pulmonary disorders
Asthma
Etiology of Asthma
Development of asthma is multifactorial and depends on the interactions among multiple susceptibility genes and environmental factors. More than100 asthma susceptibility geneshave been reported. Many are thought to involve the broad category of T-helper cells type 2 (TH2) and may play a role in inflammation. Examples include theFCER1Bgene, which encodes the beta chain of the high-affinity IgE receptor; the genes encoding certain interleukins (IL) such as IL-4, IL-13, and the IL-4 receptor; genes responsible for innate immunity (HLA-DRB1, HLA-DQB1, CD14); and genes participating in cellular inflammation (eg, genes encoding granulocyte-monocyte colony-stimulating factor [GM-CSF] and tumor necrosis factor-alpha [TNF-α]). Also, theADAM33gene may stimulate airway smooth muscle and fibroblast proliferation and remodeling; it was the first asthma risk locus found with whole-genome family linkage studies. More recently, the most replicated is at the chromosome 17q21 locus. This locus contains theORMDL3gene, which is an allergen and cytokine (IL-4/IL-13)–inducible gene implicated in epithelial cell remodeling and sphingolipid metabolism to affect bronchial hyperreactivity. Environmental risk factors for asthmamay include the following: Allergen exposure Diet Perinatal factors Evidence clearly implicates household allergens (eg, dust mite, cockroach, pet) and other environmental allergens in disease development in older children and adults. Diets low in vitamins C and E and in omega–3 fatty acids have been linked to asthma; however, several studies supporting dietary influence are limited by sample size or did not account for differences in socioeconomic, environmental, and demographic factors. Dietary supplementation with these substances does not appear to prevent asthma. Asthma has also been linked to perinatal factors, such as young maternal age, poor maternal nutrition, prematurity, low birthweight, and lack of breastfeeding. On the other hand, endotoxin exposure early in life can induce tolerance and may be protective. Air pollution is not definitively linked to disease development, although it may trigger exacerbations. The role of childhood exposure to cigarette smoke is controversial, with some studies finding a contributory and some a protective effect. Genetic and environmental components may interact. Infants may be born with a predisposition toward proallergic and proinflammatory type 2 (T2) immune responses(immune responses related to T-helper 2 cells). The proinflammatory T2 response is characterized by growth and activation of eosinophils and IgE production. Asthma with this pattern of inflammation has often been referred to as eosinophilic asthma. Early childhood exposure to bacterial and viral infections and endotoxins may shift the body to T-helper cells type 1 (TH1) responses, which suppresses TH2 cells and induce tolerance. Type 1 (T1) responses are characterized by a proliferation of type 1 T-helper cells. Trends toward smaller families with fewer children, cleaner indoor environments, and early use of vaccinations and antibiotics may deprive children of these T2-suppressing, tolerance-inducing exposures and may partly explain the continuous increase in asthma prevalence in higher income countries (the hygiene hypothesis). Reactive airways dysfunction syndrome (RADS) is the rapid onset (minutes to hours, but not > 24 hours) of an Irritant exposure and reactive airways dysfunction syndrome (RADS) that Develops in people with no history of asthma Occurs following a single, specific inhalation exposure to a significant amount of an irritating gas or particulate Persists for ≥ 3 months Numerous substances have been implicated, including chlorine gas, nitrogen oxide, and volatile organic compounds (eg, from paints, solvents, adhesives). The exposure event is usually obvious to the patient, particularly when symptoms begin almost immediately. Irritant-induced asthma refers to a similar, persistent asthma-like response following multiple or chronic inhalational exposure to high levels of similar irritants. Manifestations are sometimes more insidious, and thus the connection to the inhalational exposure is clear only in retrospect. RADS and chronic irritant-induced asthma have many clinical similarities to asthma (eg, wheezing, dyspnea, cough, presence of airflow limitation, bronchial hyperresponsiveness) and respond significantly to bronchodilators and often corticosteroids. Unlike in asthma, the reaction to the inhaled substance is not thought to be an IgE-mediated allergy; low-level exposures do not cause RADS or irritant-induced asthma. However, repeated exposure to the initiating agent may trigger additional symptoms. 