Abstract
Asthma is typically characterized by variable respiratory symptoms and airflow limitation.
Along with the pathophysiology and symptoms are immunological and inflammatory processes.
The last decades research has revealed that the immunology of asthma is highly heterogeneous.
This has clinical consequences and identification of immunological phenotypes is currently
used to guide biological treatment. The focus of this review is on another dimension
of asthma diversity, namely anatomical heterogeneity. Immunopathological alterations
may go beyond the central airways to also involve the distal airways, the alveolar
parenchyma, and pulmonary vessels. Also, extrapulmonary tissues are affected. The
anatomical distribution of inflammation in asthma has remained relatively poorly discussed
despite its potential implication on both clinical presentation and response to treatment.
There is today evidence that a significant proportion of the asthma patients has small
airway disease with type 2 immunity, eosinophilia and smooth muscle infiltration of
mast cells. The small airways in asthma are also subjected to remodelling, constriction,
and luminal plugging, events that are likely to contribute to the elevated distal
airway resistance seen in some patients. In cases when the inflammation extends into
the alveolar parenchyma alveolar FCER1-high mast cells, eosinophilia, type 2 immunity
and activated alveolar macrophages, together with modest interstitial remodelling,
create a complex immunopathological picture. Importantly, the distal lung inflammation
in asthma can be pharmacologically targeted by use of inhalers with more distal drug
deposition. Biological treatments, which are readily distributed to the distal lung,
may also be beneficial in eligible patients with more severe and anatomically widespread
disease.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Respiratory MedicineAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Asthma. Lancet. 2018; 391: 783-800
- Current concepts of severe asthma.J. Clin. Invest. 2016; 126: 2394-2403
- Unravelling the complexity of tissue inflammation in uncontrolled and severe asthma.Curr. Opin. Pulm. Med. 2019; 25: 79-86
- Therapeutic significance of distal airway inflammation in asthma.J. Allergy Clin. Immunol. 2002; 109: S447-S460
- The basic immunology of asthma.Cell. 2021; 184: 1469-1485
- After asthma: redefining airways diseases.Lancet. 2018; 391: 350-400
- Plasma-derived proteins in airway defence, disease and repair of epithelial injury.Eur. Respir. J. 1998; 11: 958-970
- Airway smooth muscle proliferation and inflammation in asthma.J. Appl. Physiol. 1985; : 2018
- Airway remodeling in asthma: update on mechanisms and therapeutic approaches.Curr. Opin. Pulm. Med. 2018; 24: 56-62
- Heterogeneity of airway smooth muscle remodelling in asthma.Am. J. Respir. Crit. Care Med. 2023; 207: 452-460
- Defective fibrillar collagen organization by fibroblasts contributes to airway remodeling in asthma.Am. J. Respir. Crit. Care Med. 2019; 200: 431-443
- Fatty airways: implications for obstructive disease.Eur. Respir. J. 2019; 54
- Pathogenesis of asthma.Clin. Exp. Allergy. 2008; 38: 872-897
- Is there a role for type 2 CD8(+) T cells in patients with steroid-resistant asthma?.J. Allergy Clin. Immunol. 2019; 144: 648-650
- Refractory airway type 2 inflammation in a large subgroup of asthmatic patients treated with inhaled corticosteroids.J. Allergy Clin. Immunol. 2019; 143: 104-113
- The immunology of asthma.Nat. Immunol. 2015; 16: 45-56
- Type-2 innate lymphoid cells in asthma and allergy.Ann Am Thorac Soc. 2014; 11: S263-S270
- Innate lymphoid cells: major players in inflammatory diseases.Nat. Rev. Immunol. 2017; 17: 665-678
- Type 2 immunity: expanding our view.Sci Immunol. 2018; 3
- Airway autoantibodies are determinants of asthma severity.Eur. Respir. J. 2022; 60: 2200442
- Airway autoimmunity, asthma exacerbations, and response to biologics.Clin. Exp. Allergy. 2022; 52: 1365-1378
- Asthma endotypes and an overview of targeted therapy for asthma.Front. Med. 2017; 4: 158
- Expression of the T helper 17-associated cytokines IL-17A and IL-17F in asthma and COPD.Chest. 2010; 138: 1140-1147
- Neutrophil cytoplasts induce TH17 differentiation and skew inflammation toward neutrophilia in severe asthma.Sci Immunol. 2018; 3
- The neutrophilic inflammatory phenotype is associated with systemic inflammation in asthma.Chest. 2012; 142: 86-93
- IL-6 pathway upregulation in subgroup of severe asthma is associated with neutrophilia and poor lung function.Clin. Exp. Allergy. 2018; 48: 475-478
- Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts.Lancet Respir. Med. 2016; 4: 574-584
- New insights into the pathophysiology of the small airways in asthma.Ann. Thorac. Med. 2007; 2: 28-33
- Unlocking the quiet zone: the small airway asthma phenotype.Lancet Respir. Med. 2014; 2: 497-506
- TH1 signatures are present in the lower airways of children with severe asthma, regardless of allergic status.J. Allergy Clin. Immunol. 2018; 141: 2048-2060 e13
- Update on the roles of distal airways in asthma.Eur. Respir. Rev. 2009; 18: 80-95
- The prevalence of small airways disease in adult asthma: a systematic literature review.Respir. Med. 2016; 116: 19-27
- Exploring the relevance and extent of small airways dysfunction in asthma (ATLANTIS): baseline data from a prospective cohort study.Lancet Respir. Med. 2019; 7: 402-416
- Recognition of the peripheral airway impairment phenotype in children with well-controlled asthma.Ann. Allergy Asthma Immunol. 2018; 121: 692-698
- Small airway disease in pediatric asthma: the who, what, when, where, why, and how to remediate. A review and commentary.Clin. Rev. Allergy Immunol. 2022; 62: 145-159
- Inflammation of small airways in asthma.J. Allergy Clin. Immunol. 1997; 100: 44-51
- Cytokine mRNA expression in asthma is not restricted to the large airways.J. Allergy Clin. Immunol. 1998; 101: 386-390
- Eotaxin and monocyte chemotactic protein-4 mRNA expression in small airways of asthmatic and nonasthmatic individuals.J. Allergy Clin. Immunol. 1999; 103: 476-483
- Relationship of small airway chymase-positive mast cells and lung function in severe asthma.Am. J. Respir. Crit. Care Med. 2005; 171: 431-439
- Distribution and degranulation of airway mast cells in normal and asthmatic subjects.Eur. Respir. J. 2002; 19: 879-885
- Mast cell densities in bronchial biopsies and small airways are related.J. Clin. Pathol. 2011; 64: 394-398
- Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids.Am. J. Respir. Crit. Care Med. 1997; 156: 737-743
- Increased mast cells and neutrophils in submucosal mucous glands and mucus plugging in patients with asthma.Thorax. 2002; 57: 677-682
- Distal lung dysfunction at night in nocturnal asthma.Am. J. Respir. Crit. Care Med. 2001; 163: 1551-1556
- Histologic findings of severe/therapy-resistant asthma from video-assisted thoracoscopic surgery biopsies.Am. J. Surg. Pathol. 2017; 41: 182-188
- The small airways and distal lung compartment in asthma and COPD: a time for reappraisal.Allergy. 2010; 65: 141-151
- Inflammatory cell distribution within and along asthmatic airways.Am. J. Respir. Crit. Care Med. 1998; 158: 565-572
- Alveolar T-helper type-2 immunity in atopic asthma is associated with poor clinical control.Clin. Sci. (Lond.). 2015; 128: 47-56
- Novel site-specific mast cell subpopulations in the human lung.Thorax. 2009; 64: 297-305
- Mast cells in human airways: the culprit?.Eur. Respir. Rev. 2014; 23: 299-307
- Alveolar mast cells shift to an FcepsilonRI-expressing phenotype in mild atopic asthma: a novel feature in allergic asthma pathology.Allergy. 2011; 66: 1590-1597
- Mast cell-associated alveolar inflammation in patients with atopic uncontrolled asthma.J. Allergy Clin. Immunol. 2011; 127 (e1-7): 905-912
- Mast cell phenotype, location, and activation in severe asthma. Data from the Severe Asthma Research Program.Am. J. Respir. Crit. Care Med. 2011; 183: 299-309
- Uncontrolled asthmatics have increased FceRI(+) and TGF-beta-positive MCTC mast cells and collagen VI in the alveolar parenchyma.Clin. Exp. Allergy. 2018; 48: 266-277
- Alveolar macrophages in allergic asthma: the forgotten cell awakes.Curr. Allergy Asthma Rep. 2017; 17: 12
- [Different phenotypes of alveolar macrophages and bronchial asthma].Zhonghua Jiehe He Huxi Zazhi. 2017; 40: 63-67
- Increased ratio of matrix Metalloproteinase-9 (MMP-9)/Tissue inhibitor Metalloproteinase-1 from alveolar macrophages in chronic asthma with a fast decline in FEV1 at 5-year follow-up.J. Clin. Med. 2019; 8
- Monocytes accumulate in the airways of children with fatal asthma.Clin. Exp. Allergy. 2018; 48: 1631-1639
- IL-4 directly signals tissue-resident macrophages to proliferate beyond homeostatic levels controlled by CSF-1.J. Exp. Med. 2013; 210: 2477-2491
- Myofibroblasts are increased in the lung parenchyma in asthma.PLoS One. 2017; 12e0182378
- Altered matrix production in the distal airways of individuals with asthma.Thorax. 2010; 65: 670-676
- Lung parenchymal and airway changes on CT imaging following allergen challenge and bronchoalveolar lavage in atopic and asthmatic subjects.Ann. Transl. Med. 2020; 8: 862
- Allergen exposure of mouse airways evokes remodeling of both bronchi and large pulmonary vessels.Am. J. Respir. Crit. Care Med. 2005; 171: 19-25
- Structural alterations and markers of endothelial activation in pulmonary and bronchial arteries in fatal asthma.Allergy Asthma Clin. Immunol. 2019; 15: 50
- Pruning of the pulmonary vasculature in asthma. The severe asthma research program (SARP) cohort.Am. J. Respir. Crit. Care Med. 2018; 198: 39-50
- Aggregations of lymphoid cells in the airways of nonsmokers, smokers, and subjects with asthma.Am. J. Respir. Crit. Care Med. 2004; 169: 712-718
- Bronchopulmonary lymph nodes and large airway cell trafficking in patients with fatal asthma.J. Allergy Clin. Immunol. 2015; 135 (7 e1-9): 1352
- Systemic vascular health is compromised in both confirmed and unconfirmed asthma.Respir. Med. 2022; 200106932
- Plasma brain-derived neurotrophic factor (BDNF) concentration and BDNF/TrkB gene polymorphisms in Croatian adults with asthma.J. Personalized Med. 2020; 10
- Neuropeptide Y may mediate psychological stress and enhance TH2 inflammatory response in asthma.J. Allergy Clin. Immunol. 2015; 135: 1061-1063 e4
- Exploring the role of nerves in asthma; insights from the study of cough.Biochem. Pharmacol. 2020; 179113901
- Eosinophils and airway nerves in asthma.Histol. Histopathol. 2000; 15: 861-868
- Role of parasympathetic nerves and muscarinic receptors in allergy and asthma.Chem. Immunol. Allergy. 2012; 98: 48-69
- An overview of the obese-asthma phenotype in children.Int. J. Environ. Res. Publ. Health. 2022; 19
- Asthma and obesity: two diseases on the rise and bridged by inflammation.J. Clin. Med. 2021; 10
- Differences in inflammatory cytokine profile in obesity-associated asthma: effects of weight loss.J. Clin. Med. 2022; 11
- Comorbid allergic rhinitis and asthma: important clinical considerations.Expet Rev. Clin. Immunol. 2022; 18: 747-758
- Small airway dysfunction is associated with poorer asthma control.Eur. Respir. J. 2014; 44: 1353-1355
- Controlled and uncontrolled asthma display distinct alveolar tissue matrix compositions.Respir. Res. 2014; 15: 67
- The relevance of targeting treatment to small airways in asthma and COPD.Respir. Care. 2020; 65: 1392-1412
- Small airway disease in asthma: pathophysiological and diagnostic considerations.Curr. Opin. Pulm. Med. 2015; 21: 68-73
- Inhaled aerosol dose distribution between proximal bronchi and lung periphery.Eur. J. Pharm. Biopharm. 2020; 152: 18-22
- Small airways response to bronchodilators in adults with asthma or COPD: a systematic review.Int. J. Chronic Obstr. Pulm. Dis. 2021; 16: 3065-3082
- The functional benefit of anti-inflammatory aerosols in the lung periphery.J. Allergy Clin. Immunol. 2006; 118: 340-346
- Real-life effectiveness of extrafine beclometasone dipropionate/formoterol in adults with persistent asthma according to smoking status.Respir. Med. 2012; 106: 811-819
- Treatment response according to small airway phenotypes: a real-life observational study.Ther. Adv. Respir. Dis. 2016; 10: 200-210
- Mepolizumab effectiveness on small airway obstruction, corticosteroid sparing and maintenance therapy step-down in real life.Pulm. Pharmacol. Ther. 2020; 61101899
- The effect of omalizumab on small airway inflammation as measured by exhaled nitric oxide in moderate-to-severe asthmatic patients.Allergy Asthma Proc. 2014; 35: 241-249
- Dupilumab improves lung function in patients with uncontrolled, moderate-to-severe asthma.ERJ Open Res. 2020; 6
- Mepolizumab improves small airway function in severe eosinophilic asthma.Respir. Med. 2019; 148: 49-53
- Maximal mid-expiratory flow detects early lung disease in alpha1-antitrypsin deficiency.Eur. Respir. J. 2017; 49
- Diagnostic value of FeNO and MMEF for predicting cough variant asthma in chronic cough patients with or without allergic rhinitis.J. Asthma. 2021; 58: 326-333
- Clinical significance and applications of oscillometry.Eur. Respir. Rev. 2022; 31
- The forced oscillation technique in clinical practice: methodology, recommendations and future developments.Eur. Respir. J. 2003; 22: 1026-1041
- Ventilation heterogeneity is associated with airway responsiveness in asthma but not COPD.Respir. Physiol. Neurobiol. 2013; 189: 106-111
- The diagnosis of asthma. Can physiological tests of small airways function help?.Chron. Respir. Dis. 2021; 1814799731211053332
- Should lung biopsies be performed in patients with severe asthma?.Eur. Respir. Rev. 2015; 24: 525-539
- Mucosal cryobiopsies: a new method for studying airway pathology in asthma.ERJ Open Res. 2022; 8
Article info
Publication history
Published online: February 20, 2023
Accepted:
February 16,
2023
Received in revised form:
February 16,
2023
Received:
October 3,
2022
Identification
Copyright
© 2023 Published by Elsevier Ltd.
