Aetiology
Asthma is a complex disease with underlying multi-gene association interacting with environmental exposure.[12][13]
The genes and genetic loci associated with the disease include, but are not limited to, ADAM 33, IL1RL1, GSDMB, chromosome 12q, polymorphisms in tumour necrosis factor, and polymorphisms in the vitamin D receptor.[14][15][16][17]
Patients' genetic make-up may predispose them to airway hyper-responsiveness when exposed to environmental triggers. Those triggers can include viral infections such as rhinovirus, respiratory syncytial virus (RSV), human metapneumovirus, and influenza virus. Infection with RSV or human rhinovirus in early life increases the likelihood of developing asthma in those with a genetic predisposition.[18] Other triggers include bacterial infections (Mycoplasma pneumoniae or Chlamydia pneumoniae), allergen exposure (e.g., tree, grass, or weed pollen, fungi, or indoor allergens), occupational exposures (e.g., animal or chemical; see Occupational asthma), food additives and chemicals (e.g., metabisulfites), irritants, or aspirin in predisposed people.[12]
Patients with asthma who smoke have been found to have elevated levels and activation of neutrophils compared with non-smoking patients with asthma.[19] One study postulated that smoking may increase the risk of allergic disease such as asthma by modulating epigenetic changes to the PITPNM2 gene, which has a possible role in neutrophil function.[20] Vaping (e-cigarette use) may also contribute to the development of asthma by increasing the risk of obstructive lung function impairment.[21][22][23]
Many air pollutants, including those found indoors (e.g., wood burning, natural gas, cooking, evaporative volatile organic compounds), have been linked to increased asthma symptoms and exacerbations.[24][25][26] Strong reactions, such as laughter, can also precipitate attacks but often no clear aetiology can be identified.[27]
Socioeconomically disadvantaged groups are more likely to live in areas with the poorest air quality and worst housing conditions, while being exposed to more psychosocial stress and having poorer diets.[10] Socioeconomic status (e.g., education and income) can also affect access to healthcare. These factors increase the risk of asthma, poor asthma control, and acute exacerbations.
Pathophysiology
There are two major elements in the pathophysiology: inflammation and airway hyper-responsiveness (AHR). The large airways and the small airways with diameters <2 micrometres are the sites of inflammation and airway obstruction.[28]
Airway inflammation occurs secondary to a complex interaction of inflammatory cells, mediators, and other cells and tissues in the airway. An initial trigger leads to the release of inflammatory mediators, including the epithelial alarmin interleukin (IL)-33, which leads to the consequent activation and migration of other inflammatory cells.[29] The inflammatory reaction is a T-helper type 2 (Th2) lymphocytic response. Type 2 inflammation, as it is more simply known, is characterised by the presence of CD4+ lymphocytes that secrete IL-4, IL-5, and IL-13, the chemokine eotaxin, tumour necrosis factor-alpha, and the leukotriene LTB4, a product of the lipoxygenase pathway, as well as mast cell tryptase.[30] This response is important in the initiation and prolongation of the inflammatory cascade.
Other white blood cells involved are eosinophils, basophils and mast cells, macrophages, and invariant natural killer (NK) T cells. Eosinophil levels are particularly elevated in type 2 inflammation. In near-fatal exacerbations of asthma, neutrophils are important.[13][31] These cells move to the airway, causing changes in the epithelium, airway tone, and related autonomic neural control and hyper-secretion of mucus, mucociliary function alteration and increased smooth muscle responsiveness. Pathological studies of fatal asthma show severe hyper-inflation and mucous plugging with the mucus-containing mucins (proteins that are present in the blood).[13] Tissue biopsies show the deposition of eosinophil granular proteins throughout the lung tissue and damage of the epithelium mediated by those proteins. Denudation of the basal layer by epithelial cell sloughing produces clumps of cells in the sputum referred to as Creola bodies. There is also sub-basement membrane deposition of collagen often referred to as thickened basement membrane, which is considered another hallmark.
Products of the inflammatory response induce smooth muscle contraction and consequent AHR. There appear to be at least two different kinds of AHR: a baseline fixed and an episodic variable element.[32] The underlying fixed AHR is possibly related to airway remodelling, whereas the variable AHR reflects the action of the inflammatory mediators, and they are distinguished by direct and indirect bronchial challenges, respectively. Finally, airway smooth muscle in asthmatic people is increased in mass, probably as a result of hypertrophy and hyperplasia, which in vitro studies display as having increased contractility.[32]
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