Asthma Intrinsic and Extrinsic

This is a general article about intrinic and extrinsic asthma.

Asthma is one of the most common chronic diseases, affecting 300 million people worldwide. There has been a significant increase in prevalence over the last 30 years, particularly in the West. Complex relationships between genetic and environmental factors, such as viral infections, allergens, and occupational agents, influence the origin and progression of the disease.

Asthma is a chronic inflammatory disorder of the airway in which many cells and cellular elements play a role, in particular, eosinophils, mast cells, T lymphocytes, neutrophils, and epithelial cells. Some patients develop structural changes of the airway, a process known as remodeling, possibly due to ongoing inflammation and abnormal repair processes. Susceptible individuals experience recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night and in the early morning. These episodes are usually associated with widespread but variable airflow obstruction, which is often reversible, and bronchial hyperresponsiveness to a variety of stimuli.

Acute asthma is a common medical emergency and requires prompt assessment and treatment. Advances in the understanding of the genetic and environmental factors that account for asthma and its pathogenesis should lead to improved management strategies.

Introduction

Historical Perspective

The symptoms of asthma were described by Aretaeus over 2000 years ago. However, despite significant progress in our understanding of its pathogenesis and considerable improvements in pharmacological treatment, we have been unable to halt the relentless increase in prevalence that has taken place over the last 30 years.

Definition

Several different definitions have been devised that describe the asthma phenotype. In 1997 the National Asthma Education and Prevention Program Expert Panel Report defined asthma as: ‘‘A chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, T lymphocytes, neutrophils, and epithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night and in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli.’’

Epidemiology

Prevalence of Asthma and Atopy

Asthma is one of the most common chronic conditions affecting 300 million people worldwide. The Global Initiative for Asthma (GINA) estimates that one in 20 people in the world now have asthma, with a significant increase in the prevalence of disease over the last 30 years. This is in parallel with an increase in other atopic diseases, such as allergic rhinitis and atopic dermatitis. These increases have been most noticeable in affluent countries with a mild climate such as the UK, New Zealand, Australia, and North America and correlate with urbanization and the adoption of a westernized life style. It is more common in children than in adults. The clearest risk factor for the development of asthma is atopy. Atopy is the genetic predisposition for the development of an IgE-mediated response to common aeroallergens. Complex relationships between atopy and environmental factors such as viral infections, allergens, and occupational agents influence the origin and progression of the disease.

Morbidity

The morbidity from asthma is considerable. Surveys of patients with asthma indicate that many have poorly controlled symptoms, impaired indices of quality of life, and are often receiving inadequate treatment. Hospital admission rates for asthma, particularly in children, increased from the 1970s until the mid 1980s and have since then remained stable. In the US during 2002 there were 13.9 million outpatient visits, 1.9 million emergency room visits, and 484 000 hospitalizations. Many children and adults with asthma lose time from school and work, respectively. The financial impact of asthma is considerable; in the US the estimated total cost exceeds $6 billion per annum, with hospitalization and emergency room visits making up 50% of that figure.

Mortality

International mortality figures for asthma are often unreliable due to misclassification of the cause of death. In Western countries, where studies were restricted to the 5–34 years age group, the mortality from asthma increased steadily from the mid-1970s to the late 1980s. More recent studies suggest a plateau or decline in deaths from asthma. Risk factors for increased morbidity and potential mortality include socioeconomic deprivation, ethnicity, urban dwelling, and comorbid issues such as drug abuse. The vast majority of deaths occur among those with chronic severe asthma; few deaths occur among those with previously mild disease. Deaths are associated with inadequate treatment with inhaled or oral steroid and with poor follow-up and monitoring.

Natural History

The findings of the Tucson Children’s Respiratory Study suggested three clinical phenotypes of childhood asthma. Transient infant wheezing occurs during infancy, but not after the age of three years. These children have no family history of atopy and have a good prognosis. The second phenotype is the nonatopic wheeze of the toddler and early school years, after an early lower respiratory tract infection. The third phenotype is persistent atopic wheeze, which describes children who continue to wheeze at age 10 and have associated atopy and airway hyperresponsiveness. Many children have a favorable outcome with spontaneous remission in their adolescence.

Risk factors for progression into adulthood include early onset with severe symptoms, poor lung function, and airway hyperresponsiveness. It occurs more commonly in girls with associated atopy. Most adults with mild-to-moderate asthma appear to continue to have symptoms of a similar severity. Remission of adult asthma is rare. Irreversible airflow obstruction can develop in nonsmokers with asthma particularly in those individuals with severe symptoms and mucus hypersecretion. Smokers with asthma have an accelerated decline in lung function.

Classification

Asthma can be classified on the basis of severity and etiology.

Severity

The severity of asthma can be graded by assessing the frequency and severity of symptoms and measurements of lung function before treatment is started or by the level of treatment required to achieve asthma control.

Etiology

In 1947, Rackeman was the first to subdivide asthma into intrinsic and extrinsic asthma. He noted that extrinsic asthma, now described as allergic asthma, started before the age of 30 years and was associated with atopy. Intrinsic or nonallergic asthma was noted to begin in middle age and was not associated with allergy, but with nasal polyps. It is more common in women.

Etiology

Genetic

Twin and family studies have demonstrated that atopic diseases cluster in families and have a genetic basis. Genome-wide scans have shown that many genes determine the risk of asthma. The region of chromosome 5q31-33 controls the production of interleukin (IL)-4 and IL-13 and has been linked to atopy. Linkage studies have implicated other candidate genes on chromosomes 2, 3, 4, 6, 7, 11, 12, 13, 17, and 19. Classical positional cloning approaches have led to the identification of new genes of potential significance such as ADAM33, IL4RA, and CD14. This may contribute to our understanding of the mechanism of disease, such as the role of ADAM33 in airway hyperresponsiveness. They may also cast light on different individual responses to therapy, as there are polymorphisms of a number of common drug targets. The delineation of the precise relationships between these genetic factors and environmental agents is now required.

Environment

Hygiene hypothesis

In 1989, Strachan noted an inverse relationship between family size and hay fever, with children with more siblings having a lower risk of atopy. It has been suggested that childhood exposure to infection may protect against risk of atopy. Low levels of infection in infancy, associated with improvements in public health, may deprive the immune system of the Th1 stimulus that normally balances the Th2 predominance of the neonate. This unrestrained Th2 response is postulated to predispose to allergic disease. European studies showing lower levels of atopic disease amongst children raised in rural communities have suggested that exposure to bacterial endotoxin may play a role in the development of tolerance to common allergens. However, the high levels of asthma associated with cockroach allergy in inner-city areas of the US, and the simultaneous increase in Th1 diseases, such as type 1 diabetes, illustrate that our understanding of the relationship between environmental exposure and disease is not yet complete.

Allergen exposure

Sensitization to the house dust mite Dermataphagoides pteronnysinus is the most common risk factor for the development of asthma in adults and children. Early exposure to the dust mite antigen Der p1 has been shown to increase the risk of asthma fivefold. Peat elegantly demonstrated the dose response relationship between dust mite level and severity of asthma symptoms across six different regions of Australia with increasing humidity levels. Dust mites thrive in a humid environment, and improved westernized building construction techniques, favoring colonization by house dust mites, may have contributed to the increase in asthma. Studies at altitudes where the levels of house dust mite are extremely low have suggested that a low allergen environment does improve symptoms of asthma. However, simple measures such as mattress covers and carpet cleaning have shown little effect on reducing the domestic burden of dust mite and asthma symptoms.

Exposure to other indoor allergens from animal dander and cockroach are also important risk factors for asthma. Removal of the pet from the family is advised to reduce exposure to the allergen. However, early exposure to cat allergen has recently been demonstrated to protect against development of asthma and the full intricacies of the relationship remain to be elucidated.

Cockroach infestation has become rampant in inner- city areas of the US and sensitization to the German cockroach Blatella germanica has become an important risk factor for asthma.

Outdoor air environment

Sensitization to the fungus Alternaria is a risk factor for asthma. It has been suggested that outbreaks of asthma after thunderstorms are related to release of fungal spores of Cladosporium.

The relationship between air pollution and asthma is complex as there has been considerable reduction in air pollution over the time period when asthma prevalence has increased. Extremely high levels of asthma have been noted in the rural Highlands of Scotland. It has been suggested that particulate pollution may protect against incidence but exacerbate symptoms in those sensitized.

Diet

Changes in the modern processed diet have been linked with an increased risk of asthma. High levels of omega-3 oils associated with eating fresh fish have been shown to reduce the risk of asthma. Breast-feeding to 3 months has also been associated with lower levels of asthma.

Cigarette smoking

There is much evidence to suggest that exposure to tobacco smoke in utero and in early childhood increases the risk of allergy and wheeze. Nevertheless, as the total numbers of smokers in the UK have fallen during the last 30 years, it is not the whole answer to the rise in asthma prevalence.

Pathology

Fatal Asthma

In cases of fatal asthma the lungs are hyperinflated due to air trapping caused by plugging of the medium to small airways with mucus and inflammatory cells, particularly eosinophils. Histologically, the airways show characteristic changes: an intense infiltration by inflammatory cells, particularly eosinophils and T lymphocytes, sloughing of the surface epithelium, thickening of the reticular basement, increase in the airway smooth muscle mass, increased numbers of epithelial goblet cells, vasodilatation, and edema. Neutrophils are found also in those who die suddenly from acute asthma.

Chronic Asthma

Information on the pathology of asthma has been obtained from bronchial biopsies obtained from patients with mainly mild asthma. The histological changes are similar although less pronounced than those obtained from cases of fatal asthma. The similarity of the histological changes in allergic or extrinsic and nonallergic or intrinsic asthma suggests a final common pathogenic mechanism in both types of asthma. Neutrophils are found more commonly in patients with severe asthma.

Clinical Features

Acute Asthma

Acute asthma is a common medical emergency. It is characterized by a progressive increase in dyspnea, cough, or wheeze. The decrease in expiratory airflow can be quantified by a fall in peak expiratory flow (PEF) or forced expiratory volume in 1 s (FEV1). Deterioration usually progresses over hours to days, although in some cases it may be more sudden and require rapid treatment within minutes. The severity of exacerbation is highly variable. Respiratory tract infections are thought frequently to precipitate attacks of asthma, particularly in children. Infections are mainly viral, especially human rhinoviruses but also respiratory syncytial virus, adenoviruses, parainfluenza, and influenza viruses. The role of infection in provoking asthma attacks in adults is less certain.

Clinical assessment

Clinical features

A short history of the features of an exacerbation should be elicited. The aims are to ascertain duration and severity of symptoms, with the perspective of current medication and prior admissions. Assessment must be rapid and accurate to permit prompt treatment. The history is usually one of increasing breathlessness and wheeze. Patients often have difficulty speaking and sleep is disturbed by the severity of these symptoms. There is increasing need for bronchodilator treatment, which becomes less effective. The patient may show signs of exhaustion and reduced conscious level. There is invariably an associated tachycardia, increase in respiratory rate, and auscultation of the chest may reveal severe wheeze or absent breath sounds that indicates very severe airflow obstruction. The chest becomes hyperinflated and patients may use accessory respiratory muscles.

Investigations

Measurement of pulse oximetry is necessary in acute asthma to evaluate oxygen saturation. The aim is to maintain SpO2492%. Arterial blood gas analysis is necessary if SpO2o92%. If oxygenation remains inadequate despite supplemental oxygen, additional complications should be considered, particularly pneumonia. The earliest abnormality is respiratory alkalosis and hypocarbia, but normal oxygen tension. As airflow obstruction increases there is uneven distribution of inspired air and changes in the normal ventilation-to-perfusion ratio. As severity increases, hypoxemia develops. The presence of normal levels of arterial carbon dioxide tension is ominous as it indicates the patient is becoming exhausted. Monitoring response to treatment should be on the basis of PEF and clinical examination. A chest radiograph may show evidence of hyperinflation, mucus plugging, and atelectasis in an acute exacerbation, but these findings may add little to management. A chest radiograph should be performed if pneumothorax is suspected.

Levels of severity

Asthma guidelines have been developed to ensure prompt, systematic history and examination, and ensure accurate assessment of severity. The British Guideline on the Management of Asthma defines a moderate exacerbation as one presenting with increasing symptoms of wheeze, dyspnea, or breathlessness and a fall in PEF to 50–75% of the best or predicted. However, if the PEF falls to 33–55% best or predicted and is accompanied by an inability to speak in complete sentences, tachypnea of 425 breaths per min, or tachycardia of 110 beats per min, the exacerbation is classified as severe. Life-threatening features are a PEF less than one-third of best or predicted or hypoxia demonstrated by arterial oxygen saturations of less than 92% on air or arterial partial pressure of less than 8 kPA. Normal levels of CO2, a silent chest on examination, or feeble respiratory effort, cyanosis, bradycardia, dysrhythmia, hypotension, exhaustion, confusion, or coma are all signs of a near fatal episode.

Chronic Asthma

The diagnosis based on a history of episodic respiratory symptoms especially after exercise or during the night is usually not difficult. Demonstration of reversible airflow obstruction gives a simple, reliable, and objective diagnosis of asthma. Evidence of reversibility can be found through the history of symptoms of episodic cough, wheeze, chest tightness, or dyspnea, measurement of PEF, or spirometry, and trials of therapy.

Clinical assessment

Clinical features

Asthma may present with wheeze, shortness of breath, cough, or chest tightness. The hallmark of asthma is that these symptoms tend to be variable and intermittent. They are often worse at night and early morning and provoked by triggers such as allergens or exercise. Less common factors are rhinitis, bacterial sinusitis, menstruation, gastroesophageal reflux, and pregnancy.When cough is the predominant symptom without wheeze, this is referred to as cough-variant asthma. The physical sign of wheezing (usually expiratory, bilateral, polyphonic, and diffuse) is associated with asthma but has low sensitivity and specificity, and in many patients examination will be normal.

Investigation

A simple measure of pulmonary function by PEF is helpful, not only for initial assessment, but also to monitor symptoms, alert to deterioration in airflow obstruction, and evaluate response to treatment. Twice-daily recording of PEF for two weeks is a simple and cheap method of demonstrating variation in airflow obstruction, with a diurnal variation of greater than 15% confirming the diagnosis. However, in patients with mild asthma, the PEF may show normal variability. Spirometry demonstrates an obstructive pattern with reduction of the ratio of FEV1 to forced vital capacity (FVC). The key feature is that this airway obstruction may be reversible. Administration of a bronchodilator typically causes an increase in FEV1 of 12–15%. However, failure to demonstrate reversibility does not exclude asthma, or prove irreversible disease.

Airway hyperresponsiveness is a characteristic feature of asthma and can be demonstrated by bronchial provocation techniques. The most common methods are provocation by inhalation of methacholine or histamine and exercise challenge. Fall in FEV1 is measured by serial spirometry after inhalation of increasing concentrations of methacholine. Results are expressed as the concentration of the agent that elicits a fall of 20% in FEV1. This concentration defines the degree of bronchial responsiveness and severity of disease. Skin prick testing, measurement of total and specific IgE levels, and blood eosinophilia are difficult to interpret in asthma because they have variable sensitivity and specificity. Routine chest radiographs in asthma may yield no new information and may be normal in chronic asthma.

Assessment of control

Asthma control can be determined by assessing symptoms, inhaled b2 adrenoceptor agonists use, lung function as well as rate of exacerbations, number of emergency consultations for asthma, and hospital admissions. Good control is described as the presence of minimal symptoms during day and night, minimal need for reliever medication, no exacerbations, no limitation of physical activity, and normal lung function. It may not be possible to achieve good asthma control in patients with moderate or severe persistent asthma.

Specific clinical problems

Asthma during pregnancy

The course of asthma during pregnancy varies, with a similar proportion of women improving, remaining stable, or worsening. The risk of an exacerbation of asthma is high immediately postpartum, but the severity of asthma usually returns to preconception level after delivery. Changes in b2-adrenoceptor responsiveness and changes in airway inflammation induced by high levels of circulating progesterone have been proposed as possible explanations for the effects of pregnancy on asthma.

Gastroesophageal reflux

Gastroesophageal reflux can trigger attacks of asthma although the incidence is unclear. The mechanism is unknown; possibilities include aspiration or an esophagio-bronchial reflux triggered by acid irritation of the esophageal mucosa.

Pathogenesis

The pathogenesis of asthma involves acute and chronic inflammation as well as remodeling. The underlying process is one of inflammation involving eosinophils and T lymphocytes, with the release of various mediators and cytokines, although recent evidence indicates a role for other cells including mast cells, neutrophils, macrophages, and epithelial cells. Some patients develop structural changes of the airway, a process known as remodeling. The mechanisms involved in remodeling remain to be clarified but probably consist of ongoing inflammation and abnormal repair processes. Remodeling occurs in many asthmatic patients, although the extent varies. It is thought that remodeling may play an important role in causing symptoms and loss of lung function in severe asthma, although this hypothesis remains to be established.

Airway Inflammation

There are two distinct responses to inhalation of an allergen. The immediate hypersensitivity reaction, in which wheeze occurs within minutes, is comparable to the wheal-and-flare response of skin. Further wheeze is caused by the late phase response, mounted between 6 and 9 h after allergen provocation.

The immediate reaction involves the activation of mast cells by allergen cross-linking two IgE antibodies (Figure 4). IgE antibodies are produced by B cells in response to processed antigen, which is presented by airway dendritic cells in the draining lymph node. The IgE antibodies bind mast cells by their high-affinity receptors (FceRI). Cross-linking by allergen of IgE antibodies initiates signal transduction by the FceRI effecting degranulation of the mast cell. This promotes release of mediators such as histamine, tryptase, eicosanoids, and reactive oxygen species. These spasmogens cause secretion of mucus, smooth muscle constriction, and vasodilation. Leakage of plasma protein causes edema of the airway wall, impedes clearance of mucus, and causes formation of plugs; all result in reduced airway conductance. The late phase reaction includes the accumulation of activated eosinophils, lymphocytes, macrophages, neutrophils, and basophils. The ability of cytokines to induce the expression of adhesion molecules provides a mechanism for cell migration from the circulation to the airway.

Eosinophils are thought to play a central role in the pathogenesis of chronic asthma. IL-5 controls the production of eosinophils by the bone marrow and their subsequent release into the circulation. They migrate from circulation to the airway under the influence of chemokines and release toxic granule proteins, including major basic proteins, eosinophil peroxidase and eosinophil cationic protein, Th2 cytokines, and leukotrienes. Major basic proteins causes direct airway damage with epithelial shedding. Leukotrienes increase vascular permeability and constrict smooth muscles. Challenge of the airway with allergen increases the local levels of IL-5, which correlates directly with the degree of airway eosinophilia. Recently, doubts have arisen about the role of eosinophils in causing airway hyperresponsiveness in asthma. Treatment of patients with allergic asthma using anti-interleukin-5 monoclonal antibody does not prevent allergen-induced bronchoconstriction or airway hyperresponsiveness, despite markedly suppressing eosinophil numbers within the airways.

T cells are found in abundance in the inflamed airways of asthma patients and it is widely held that the Th2 subset is a driving force in allergic inflammation. The T helper subsets were characterized by Mosman on the basis of their signature cytokines. Th2 cell cytokines include IL-4, IL-5, and IL-13. IL-5 is involved in eosinophil maturation and activation, whereas IL-4 and IL-13 control synthesis of IgE. However, the Th2 paradigm for allergic asthma is now thought to be too simplistic and an additional role for Th1 cells has been postulated.

The mast cell degranulation is crucial to the acute response to allergen, with release of histamine and synthesis of mediators effecting early recruitment, adhesion, and proliferation of cells. It may also contribute to remodeling as it contains proteoglycans with various functions, including support structures for remodeling.

The role of other inflammatory cells in the pathogenesis of asthma including neutrophils and macrophages is less clearly characterized. There are also complex interactions between neural control of airways and inflammation.

Airway Remodeling

There has been considerable evidence that inflammation alone may not explain the full pathophysiology of asthma. Two large longitudinal studies of inhaled corticosteroids have shown little effect on the natural history of asthma. Acute airway inflammation should be resolved to permit resumption of normal function. In chronic asthma, a state of increased injury and repair is thought to lead to remodeling. It is coordinated by inflammatory cells, such as eosinophils, mast cells and T cells, and structural cells such as fibroblasts. Growth factors are secreted in response to epithelial damage and cause thickening of the smooth muscle and basement membrane, resulting in airway narrowing. It is thought that a primary abnormality of the epithelium predisposes to such damage by toxins. The interaction between the thickened basement membrane and altered submucosa, known as the epithelial-mesenchymal trophic unit, is postulated to be important early in the origins of disease. This hypothesis is supported by the recent identification of ADAM33 as an asthma susceptibility gene expressed abundantly by the smooth muscle and fibroblasts, but not by inflammatory cells.

Animal Models

Animal models have been used to study both the pathogenesis and treatment of asthma. Asthma does not occur spontaneously in animals although both horses and the Berenji greyhound develop a respiratory condition that has some features of asthma. Most animal models involve sensitization to an allergen such as ovalbumin or house dust mite allergen challenge. The species commonly used include mice, guinea pigs, sheep, rats, monkeys, and dogs. The mouse is often used in these models, mainly because this species allows for the application in vivo of gene deletion technology as well as the low cost and availability of inbred species with known characteristics. Animal models of allergen-induced airway inflammation and hyperresponsiveness have provided important information on the acute inflammatory response to allergen exposure but have been less relevant to the study of mechanisms of chronic asthma and airway remodeling. The interpretation of data from experiments in animal models is influenced by the protocol used to sensitize and challenge the animal and the strain of animal used.

Further Reading

Barnes P, Drazen J, Rennard S, and Thomson NC (eds.) (2002) Asthma and COPD – Basic Mechanisms and Clinical Management. London: Academic Press.

Bel E (2004) Clinical phenotypes of asthma. Current Opinion in Pulmonary Medicine 10(1): 44–50.

Bousquet JP, Jeffery Busse W, Johnson M, and Vignola A (2000) Asthma – from bronchoconstriction to airways inflammation and remodeling. American Journal of Respiratory and Critical Care Medicine 161: 1720–1745.

British Thoracic Society (2003) British guideline on the management of asthma. Thorax 58: i1–i94.

Busse W (2001) Asthma. New England Journal of Medicine 5: 350–362.

GINA (2004) Self-reported wheezing in the previous 12 month period in 13- to 14-year-old children. Global Burden of Asthma, p. 6.

GINA (2004) Global Strategy for Asthma Management and Prevention, Chapter 7, Part 4A, Figure 5–7, p.7.

Kay AB (2001) Allergy and allergic diseases. New England Journal of Medicine 344: 30–37.

Kips JC, Anderson GP, Fredberg JJ, et al. (2003) Murine models of asthma. European Respiratory Journal 22(2): 374–382.

Larche M, Robinson R, and Kay AB (2003) The role of T lymphocytes in asthma. Journal of Allergy and Clinical Immunology 111: 450–459.

McFadden E (2003) Acute severe asthma. American Journal of Respiratory and Critical Care Medicine 168: 740–759.

National Asthma Education and Prevention Program Expert Panel Report: guidelines for the diagnosis and management of asthma, Update on Selected Topics – 2002. Journal of Allergy and clinical Immunology 110(5 pt 2): S141–S219.

NHLBI/WHO (2004) Global initiative for asthma: global strategy for asthma management and prevention. NHLBI/WHO Workshop Report NIH 02-3659. Bethesda: NIH.

O’Byrne PM and Thomson NC (eds.) (2001) Manual of Asthma Management, 2nd edn. London: W B Saunders.

Rodrigo G, Rodrigo M, and Jesse B (2004) Acute asthma in adults: a review. Chest 125(3): 1081–1102.

Tattersfield A, Knox A, Britton J, and Hall I (2002) Asthma. Lancet 360: 1313–1322.

Thomson NC, Chaudhuri R, and Livingston E (2004) Asthma and cigarette smoking. European Respiratory Journal 24: 822–833.