Etiology

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Astma bij volwassenen: diagnose en monitoring in de eerste lijnPublished by: Werkgroep Ontwikkeling Richtlijnen Eerste Lijn (Worel)Last published: 2020Asthme chez l’adulte : diagnostic et surveillance en soins de santé primairesPublished by: Groupe de Travail Développement de recommmandations de première ligneLast published: 2020

Asthma is a complex disease in which multiple genetic risk factors likely predispose patients to airway hyperresponsiveness when exposed to triggers.[11][12][13][14]

A parental history of asthma is a major risk factor for the early development of asthma.[1] Genes and polymorphisms associated with asthma development include nitric oxide synthase (NOS), cytokines (e.g., IL-13, IL-4,IL-4R, TNF-α), beta-2 adrenergic receptor (ADRB2), thymic Stromal Lymphopoietin (TSLP), and the vitamin D receptor (VDR); research in this field is ongoing.[12][14]​​[15][16]​​[17]​​[18][19][20]​​

Etiological triggers can include viral infections, such as rhinovirus, respiratory syncytial virus (RSV), human metapneumovirus, and influenza virus. For example, infection with RSV or human rhinovirus in early life increases the likelihood of developing asthma in those with a genetic predisposition.[21] 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), food additives and chemicals (e.g., metabisulfites), irritants, or aspirin in predisposed people.[22]

Aspirin-exacerbated respiratory disease (AERD), which includes other nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase-1 (COX-1) inhibitors, occurs in about 9% of the adult population with asthma; this group typically develops sensitivity after a history of chronic rhinosinusitis and/or polyps.[3][23]​​​​[24][25]

Patients with asthma who smoke have been found to have elevated levels and activation of neutrophils compared with nonsmoking patients with asthma.[26]​​ 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.[27]​ Vaping (e-cigarette use) may also contribute to the development of asthma by increasing the risk of obstructive lung function impairment.[28][29][30]

Air pollution increases the risk of asthma and poor asthma control. Outdoor pollution includes traffic-related air pollution, such as NO₂, particulate matter ≤2.5 micrometers (PM2.5), and black carbon.[11][31][32]​ Indoor pollutants include PM2.5 (e.g., from wood burning, natural gas, cooking, smoking, candles) and evaporative volatile organic compounds (e.g., from household cleaning agents, glue, personal care products).[32][33][34]​​​[35][36]​​[37]​​

A high body mass index increases the likelihood of developing asthma, and significant weight loss can improve asthma control.[5][38][39][40]​​​ Obesity also affects the time-to-first exacerbation in patients with moderate-to-severe asthma, independent of drug therapy.[41]​​​​​ Patients with obesity have higher use of all asthma drugs and higher inhaled corticosteroid doses than their healthy-weight peers.[42]​​[43]

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 stressors and having poorer diets.[44]​ These factors increase the risk of asthma, poor asthma control, and acute exacerbations. Socioeconomic status (e.g., education and income) can also affect access to healthcare. Black and Hispanic people are disproportionately affected by lower socioeconomic status in the US.[44]

Workers may develop sensitivities to occupational triggers. See Occupational asthma.

Pathophysiology

There are two major elements in the pathophysiology: inflammation and airway hyperresponsiveness (AHR). The inflammation and obstruction occur in large airways and in small airways with diameters <2 micrometers.[45]​​

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 alarmins interleukin (IL)-33 and thymic stromal lymphopoietin (TSLP), which leads to the consequent activation and migration of other inflammatory cells.[46]​ The immune response in the respiratory tract is mainly driven by CD4+ T-helper (Th) cells, including Th1, Th2, and Th17 cells; however, it is most commonly a Th2-driven lymphocytic response.​[47][48][49][50]​​​​​​​​ This type 2 inflammation, as it is more simply known, is characterized by the presence of CD4+ lymphocytes that secrete IL-4, IL-5, and IL-13, the chemokine eotaxin, tumor necrosis factor-alpha, and the leukotriene LTB4, a product of the lipoxygenase pathway, as well as mast cell tryptase.[51]​ This response is important in the initiation and prolongation of the inflammatory cascade.

Other white blood cells that take part include eosinophils, basophils and mast cells, macrophages, and invariant natural killer (NK) T cells. Eosinophil levels are particularly elevated in type 2 inflammation, while neutrophils play a significant role in near-fatal exacerbations.[52][53]​​ The various white blood cells move to the airway, causing changes in the epithelium, airway tone, and related autonomic neural control, that are associated with hypersecretion of mucus, alteration of mucociliary function, and increased smooth muscle responsiveness. Pathologic studies of fatal asthma show severe hyperinflation and mucous plugging with the mucus-containing mucins (proteins that are present in the blood).[52]​ Tissue biopsies show damage of the epithelium mediated by the deposition of eosinophil granular proteins throughout the lung tissue. Denudation of the basal layer by epithelial cell sloughing produces cell clumps in the sputum referred to as Creola bodies. A hallmark of asthma is the sub-basement membrane deposition of collagen, often referred to as a thickened basement membrane.

Products of the inflammatory response induce smooth muscle contraction with baseline fixed AHR and episodic variable AHR elements.[54]​ The underlying fixed AHR is possibly related to airway remodeling, whereas the variable AHR reflects the action of inflammatory mediators; these elements are distinguished by direct and indirect bronchial challenges, respectively. People with asthma also have increased smooth muscle mass in their airways, likely due to hypertrophy and hyperplasia, and show increased contractility in vitro.[54]

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