subject: Asthma epidemiology and pathogenesis [print this page] Definition Definition
The American Thoracic Society defines asthma as 'a diseasecharacterized by increased responsiveness of the bronchi tovarious stimuli, manifested by widespread narrowing of theairways that changes in severity either spontaneously or asa result of treatment'. Asthmatics may be said to have'twitchy' airways, and it is an essential feature of the resultingbronchoconstriction that it is usually reversible, at leastin part, with the administration of inhaled bronchodilators.
Epidemiology
Asthma is common, affecting between 5% and 7% ofpeople in Europe and the United States. The peak age ofonset is under 5 years, and in this age group it is morecommon in boys by a ratio of 3:2; over 5 years there is anequal sex ratio. There is an allergic component in one-thirdto half of all cases. About 2000 patients die from asthma inthe UK each year, and it is likely that many of these deathsare preventable.
There is a worldwide increase in theprevalence of allergy and asthma, especially in the developedcountries. An international survey of asthma andallergy in childhood which assessed children aged 13-14years demonstrated an over 20-fold difference in reportedasthma symptoms worldwide. Symptoms were quite uncommonin eastern European countries and in Asia, andthe highest prevalence was in the UK, Australia and NewZealand.
There was a poor relationship between the incidenceof allergic symptoms such as eczema and rhinitis andthose of asthma, which might suggest that the risk factorsare different or that they are following different timetrends. Local environmental factors may play a part.In addition to the increasing prevalence there appears tobe a trend towards increasing severity: in particular, in somecountries such as New Zealand and Australia there is agreatly increased hospital admission rate, and worldwidethere is a steady increase in the use of anti-asthma medications.
It is possible that environmental pollution and theconsequent damage to protective epithelium may be contributingto this, allowing allergens to penetrate the airwaylining. Furthermore, there have been disturbing epidemicsof asthma deaths in recent years in England, New Zealandand elsewhere. It is possible that misuse and overrelianceon inhaled (3-agonist bronchodilators may have played apart in these epidemics.
Other risk factors for asthma mortalityinclude cigarette smoking, previous hospital admission,and in particular admission to an intensive care unit,old age, social disturbance, ethnicity, dampness in the homeenvironment, and the keeping of pets such as cats or dogs.Some of these factors may interact with and amplify otherrisk factors. There is one intriguing suggestion that lackof exposure to childhood viral infections (sometimes seenin single-child families) may actually predispose to thesubsequent development of asthma.
Pathogenesis
Cellular and molecular mechanisms in asthma
About 70% of asthmatics have demonstrable atopy, withthe production of specific IgE to environmental allergens,and positive skinprick tests with elevated serum IgE levels.Those who do not have atopy are labelled 'intrinsic'; theytend to have asthma that comes on later in life, are morecommonly women, and may have aspirin sensitivity andnasal polyps.
It is still a subject of speculation whether lowgradeallergy plays a part in intrinsic asthma.Inhaled allergens are critical to the initiation and perpetuationof airway inflammation in atopic individuals.Antigen-presenting cells are located in the bronchialepithelium and will present allergen to resident T cells,resulting in their activation and Th2 differentiation. Th2-type cytokines (IL-4, IL-5, IL-10, IL-13 and GM-CSF) arederived from these activated T cells. The T cells also playan important part in the switching of B cells to IgE synthesisand mast cell survival, thus facilitating the inflammatoryprocess by the activation and recruitment andstimulating survival of eosinophils in the airway.
Thehyperresponsiveness demonstrated in asthmatic airwayscorrelates with severity, and these two factors in turn havebeen related to the numbers of activated eosinophilsand T cells expressing IL-5 in asthmatic airways. Airwaydamage is one of the characteristics of asthma, and inflammatorymediators released by activated eosinophils suchas MBP (major basic protein), ECP (eosinophil cationicprotein) and LTC4 (leukotriene C4) play an important partin this.
The role of the neutrophil is still being explored,but one important observation has been that in asthmaticsdying suddenly from their disease, eosinophils are scarcein the airways but there is a marked neutrophil inflammation;in asthmatics whose death has been caused by a moreindolent and slow downhill progression the eosinophil isthe predominant inflammatory cell found in the airway atpostmortem.
Bronchial 'hyperreactivity' appears to be the key to theasthmatic reaction. It is the unique property of asthmaticairways to react, by bronchoconstriction, inflammation andmucus production, to stimuli that would not elicit this reactionin normal airways.
When asthmatic subjects are challenged with appropriateinhaled antigen and lung function is measured, theymay show an immediate bronchoconstriction responsewithin a few minutes. Lung function then returns towardsbaseline, but a further apparently unprovoked fall mayoccur 4-6 hours later.
The early response is thought, in the main, to be due tothe acute effect of histamine release from mast cells. Thelate response is more complex, mediated through theactions of inflammatory mediators such as leukotrienesand platelet-activating factor and the recruitment andactivation of inflammatory cells. This highly complexpathogenic mechanism is the focus of much research, asit may represent a model for the ongoing inflammatoryreaction in asthma and therefore be the target for antiinflammatoryprophylactic drugs.
The balance of autonomicnervous control is important. The cholinergic vagalimpulses have bronchoconstrictor and secretory actions.These effects are opposed by pYadrenergic receptors,which are bronchodilator and antisecretory. The (3-adrenergic mechanism is supported by circulating catecholamines. In patients with asthma, vagal reflexes mayplay an important part in bronchial hyperreactivity,particularly to stimuli such as cold air and exercise.Other mechanisms may play a part in bronchial hyperreactivity.Calcium flux across cell membranes is importantfor smooth muscle contraction and for mast cell degranulation,and agents that block this flux may prove to beuseful in treatment.
Finally, there is some evidence that the'tight junction' between epithelial cells on the surface ofthe bronchial epithelium may be abnormally 'leaky', allowingantigen readier access to the mast cells underneath.It is therefore clear that no single mediator or mechanismis responsible for the asthmatic reaction, and researchcontinues to elucidate this highly complex process.
