • Asthma in special circumstances • Developments

• Language: English
• Publisher: S. Karger
• Release date: Apr 29, 2021
• ISBN: 9781910797754

Book preview

Introduction

Asthma is the world’s most common chronic respiratory condition, affecting over 350 million people worldwide and inflicting a heavy individual, social and economic burden of disease.¹ In developed countries, severe and difficult-to-treat asthma remain major problems in terms of healthcare costs, hospital admissions, pressure on healthcare providers and individual quality of life. In low- and middle-income countries, asthma and associated allergy are increasing in prevalence, while high mortality rates point to inadequate diagnosis and lack of use of affordable, effective asthma treatments. However, the field is rapidly changing. As well as a plethora of new inhaled therapies and devices, a better understanding of disease phenotyping and biology has led to the emergence of a growing range of highly effective biological therapies for selected patients with severe disease and greater precision in treating those with mild asthma.

This fully updated fifth edition of Fast Facts: Asthma reflects these recent developments. Perhaps the key paradigm shift over the past 6 years has been an emphasis on carefully differentiating asthma into distinct phenotypes, deconstructing diseases of the airways into specific traits that can be measured and, in some cases, modified (treatable traits), facilitated by the identification of simple biomarkers. This shift away from considering asthma as a homogeneous disease on a single continuous spectrum of severity has direct clinical applicability, enabling the practice of ‘personalized medicine’, targeting specific therapies and approaches to those patients most likely to derive the greatest benefit from them.

In light of this appreciation of treatable traits, an understanding of the biology of disease and the biological relevance of biomarkers is increasingly important. We have updated and expanded our review of the basic biology of airway diseases to reflect the previously unappreciated role of alarmins and the role of innate-like lymphocytes and type-2 cytokine-secreting CD8+ T cells (Tc2 cells). This is linked to the mechanism of action of novel biological therapies, which are outlined in a new section encompassing agents that target immunogloblin (Ig) E and the type-2 cytokine pathway. We point to future biologics that target alarmins and to a potential future generation of orally active type-2 cytokine inhibitors.

Given the complex and heterogeneous nature of asthma, definitions of the disease and its classification have evolved and are revised in this edition. We have also updated algorithms for the stepwise management of asthma to reflect the latest international management guidelines. These have been influenced by recent trial data on the utility of fixed-dose as-required fast-acting β2 agonist/inhaled corticosteroid (ICS) combination inhalers.

We have incorporated several other recent changes in therapeutics, including an updated section on new inhaler devices, a discussion of fixed airflow obstruction – a source of significant recent debate – and an important new section on the role of macrolides in non-eosinophilic asthma. Lastly, consonant with these rapid changes in therapeutics, we have entirely revised the section on future developments.

Overall, the field of asthma is exciting and rapidly evolving. Our aim with this new edition of Fast Facts: Asthma is to incorporate recent trends in an easy-reference format, while highlighting imminent new developments, to provide a valuable resource for general practitioners, specialist asthma nurses and others with a keen interest in improving the outcomes of the very many people living with asthma.

Reference

1. GBD 2015 Chronic Respiratory Disease Collaborators. Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Respir Med 2017;5:691–706.

Airway structure

The conducting airways are comprised of a mucosal epithelium, a basement membrane (lamina propria), and a submucosal layer of smooth muscle cells, mast cells, blood vessels and fibrocartilaginous or fibroelastic-supporting connective tissue (Figure 1.1). The mucosal epithelium of the main conducting airways is composed of ciliated epithelial cells, mucus-secreting goblet cells and basal cells, while the terminal bronchioles have a fourth cell type called club cells. The main components of cellular immunity comprise mast cells, basophils, eosinophils, neutrophils and macrophages, which are responsible for mediator release. These effector cells are regulated by infiltrating lymphocytes including T cells, B cells and innate lymphoid cells.

Figure 1.1 Main airway anatomy.

The asthmatic airway

Asthma is a chronic inflammatory condition of the airways. It is characterized by recurrent episodes of airflow limitation which, depending on the severity of the attack, produce symptoms such as breathlessness, wheezing, chest tightness and cough. Acute exacerbations can be rapid or gradual in onset and may be severe and potentially life-threatening.

Autopsy studies of patients who have died from asthma show hyperinflated lungs, with both large and small airways blocked by plugs containing a mixture of mucus, serum proteins, inflammatory cells and cell debris.¹,² Microscopic examination reveals extensive inflammatory infiltration of the airways (Figure 1.2), with edema due to vasodilatation and blood vessel engorgement, and epithelial disruption. Biopsy studies have shown increased numbers of leukocytes, particularly eosinophils, mast cells and T lymphocytes, in the airways together with increases in the markers of lymphocyte activation.³ Structural changes resulting from chronic inflammation include bronchial smooth muscle hypertrophy and hyperplasia, new vessel formation, interstitial matrix deposition resulting in basement membrane thickening, and airway wall remodeling.⁴–⁶

Figure 1.2 Pathological features associated with death from asthma. Airways are blocked by plugs of mucus and inflammatory exudate. There is also vasodilatation and edema, vascular remodeling, smooth muscle hypertrophy and thickening of the basement membrane.

Disease mechanisms

In many cases, asthma is an allergic disorder, mediated in part by IgE-dependent mechanisms.⁷ Exposure to allergen results in allergen uptake and its presentation by dendritic cells to T helper (Th) lymphocytes (Figure 1.3). In neutrophilic disease, airway microbes may also activate dendritic cells.

Figure 1.3 Role of IgE in airway inflammation and asthma symptoms. Exposure to allergen leads to epithelial expression of alarmins (interleukin [IL]-33 and -25 and thymic stromal lymphopoietin [TSLP]), activation of T lymphocytes and type-2 innate lymphoid cells (ILC2) with cytokine expression, and release of IgE from B lymphocytes. IgE binds to cells involved in inflammation, which then release inflammatory mediators.

Production of type-2 cytokines. The inflammatory milieu is categorized according to the dominant pattern of cytokines secreted by lymphoid cells. Those secreting the ‘type-2 cytokines’ interleukin (IL)-4, IL-5 and IL-13 stimulate the production of IgE from B lymphocytes and drive chemotaxis and activation of eosinophils. Conversely, Th1 lymphocytes produce interferon (IFN)γ, which facilitates the secretion of IgG by B lymphocytes. T lymphocytes in asthmatic epithelium predominantly release a type-2 pattern of cytokines, indicating the cardinal importance of Th2 lymphocytes in driving the eosinophilic inflammation that is characteristic of asthma.⁸ Other cell types contribute to type-2 cytokine production, including CD8+ Tc2 cells and type-2 innate lymphoid cells (ILC2).⁹,¹⁰ These other cell types are important as they are less responsive to corticosteroids and are activated by innate immune pathways through epithelial stimulation.

Production of inflammatory mediators. The IgE produced by the stimulated B lymphocytes binds to mast cells and, possibly, other cells involved in inflammation (e.g. eosinophils), leading to the release of inflammatory mediators. Antigens can also provoke T-cell activation, cytokine and chemokine release, and production of inflammatory mediators. Inflammatory pathways can also be activated by the innate immune response to infectious organisms and pollutants and their effects on epithelium.

A characteristic finding in asthma is the presence of mast cells distributed within airway smooth muscle.³ Moreover, in contrast to the mast cells in the mucosa, which are T-cell dependent and contain the granule enzyme tryptase (MCT), the mast cells in smooth muscle are of the connective-tissue type and contain chymase as well as tryptase (MCTC). Stimulation of mast cells through IgE–antigen binding or other mechanism results in the release of these mediators together with histamine and newly generated bronchoconstrictors such as prostaglandin D2 and cysteinyl leukotrienes LTC4 and LTD4.

As asthma becomes more severe, the number of MCTC increases in the mucosa at the expense of MCT. This may be important, as MCTC are more dependent on stem cell factor (ckit ligand) from mesenchymal and epithelial cells and less responsive to Th2 cytokines and programmed cell death induced by corticosteroids.

Dysfunction of the airway epithelium. A major factor driving this dysregulation of innate and adaptive immunity is a fundamental abnormality in the asthmatic airway epithelium.¹¹ Early-life exposures such as respiratory infections lead to long-lasting changes in the behavior of the airway epithelium. Dysfunction of the airway epithelial tight junctions leads to greater permeability of the airway surfaces to inhaled particles. These particles can then penetrate the epithelial barrier and elicit inflammatory responses by contact with inflammatory cells such as mast cells and lymphocytes and subepithelial neural pathways. Furthermore, the airway responds to protease-containing allergens, such as house dust mites, or non-allergenic triggers, such as bacteria, smoke and air pollutants, by producing potent pro-inflammatory alarmins, including IL-25, IL-33 and thymic stromal lymphopoietin (TSLP).¹² These induce type-2 cytokine production from T cells and ILC2 (see Figure 1.3). Because alarmins act upstream of type-2 cytokines, and are also important in non-allergic asthma, therapeutic blockade may be effective in a broader range of phenotypes.

In addition, the asthmatic epithelium responds to oxidant stress and pathogenic stimulation differently from the non-asthmatic epithelium. Reduced production of the antiviral cytokines IFNβ and IFNλ has been described, resulting in impaired clearance of respiratory viruses and, consequently, greater viral replication and persistence during infection of the asthmatic epithelium.¹³,¹⁴ This induces inflammation that is more neutrophilic in nature, which characterizes asthma exacerbations. It may also, in part, account for the increased morbidity from respiratory viruses in asthma at certain times of the year, that is, when respiratory viruses such as those causing the common cold in winter months (for example, rhinoviruses) are prevalent.

Disordered lung function

Chronic inflammation is responsible for the two principal manifestations of disordered lung function in asthma: bronchial hyperresponsiveness and acute limitation of airflow (Table 1.1). Patients with asthma show an enhanced airway narrowing (bronchoconstrictor) response to a variety of stimuli such as histamine and methacholine (which act directly on airway smooth muscle), and exercise, hypertonic stimuli (for example, saline,