Acute Exacerbations of Asthma

Acute exacerbations of asthma are acute worsenings of asthma symptoms accompanied by reductions in lung function, normally provoked by some external event or combination of events.

Exacerbations may be relatively mild or severe. The most severe may lead to asthma death. Symptoms include increased breathlessness, wheeze, cough, or chest tightness. Severity is graded on a combination of symptoms, clinical signs, and lung function. The majority of asthma exacerbations, particularly in children, are precipitated by acute respiratory tract viral infections. These may interact with a number of other cofactors such as allergen exposure, air pollution, and exercise.

Exacerbations are more likely to occur on a background of poorly controlled rather than well-controlled underlying disease. Pathology involves increased airway inflammation with most inflammatory cell types implicated in pathogenesis. Most prominent, however, are neutrophils, lymphocytes, and eosinophils. A wide variety of acute inflammatory mediators are increased during exacerbations.

Severity of virus infection is the major determinant of severity of exacerbation. Asthmatics have increased susceptibility to viral and bacterial infection. Treatment includes optimal control of underlying disease, inhaled/ oral steroids, and bronchodilators. The role of anti-infective therapy is under investigation.

Introduction

Asthma is itself a heterogeneous disease. Asthma exacerbations also, therefore, are by definition heterogeneous as exacerbations are defined as a worsening of a pre-existing state. Given that the etiology (see below) of exacerbations is also heterogeneous, heterogeneity of both the underlying cause and of the etiology of the exacerbation makes the exacerbation itself very varied in its presentation. One of the difficulties in clinical practice and clinical research is defining exacerbations accurately and differentiating them from poor control of the underlying disease. There is no agreed definition of an exacerbation, but most clinicians and clinical researchers would agree on something like ‘episodes of relatively sudden onset and rapidly progressive increase in symptoms of shortness of breath, cough, wheeze, or chest tightness accompanied by reduction in lung function and normally provoked by some external event or combination of events’.

Exacerbations of asthma are very important as they are the major cause of morbidity and mortality in asthma and are also responsible for the greater part of healthcare costs associated with asthma treatment. Currently available treatments for asthma exacerbations include supportive care, oxygen if required, bronchodilators, and oral/inhaled corticosteroids. This treatment is at best only partially effective. Understanding the causes and mechanisms of asthma exacerbations is therefore of great importance as there is an urgent need for more effective preventive and interventional therapy.

Etiology

In infants and young children the vast majority (approaching 100%) of exacerbations are precipitated by acute respiratory tract virus infections. Respiratory syncytial virus (RSV) is the major cause of acute wheezing illness severe enough to require hospitalization in infants and 1–2-year-old children. There is, however, increasing evidence that rhinoviruses also play an important role and most recent data suggest RSV is implicated in 70–80% of hospitalized wheezing lower respiratory tract infections and rhinoviruses in around 40%. The incidence of dual infection with these two viruses and with a variety of other respiratory viruses is likely to be as high as 20–30%. There is much less data available on community lower respiratory wheezing illness but birth cohort studies have now reported that rhinoviruses are the dominant cause of acute attacks of wheezing in this age group, perhaps causing around three times as many episodes of wheezing illness as RSV and other respiratory viruses.

In school-age children and teenagers, viruses precipitate at least 80% of acute asthma exacerbations. Rhinoviruses again are by far the most common virus implicated accounting for around two-thirds of viruses detected. In adults, viruses likely cause around two-thirds to three-quarters of asthma exacerbations. In adults in particular where virus loads tend to be much lower than in children, the evidence is less strong than it is in children and further work is required to clarify the role of viruses.

In all these age groups, viruses can interact with a number of other factors in provoking asthma exacerbations. There are good data in both adults and children that virus infection and exposure to an allergen to which the patient is sensitized interact in a synergistic manner in increasing the risk of exacerbation. There is also evidence that air pollution interacts with virus infection in increasing the risk of lower respiratory illness when infected and it is possible that a number of other cofactors also play a role.

Poor control of the underlying disease is a major risk factor for asthma exacerbation and treatment with prophylactic therapy, principally with inhaled corticosteroids, but also with leukotriene receptor antagonists and long-acting beta-agonists is a major protective factor against exacerbation.

Asthma exacerbations show marked seasonality in all age groups, peaking 1–2 weeks after school return, most especially in the autumn and most especially in school-age children. This seasonal pattern is important as it emphasizes the times at which prophylactic therapy is most needed.

Asthmatics have recently been shown to have increased susceptibility to virus infection through impaired innate immunity and there is a biological rationale that they are also likely to have impaired acquired antiviral immunity. Clinical studies confirm that asthmatics are more susceptible to virus infection and bacterial infection, having a greater risk of invasive pneumococcal disease. To date, very little is known about susceptibility to infection in asthma but this is an important area for future research. Genetic susceptibility is also an underresearched area and very little is known in this regard.

Finally, there is increasing evidence that chronic infection with the atypical bacteria Chlamydophila pneumoniae and Mycoplasma pneumoniae may play a role in exacerbations of asthma and a recent study confirms therapeutic benefit of treating asthma exacerbations with an antibiotic active against these organisms. Further studies are required to confirm these findings and to shed further light on the role of chlamydia and mycoplasma.

Pathology

Relatively little is known about the pathology of asthma exacerbations for an obvious reason: sampling the lower respiratory tract during an exacerbation is extremely difficult. In one study asthmatic patients were bronchoscoped during naturally occurring colds, and eosinophilic, neutrophilic, and CD8þ T-cell inflammatory responses were found. Studies of post-mortem samples from patients dying of asthma exacerbation also reveal CD8þ T cells, activated CD8þ T cells, increased perforin expression, and impaired ratios of interferon gamma (IFN-g) to interleukin- 4 (IL-4), possibly implicating impaired antiviral immunity in asthma death. Noninvasive methods of sampling the lower airway include measurement of exhaled breath condensate or exhaled nitric oxide, and sputum sampling. Studies with sputum again show both eosinophilic and neutrophilic inflammation with increased levels of IL-8 and fibrinogen. Markers of both eosinophil and neutrophil activation are also increased and sputum lactate dehydrogenase (LDH) as a marker of virus-induced cytotoxicity is also markedly elevated. Levels of sputum LDH and eosinophil cationic protein were associated with longer hospital stay, indicating that virus-induced cell damage was the major predictor of the severity of asthma exacerbation and that eosinophilia as a consequence of either viral and/or allergen exposure was also an important contributor.

Clinical Features

Asthma exacerbations present with a sudden worsening of wheeze, cough, shortness of breath, and chest tightness with a reduction in lung function. Exacerbations can range from mild to severe, the most severe leading to asthma death. Diagnosis is normally made on the clinical history with the assistance of peak expiratory flow measurement and/or spirometry.

Clinical examination will normally reveal a distressed, anxious patient with tachycardia, tachypnea, and audible wheeze on auscultation (though in the most severe exacerbations the chest can be almost silent). Patients will have prolonged expiration, and signs of severe exacerbation include inability to talk in complete sentences, tachycardia above 110 beats min1, a respiratory rate above 25 breaths min1, and a peak expiratory flow below 50% of predicted or best. Presence of pulsus paradoxus also indicates a severe attack and life-threatening attacks are suggested by a silent chest, presence of cyanosis, bradycardia, or hypotension, and a peak expiratory flow below 30% of predicted or best.

Measurement of blood gases should be carried out. Hypoxia is usual. In milder exacerbations, hypocapnia is common due to hyperventilation while in more severe and life-threatening exacerbations, PCO2 starts to rise. A raised PCO2 or rising PCO2 is an indication for intensive care.

Chest X-rays should be performed to exclude pneumonia and pneumothorax. The response to therapy and the progress of the exacerbation are monitored with serial peak expiratory flow or spirometry testing. Routine hematology and biochemistry are indicated but other blood testing is not normally required.

Pathogenesis

Asthma exacerbations are always mixed in their pathogenesis. They involve a mixture of acute and chronic inflammation provoked by virus infection and other stimuli including allergen exposure, air pollution, tobacco smoke, etc. Much of the information we have gained regarding the pathogenesis of asthma exacerbations has come from experimental studies of rhinovirus infection in asthmatic and normal subjects. These studies have implicated neutrophils, CD4þ and CD8þ lymphocytes, and eosinophils, but in addition mast cells, macrophages, and mediators of acute inflammation are also shown to play important roles, including leukotrienes. Most cytokines/chemokines that have been investigated have been found to be elevated in exacerbations. Perhaps the most prominent are interleukin-8, interleukin-1b, tumor necrosis factor alpha (TNF-a), the regulated upon activation normally T-cell expressed and secreted factor (RANTES), and IFN-g. The mechanisms of induction of lower airway inflammation in the context of respiratory virus infection are of great interest as these represent potential targets for interventional therapy. Nuclear factor kappa B (NF-kB) is very strongly implicated in virus-induced inflammation, as is activating protein 1 (AP-1). However, a number of other transcription factors are also implicated. Mechanisms of induction of mucus secretion are also of great interest – complex pathways are involved, but NF-kB, Sp1 transcription factors, and the epidermal growth factor receptor signaling pathway are all implicated.

Airway obstruction is a result of acute smooth muscle contraction, chronic smooth muscle hypertrophy, mucus secretion, acute tissue edema, and chronic tissue inflammation with airway fibrosis/remodeling. An important aspect of pathogenesis is host resistance to infection as virus infection is the major precipitant to exacerbation. Recent studies have confirmed that asthmatic bronchial epithelial cells mount defective apoptotic and IFN-b innate immune responses to rhinovirus infection. In consequence, rhinovirus infection is robust while in normal epithelial cells infection is largely abortive. The clinical studies indicating increased susceptibility to virus infection in asthma are consistent with this biological evidence, and more recent evidence that asthmatics are also susceptible to invasive pneumococcal disease possibly indicates a more generalized immune deficit. There is an urgent need to increase our understanding of host immunity to both viral and bacterial infection in asthma.

Experimental Models

There are no small-animal models of rhinovirus infection as rhinoviruses only infect humans and nonhuman primates. There are animal models of other virus infections including influenza, RSV, and parainfluenza, and these models have been combined in some instances with allergen exposure to try to increase our understanding of the pathogenesis of virus-induced asthma exacerbations. These studies indicate that impaired T helper (Th)-1 immune responses increase susceptibility to virus infection and that airway inflammation, airway obstruction, and bronchial hyperreactivity are increased when virus infection occurs in the presence of ongoing allergic inflammation. Other studies have confirmed an increased risk of developing allergen sensitization if allergen exposure occurs in the context of an acute respiratory virus infection. Studies with RSV indicate that the major protective immune responses are production of neutralizing antibody, natural killer (NK) cell, and CD8þ T-cell IFN-g responses. A great deal of further work is needed to increase our understanding of the interaction between virus infection and allergen exposure in the context of asthma exacerbations.

In the absence of an animal model, investigators have carried out human rhinovirus experimental infections in asthmatic and normal subjects, and have demonstrated bronchial hyperactivity and airway obstruction in asthmatic volunteers. These studies have also implicated Th1 responses in increased susceptibility to virus infection and further work in these models is ongoing to try to increase our understanding of the pathogenesis of virus-induced asthma.

In vitro models of host immunity to virus infection and of virus-induced lower airway inflammation include infection of airway epithelial cells and macrophages with a variety of respiratory viruses including rhinoviruses, RSV, and influenza. These studies demonstrate that virus infection induces many proinflammatory cytokines and chemokines, dependent upon transcription factor activation such as NF-kB, AP-1, and NF-IL-6. In turn, much of the activation of transcription factors is dependent upon activation of oxidant pathways. Production of nitric oxide appears to exert some degree of protection against virus infection.

Management and Current Therapy

Perhaps the most important aspect to management of asthma exacerbations is prevention of asthma exacerbations. Optimal control of underlying disease with optimal therapy including inhaled corticosteroids, leukotriene modifiers, and long-acting betaagonists has been shown to reduce exacerbation frequency by approximately 50%.

Once exacerbations occur, the initial response is to give short-acting bronchodilators, if mild via inhalation through a spacer, and if more severe by nebulization. Short-acting beta-agonists are initial therapy. The addition of anticholinergic bronchodilators has been shown to further improve lung function and to reduce the need for hospitalization. In mild exacerbations, increasing the dose of inhaled corticosteroids can reduce the severity of the exacerbation and speed recovery. However, evidence indicates that doubling the dose is usually not adequate and that quadrupling the dose or giving high-dose therapy may give better responses. In moderate to severe exacerbations, oral/systemic corticosteroid therapy is indicated.

Intravenous magnesium has been shown to be of some benefit in more severe exacerbations failing to respond to initial therapy. Oxygen and supportive care should be given to all exacerbations where hypoxia is a feature. Leukotriene modifiers have been shown to be more beneficial in exacerbations in infants and young children. Their intravenous use in the acute setting has also been shown to produce some benefit, though there is not much evidence available as yet.

Use of standard antibiotics in two placebo-controlled studies has produced no evidence of benefit. However, a recent study with an antibiotic active against atypical bacteria and with anti-inflammatory properties has shown clinically significant benefit over placebo. The most severe exacerbations require high dependency unit or intensive care monitoring and some require invasive ventilation.

Hospitalization with acute exacerbation is a major risk factor for asthma mortality, and preventive therapy including inhaled corticosterioids and self-management plans are strongly indicated in such patients. 

Further Reading

British Thoracic Society, Scottish Intercollegiate Guidelines Network (2003) British guidelines on the management of asthma. Thorax 58(Supplement 1): 11–94.

Corne JM, Marshall C, Smith S, et al. (2002) Frequency, severity, and duration of rhinovirus infections in asthmatic and nonasthmatic individuals: a longitudinal cohort study. Lancet 359(9309): 831–834.

Gern JE (2002) Rhinovirus respiratory infections and asthma. American Journal of Medicine 112(Supplement 6A): 19S–27S.

Gern JE and Busse WW (2002) Relationship of viral infections to wheezing illnesses and asthma. Nature Reviews: Immunology 2(2): 132–138.

Gern JE and Lemanske RF Jr. (2003) Infectious triggers of pediatric asthma. Pediatric Clinics of North America 50(3): 555–575.

Green RM, Custovic A, Sanderson G, et al. (2002) Synergism between allergens and viruses and risk of hospital admission with asthma: case-control study. British Medical Journal 324(7340): 763. (Erratum British Medical Journal 324 (7346): 1131.)

Johnston SL and Martin RJ (2005) Chlamydophila pneumoniae and Mycoplasma pneumoniae: a role in asthma pathogenesis? American Journal of Respiratory and Critical Care Medicine, doi: 10.1164/rccm.200412–1743pp.

Message SD and Johnston SL (2002) Viruses in asthma. British Medical Bulletin 61: 29–43.

Message SD and Johnston SL (2004) Host defense function of the airway epithelium in health and disease: clinical background. Journal of Leukocyte Biology 75(1): 5–17.

Talbot TR, Hartert TV, Mitchel E, et al. (2005) Asthma as a risk factor for invasive pneumococcal disease. New England Journal of Medicine 352(20): 2082–2090.

Wark PA, Johnston SL, Bucchieri F, et al. (2005) Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. Journal of Experimental Medicine 201(6): 937–947.

Wark PA, Johnston SL, Moric I, et al. (2002) Neutrophil degranulation and cell lysis is associated with clinical severity in virusinduced asthma. European Respiratory Journal 19(1): 68–75.