Airway Hyperresponsiveness

Airway hyperresponsiveness is considered to be the cardinal pathophysiologic abnormality in asthma. It represents an exaggerated bronchoconstrictor response to a variety of largely exogenous inhaled stimuli causing bronchoconstriction, either by a direct effect on airway smooth muscle or indirectly by interacting with neural pathways or mast cells. Airway hyperresponsiveness is likely to be the basis for the variable airflow obstruction that is responsible for many of the day-to-day symptoms of asthma, including those associated with exercise-induced asthma, nocturnal asthma, and asthma induced by fumes or cold air.

Airway hyperresponsiveness can be objectively demonstrated as a 20% fall in the forced expiratory volume in 1 second (FEV₁) after inhalation of histamine or methacholine) at a concentration below 8 mg/mL. This represents an abnormal effector response of airway smooth muscle, characterized by heightened pharmacologic sensitivity and reactivity to the bronchoconstrictor stimulus (Figure 39-1). Naturally occurring airway hyperresponsiveness reflects an abnormally amplified response of airway nerves and mast cells to exogenous stimuli, as well as an intrinsic abnormality of the airway smooth muscle response. The basis for this generalized hyperresponsiveness is not entirely clear, but sensitization of airway nerves, mast cells, and smooth muscle by inflammatory mediators, along with loss of epithelial barrier function, reduced production of bronchoprotective factors, an intrinsic abnormality of airway smooth muscle, and structural changes to the airway, all are likely to play a part (Figure 39-2). One key pathologic feature associated with airway hyperresponsiveness in asthma not seen in nonasthmatic eosinophilic bronchitis is infiltration of the bronchial smooth muscle layer by mast cells, implying that the interaction between these cells is fundamentally important in the pathogenesis of airway hyperresponsiveness.

Figure 39-1 Airway responsiveness measured as the fall in forced expiratory volume in 1 second (FEV₁) after increasing inhaled concentrations of methacholine. Severe (yellow), moderate (green), and mild (blue) airway hyperresponsiveness are shown. Note increased airway responsiveness is associated with a lower provocative concentration required to cause a 20% fall in FEV₁ (PC₂₀) (see green line), a steeper gradient, and a higher maximum % fall in FEV₁.

Figure 39-2 Schematic diagram of the inflammatory and remodeling processes in the airway that may potentially contribute to airway hyperresponsiveness and airflow obstruction.

(Courtesy Professor Mark Inman.)

Chronic Airway Inflammation

Histopathologic examination of postmortem specimens from patients with fatal asthma show an inflammatory response characterized in many cases by the presence of airway eosinophilia. Typically, eosinophilic infiltration can be found throughout the airway wall, within thick viscid plugs that occlude the airway lumen and often extend into the lung parenchyma and alveolar spaces and even into adjacent blood vessels (see Figure 39-2). In addition, extensive eosinophilic degranulation with deposition of major basic proteins occurs. Associated findings include widespread shedding of the airway surface epithelium, thickening of the reticular basement membrane, and enlargement of airway smooth muscle and submucosal glands. A minority of patients dying from asthma, particularly those with sudden-onset fatal asthma, exhibit evidence of eosinophilic inflammation. In these cases it is believed that widespread mast cell degranulation is the primary event with evidence for a relative excess of neutrophils in the distal airways and parenchyma.

Bronchoscopy and bronchial biopsy studies in patients with mild asthma show similar although less dramatic changes. Eosinophil numbers are increased in bronchial biopsy specimens and bronchoalveolar lavage (BAL) fluid, and the eosinophils are activated, with increased concentrations of major basic proteins and leukotrienes found in BAL fluid. Endobronchial biopsy specimens also show increased numbers of CD4⁺ T cells of T_H2 type, producing the interleukins IL-4, IL-5, and IL-13. These cytokines increase production of IgE and play an important role in the maintenance of eosinophilic airway inflammation.

The limited number of patients studied by bronchoscopy makes it difficult to investigate heterogeneity of the lower airway inflammatory response, but less invasive assessment of airway inflammation using induced sputum analysis has shown that a significant proportion of patients with asthma studied when stable and during an attack have normal eosinophil numbers in induced sputum samples. This sputum cell profile has been reported in patients with severe asthma and in patients who are not treated with inhaled corticosteroids, and the absence of eosinophilic airway inflammation has been confirmed by bronchoscopy studies. Thus, the presence of a distinct noneosinophilic corticosteroid-resistant asthma phenotype across the range of asthma severity seems secure. Noneosinophilic asthma is discussed in more detail later in the chapter.

Disordered Airway Mucosal Immunity

The airway mucosa in persons with asthma mounts an abnormally amplified immunologic response to a variety of exogenous stimuli, including inhaled allergens, cigarette smoke, infectious agents, and air pollutants. Some or all of these abnormal responses may be the consequence of failure of maturation of the immune response in early life as a result of reduced exposure to pathogens at a critical point in development.

Particular interest has focused in the response to allergen, because atopy is twice as common in patients with asthma as in control subjects without asthma, and inhalation of allergen in a patient with atopic asthma who is sensitized to the allergen results in a marked eosinophilic airway inflammatory response, developing 4 to 6 hours after inhalation associated with airflow obstruction (the late response) and increased airway responsiveness lasting for days and weeks. Common aeroallergens in many Westernized countries include house dust mite, cat fur, grass pollen, ragweed, and Aspergillus fumigatus spores. Most patients with childhood-onset asthma are sensitized to one of more of these allergens, and many have extrapulmonary manifestations of allergy, including eczema and allergic rhinitis. Opinions regarding the significance of the response to allergen vary, ranging from a fundamentally important role in the pathogenesis of airway inflammation and dysfunction in asthma to a position in which it is seen as a more peripheral mechanism. The occurrence of histopathologically similar forms of asthma in nonatopic patients and the disappointing therapeutic effect of allergen avoidance and anti-IgE treatment suggest that the latter position is correct, although uncertainty remains.

Growing evidence points to an abnormal airway response to infecting respiratory viruses, resulting in an amplified airway inflammatory response and more pronounced clinical consequences. The molecular mechanisms of this remain uncertain but constitute an active area of current study. There is little doubt that viral infection is an important trigger for acute severe asthma. Smoking and perhaps exposure to other environmental pollutants have been linked to worsening of symptoms, an increased risk of asthma attacks, and the development of fixed airflow obstruction. This association may reflect an abnormality of the innate immune response; patients with asthma who smoke or are exposed to environmental pollutants tend to have noneosinophilic, neutrophilic airway inflammation.

Structural Changes to the Airway

Structural changes in airway morphology (airway remodeling) probably occur as a result of chronic airway inflammation and dysfunction. These changes are likely to be the basis for the accelerated lung function decline and fixed airflow obstruction seen in some patients with asthma. Key features of airway remodeling include thickening of the subepithelial basement membrane caused by abnormal deposition of collagen, increased airway smooth muscle bulk, increased mucus-secreting cells, and increased airway vascularity (see Figure 39-2). In severe asthma, bronchiectasis, small airway fibrosis, and emphysema may be features. The bronchiectasis is associated with sensitization to Aspergillus.

History

Asthma symptoms typically are variable reflecting variability in airflow obstruction and other aspects of the disease. Exaggerated diurnal variation in physiologic bronchomotor tone causes airflow obstruction and symptoms at night, maximally at 4 AM. Other symptoms reflect airway hyperresponsiveness to a multitude of possible trigger factors. Symptoms occurring after exercise, after exposure to allergens, and in response to inhaled noxious fumes such as cigarette smoke are most commonly reported. Box 39-3 lists some of the symptoms that increase and decrease the probability of asthma. An assessment of disease severity can be made from the frequency of daily symptoms, exercise limitation, nocturnal wakening, and exacerbation frequency (Table 39-1).

The pattern of daytime symptoms and seasonal variations can help identify common triggers. In patients with adult-onset symptoms, the possibility of occupational asthma or an alternative diagnosis should be carefully explored. Symptoms that worsen at work but remit outside of the workplace should alert the clinician to the possibility of occupational asthma.

Clinical Examination

Findings on the clinical examination frequently are normal in persons with well-controlled symptoms. Patients with persistent symptoms may display features of obstructive airway disease, notably a hyperinflated and hyperresonant chest and diffuse polyphonic expiratory wheeze. These signs are indistinguishable from those found in chronic obstructive pulmonary disease (COPD). Physical examination is helpful for identifying features of an alternative diagnosis.

Measuring Variability in Airflow Obstruction

The spirogram frequently is normal in patients with asthma who are asymptomatic at the time of testing. In this clinical scenario, measurement of variability in airflow obstruction will provide useful additional information. A number of different methods exist to measure variability:

Diurnal variation in peak expiratory flow (PEF): Calculated from serial PEF measurements (see Figure 39-3); typically expressed as the difference between the highest and lowest daily readings as a percentage of the mean (see Table 39-1)

Assessment of the bronchodilator response: Measured as the change (improvement) in FEV₁ or PEF from baseline with either a short-acting bronchodilator (bronchodilator responsiveness) or after a therapeutic trial of corticosteroid (steroid responsiveness)

Assessment of airway responsiveness: Measuring the fall in FEV₁ in response to bronchoconstrictor stimuli, including pharmacologic agents (methacholine or histamine challenge tests), exercise, and allergen challenge (see Figure 39-1)

The measurement characteristics of the various tests to assess variable airflow obstruction and asthma in general are outlined in Table 39-1. An algorithm for the assessment of patients with suspected asthma is presented in Figure 39-4.

Figure 39-4 Algorithm for the initial investigation of suspected asthma. FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity.

Diagnostic Pathway

The diagnostic pathway followed will depend on the pretest probability for the diagnosis, response to therapy, and level of clinical suspicion for an alternative diagnosis. The scope of the differential diagnosis is quite different in patients with and without airflow obstruction (see Box 39-2), and the main diagnostic question also is different. In the former, the clinician often is seeking support for a clinical diagnosis of asthma and the initiation of antiasthma therapy; in the latter, the evidence for an airway problem is more clear-cut, and the question is not whether inhalers should be used but how intensive the corticosteroid component of that therapy should be.

The key point in the history is to establish that symptoms are variable and linked to airflow obstruction and/or variable eosinophilic airway inflammation. Problems arise when symptoms are clearly associated with infections. A prolonged postviral cough is common in otherwise healthy persons but also can be the presenting manifestation of asthma. Recurrent bouts of bronchitis in a patient with a long-standing chronic productive cough and focal coarse crackles should raise the possibility of bronchiectasis. Prominent dizziness, panic, peripheral tingling, light-headedness, and chest tightness are very suggestive of dysfunctional breathing.

Vocal cord or glottic dysfunction is an important condition that can cause serious diagnostic difficulty in both adolescents and adults and, if not recognized, unnecessary overtreatment. Wheezing that arises from the glottis is heard throughout the lung fields but also is easy to hear without the stethoscope, with prominent noises arising from the neck. Direct visualization of the glottis by laryngoscopy may reveal the characteristic inspiratory apposition of the cords. Sometimes persons who have asthma make this noise, because they subconsciously feel the need to impress on the examiner the severity of their condition. In other patients, the noise occurs for purely psychological reasons, and no evidence of asthma is found. Patients may be of either gender but are often women in the age range of 16 to 50 years, who may have a paramedical background. Their “asthma” seems “resistant” to standard treatments, and often they have been hospitalized on many occasions and been treated unsuccessfully with large doses of corticosteroids and other treatments. Home peak flow readings and attempts at spirometry may be variable but show little correlation with attacks or treatment. Flow-volume curves may show a characteristic “fluttering” of the inspiratory curve. Measurement of total airway resistance in a body plethysmograph may be diagnostic, because the panting maneuver necessary for such measurement abolishes the vocal cord adduction, and airway resistance can be shown to be normal. Occasionally patients end up being mechanically ventilated because of “severe” asthma, but once pharmacologic paralysis is achieved, it can be seen that airway resistance is normal and that there is no necessity for high inflation pressures.

Vocal cord dysfunction probably is much more common than has been appreciated and if the condition is underdiagnosed or the relevant symptoms are mistaken for asthma, overtreatment is likely. Correct diagnosis is essential, and if vocal cord dysfunction is the sole or major part of the wheezing disorder, speech therapy can be helpful.

Aims

Three major consequences of clinical importance in asthma are recognized, as reflected in the following management goals:

Both pharmacologic and nonpharmacologic measures play an important role in achieving these aims (Box 39-4; Figures 39-5 and 39-6).

Figure 39-5 Stepwise approach to asthma management in adults.

(Modified from British Thoracic Society/Scottish Intercollegiate Guidelines Network.)

Figure 39-6 The effect on management options on the goals of asthma therapy. *The prevention of exacerbations with long-acting β-agonists is only in conjunction with inhaled corticosteroids.

Pharmacotherapy in Asthma

Inhaled pharmacologic therapies are central to asthma management. The range of available drugs may be categorized mechanistically into bronchodilators and antiinflammatory agents.

Stepwise Algorithm for Asthma Treatment

Guidelines recommend the titration of therapy for asthma in a stepwise manner, with the primary aim of satisfactorily controlling symptoms at the lowest dose of corticosteroid (see Figure 39-5). Changes in therapy should be reviewed every 3 months until stability is achieved. This algorithm assumes clinical control is concomitantly associated with control of underlying airway inflammation and therefore fulfillment of all three targets of care.

Of note, step 3 of the British Thoracic Society (BTS) treatment pathway recommends the addition of a long-acting β-agonist to low-dose corticosteroid therapy over an increase in corticosteroid dose. There is molecular evidence for a synergistic effect between the two drug classes. In clinical practice, the strategy achieves clinical improvement, as indicated by reduction of symptoms, optimization of lung function, and a fall in exacerbation frequency, comparable with that provided by a dose escalation in corticosteroid alone. Combination inhalers of long-acting β-agonists and inhaled corticosteroids have been developed and are now commonly prescribed. They have the advantage of patient convenience but do not allow independent dose alterations of the component drugs.

Monitoring Asthma Control and Guided Self-Management Plans

A number of potential tools are available to assess asthma (see Table 39-1). All such tools assess different aspects of the disease, and it is likely that they provide complementary information. Objective symptom scores are particularly useful, because patients may adjust to their impairment and not question symptoms that are potentially reversible. The extent to which these assessments allow risk stratification is unclear; this is an important area for further study. Table 39-1 outlines the characteristics of some of the most common methods used to assess asthma.

Regular review appointments also provide an opportunity to review patient education, inhaler technique, and self management skills. Self-management plans are individualized written protocols instructing patients in recommended courses of action on the basis of their asthma control that is graded and risk-stratified according to symptoms or peak flow (Figure 39-7). They are attractive for being patient-centered. Both symptom- and peak flow–guided plans lessen asthma morbidity and reduce the frequency of hospitalizations and unscheduled doctor visits. Although little evidence has been found for the superiority of one strategy over another, a peak flow–based plan may be more appropriate in patients with impaired perception of airflow obstruction.

Figure 39-7 Page from a typical preprinted self-treatment plan.

(From Partridge MR: Asthma: clinical features, diagnosis, and treatment. In Albert RK, Spiro SG, Jett JR, editors: Clinical respiratory medicine, ed 3, Philadelphia, Mosby, 2008.)

Referral to a Specialist

Asthma often is managed very successfully in primary care. Patients for whom referral for specialist care typically will be required fall into three broad groups:

• Patients with suspected occupational asthma

• Patients with treatment-refractory asthma, defined as those failing to achieve control despite appropriate high-dose therapy (BTS step 4 or 5). Although constituting 5% to 10% of the asthma population, this group accounts for over 60% of health care resource utilization for asthma in the United Kingdom. The reasons for a poor therapeutic response are multifactorial (Box 39-5).

• Patients at higher risk for asthma-related death (Box 39-6). Relative risk is additive; accordingly, patients with several minor risk factors, as well as those with a single major risk factor, require referral.

Box 39-5

Factors Contributing to Refractory or Severe Asthma

Patient Factors

Disease Factors

Poor inhaler technique and incorrect use of inhalers Poor compliance with therapy Particularly in younger patients and those with psychological disorders Persistent exposure to sensitized allergen Occupation Pets Smoking Associated with increased symptoms, accelerated decline in lung function, and impaired steroid responsiveness Obesity Associated with increased symptoms and impaired steroid responsiveness Concomitant psychological morbidity Both anxiety and depression can heighten perception of breathlessness, leading to increased symptoms

Coexistent aggravating disorders

Dysfunctional breathing disorders

Rhinosinusitis

GERD

Cardiac failure

Aspergillus-associated asthma

Associated with more intense eosinophilic airway inflammation and bronchiectasis

Churg-Strauss syndrome

True steroid-resistant asthma

This subgroup constitutes a minority of patients with refractory asthma

High doses of oral or parenteral steroid usually overcome the impaired response to conventional therapy

Absence of demonstrable eosinophilic airway inflammation (noneosinophilic asthma)

Patients with this condition have corticosteroid resistance, so escalation of steroids unlikely to be helpful

Best management uncertain

GERD, gastroesophageal reflux disease.

Patient Education

Appropriate patient education is essential for the provision of care based on self-management. Several aspects of this component of the management program have been identified:

Specialist asthma nurses are central providers of information and education for patients. Regular follow-up with an asthma nurse reinforces key messages and leads to superior asthma control.

Inflammometry

Several important observations have increased interest in the use of inflammometry in the clinical assessment of asthma and other airway diseases. First, the presence of eosinophilic, corticosteroid-responsive airway inflammation is not closely related to either the pattern or the severity of the airway dysfunction or symptoms. A raised sputum eosinophil count is seen in 70% to 80% of corticosteroid-naive patients with asthma, 50% of corticosteroid-treated patients with symptomatic asthma, 30% to 40% of patients with cough, and up to 40% of patients with COPD. Within diagnostic groups, a weak correlation has been noted between the presence of eosinophilic airway inflammation and the severity of symptoms or disordered airway function. Thus, little can be deduced about the presence and severity of eosinophilic airway inflammation from a standard clinical assessment, and if this information is required, then measurement of the sputum eosinophil count is informative.

Second, the presence of eosinophilic airway inflammation is more closely associated with a positive response to corticosteroids than any other clinical measure. Moreover, a positive response to corticosteroids is seen irrespective of the pattern of airway disease in which eosinophilic airway inflammation occurs. Thus, if the clinical question were whether a patient with chronic respiratory symptoms should receive corticosteroid treatment, then the identification of a raised sputum eosinophil count or FENO would be a better basis for making this decision than the findings of other tests.

Third, the sputum eosinophil count is a better marker for titrating corticosteroid therapy than are standard clinical measures. Studies in asthma and COPD have shown that use of management strategies in which decisions about corticosteroid use and dose are guided by the sputum eosinophil count results in a lower frequency of exacerbations and more economical use of corticosteroids in comparison with management guided by traditional clinical measures. FENO measurements also have been used to guide corticosteroid treatment, but with more mixed results. Studies thus far have suggested that FENO-based management may allow more economical use of corticosteroids by more accurately identifying patients in whom reduced doses will suffice.

The link between eosinophilic airway inflammation and corticosteroid responsiveness, together with the development of inexpensive nitric oxide monitors, has opened the way for a new approach to the management of airway disease in clinical practice, with the emphasis more on assessing airway inflammation than on diagnostic labeling. Figure 39-8 outlines an approach to assessment of patients presenting with new-onset airway disease whereby decisions about the use of corticosteroids are based on assessment of eosinophilic airway inflammation or FENO, rather than on recognition of patterns of symptoms and airway dysfunction.

Figure 39-8 Suggested algorithm for assessment of airways disease. Eosinophilic airway inflammation can be assessed using induced sputum eosinophils or FENO. *Potentially treatable aggravating factors include rhinitis, anxiety-hyperventilation syndrome, vocal cord dysfunction, bronchiectasis, and gastroesophageal reflux disease. †Symptomatic therapy includes short- and long-acting bronchodilator therapy, oral theophylline, and mucolytics, as well as specific treatments for the aggravating factors. ‡As supported by limited evidence, some patients with symptoms suggesting airways disease have raised FENO that is not reflective of eosinophilic airway inflammation and is not corticosteroid-responsive. Therefore, a persistently raised FENO after corticosteroid treatment should prompt a more thorough assessment of airway inflammation using induced sputum specimens when available. The suggested cutoff points for “high” and “low” FENO in adults are 25 ppb and 50 ppb, respectively, but this is a very loose guideline. The interpretation of FENO in the range of 25 to 50 ppb varies between individual patients, and in some instances, different cutoff points may apply.

Single-Inhaler Therapy

The combination of budesonide and formoterol is licensed for use in a single combination inhaler for relief of symptoms and maintenance of asthma control. This dual role is made possible because formoterol is a long-acting β-agonist with a rapid onset of action, comparable with that of salbutamol. Thus, the frequency of inhaler use will be governed by the severity and frequency of symptoms, ensuring higher doses of corticosteroid during periods of poor control. This is appropriate if deteriorating symptoms are associated with worsening underlying airway inflammation. Studies have shown improvements in lung function, reduction in exacerbation frequency, and better symptom control with this approach. It may be particularly applicable in patients with variable treatment adherence.

Monoclonal Antibody Therapies

A growing number of monoclonal antibodies are being developed to target key proinflammatory mediators of the T_H2 pathway that are considered important for perpetuating inflammation in asthma. Of these, mepolizumab, a monoclonal antibody blocking IL-5 (a key cytokine responsible for eosinophil maturation and recruitment) has been shown to reduce the frequency of severe exacerbations in patients with severe asthma and eosinophilic airway inflammation. Trials exploring blocking antibodies to IL-4 and IL-13 and oral antagonists of the PGD₂ receptor CRTH₂ also are under way. It is likely that all of these agents will work best in the subgroup of patients with an eosinophilic T_H2-type pattern of airway inflammation and that the main benefits of treatment will be a reduction in frequency of asthma attacks. Identification of these patients by means of inflammometry will become increasingly important.

Bronchial Thermoplasty

Bronchial thermoplasty offers a nonpharmacologic approach to asthma treatment. The technique is targeted at the airway smooth muscle, which is considered central to airway dysfunction in asthma. Thermal energy is applied bronchoscopically to the bronchial wall using a wire basket. (A video of the procedure is available on Expert Consult.) Bronchial thermoplasty is thought to prevent bronchoconstriction by disrupting airway smooth muscle bundles. A sham-controlled study has shown improvement in asthma-related quality of life and reduced exacerbation numbers for at least a year after the procedure.

Severe Asthma

A proportion of patients will have persistent symptoms despite appropriate treatment for moderate persistent asthma as just outlined. Although representing a relatively small minority, these patients experience much morbidity, consume significant health care resources, and probably are best managed in specialist settings. Severe asthma can be defined simply as asthma that continues to cause significant morbidity despite high-level antiasthma therapy (i.e., step 4 of the BTS asthma management guidelines) (see Figure 39-5).

Before additional therapeutic measures are considered, it is important to accurately confirm the diagnosis, to ensure that persistent symptoms are due to asthma, rather than to other aggravating or coexisting factors such as dysfunctional breathing, vocal cord dysfunction, obesity, bronchiectasis, COPD, rhinitis, or gastroesophageal reflux (see Box 39-5). Box 39-3 lists some features that increase the probability that non–asthma-related factors are responsible for persistent morbidity. Next, it is important to assess compliance with existing therapy, ideally using relatively objective measures such as prescription refill rates and blood theophylline and/or prednisolone levels. Poor adherence is very common in patients with severe asthma and has been linked with poor outcomes, notably an increased risk of fatal and near-fatal attacks. The best means to detect poor treatment adherence and to tackle it have yet to be established. This is an important area for further study.

Once these issues have been addressed, current guidelines advocate a step up in treatment, usually to regular oral steroids. The response to oral steroids, however, is known to be mixed, and side effects are an important issue; moreover, the efficacy of alternative drugs in patients with severe asthma often has not been well established. Much of the current research effort in severe asthma focuses on patients with severe asthma, and there is increasing realization that new treatments are unlikely to be helpful in all patients. The future is likely to be individualization of treatment based on a more complete understanding of the mechanism of persistent morbidity and the ways in which this can be modulated.

Recently there have been attempts to identify clinically important groups of patients using mathematical techniques such as factor analysis and cluster analysis. Figure 39-9 shows the results of one of the first attempts to phenotype patients with asthma recruited from primary care practices and from a severe asthma cohort being seen in a specialist hospital clinic. The main finding was that patients with severe asthma had more marked discordance in expression of symptoms and airway inflammation. The presence of these discordant phenotypes in patients with refractory asthma in particular suggests that a management approach which relies on symptoms to guide antiinflammatory treatment would result in suboptimal outcomes in a significant number of patients and that management guided by an objective measure of corticosteroid-responsive inflammation (i.e., eosinophilic airway inflammation) may be better. This is exactly what has been found in trials that have compared inflammation-guided use of steroids with symptom-guided use. The main outcome of these trials has been a reduction in the frequency of asthma attacks, suggesting that the main clinical benefit of controlling eosinophilic airway inflammation is to reduce the risk of attacks.

Figure 39-9 Clinical phenotypes of asthma: A summary of phenotypes identified using cluster analysis in primary and secondary care asthma populations. The clusters are plotted according to their relative expression of symptoms and inflammation, because these are the two clinically pertinent and modifiable dimensions of the disease. The plot highlights greater discordance to be a feature of secondary care asthma. Although reasons for this dissociation are unclear, the use of measures of airway inflammation in these subgroups is clinically informative. BMI, body mass index.

(Reproduced with permission from Haldar P, Pavord ID, Shaw DE, et al: Cluster analysis and clinical asthma phenotypes, Am J Respir Crit Care Med 178:218–224, 2008.)

The recognition of these various groups of patients not only helps to guide corticosteroid treatment but also may identify patients for whom alternative noncorticosteroid treatments may be helpful. Long-term low-dose macrolide antibiotics may be particularly effective in patients with refractory noneosinophilic asthma. Bronchial thermoplasty, a treatment that specifically targets airway smooth muscle but has no known effect on airway inflammation, may also be a helpful treatment in patients with predominant airway dysfunction. Patients with inflammation-predominant disease, without much in the way of day-to-day symptoms or disordered airway function, may benefit from specific antiinflammatory treatments such as anti-IL-5, omalizumab, and, if they are sensitized to Aspergillus, antifungal treatment. Mepolizumab, the monoclonal antibody against IL-5, is a particularly attractive treatment option, because it is a very specific and effective inhibitor of the eosinophilic airway inflammation.

Aspirin-Induced Asthma

Around 5% of adults with asthma develop significant bronchoconstriction, often with rhinorrhea and urticaria, after ingesting aspirin and other cyclooxygenase inhibitors. Bronchoconstriction occurs as a consequence of inhibition of production of bronchoprotective prostaglandin E₂ and unchecked production of cysteinyl leukotrienes. Aspirin-induced asthma usually is seen in patients with nonatopic, adult-onset disease, many of whom have, in addition, rhinitis and nasal polyps (i.e., Samter’s triad). Patients tend to have severe eosinophilic airway inflammation that often is difficult to control with inhaled corticosteroids alone, and a high proportion of patients require, and do well with, oral corticosteroids taken either intermittently or continuously. Drugs blocking the production and action of leukotrienes may be particularly helpful in patients with aspirin-induced asthma.

Churg-Strauss Syndrome

Churg-Strauss syndrome is characterized by vasculitis and histologic evidence of extravascular granulomas in a patient with asthma and allergic rhinitis. The criteria for diagnosis of Churg-Strauss syndrome are summarized as follows:

Biopsy of easily accessible affected tissue can be helpful to confirm the presence of vasculitis and extravascular granuloma (Figure 39-10) but should not delay institution of treatment. Antineutrophilic cytoplasmic antibodies (ANCA) are present in two thirds of cases, but this finding is not specific. The key to prompt diagnosis is maintaining clinical awareness of the condition, especially in an adult patient who presents with allergic rhinitis, sinusitis, asthma, or an eosinophilia (which can be marked), together with systemic features such as fever, rash (especially lower limb purpura), weight loss, or arthralgia. Other features include pulmonary infiltrates, peripheral neuropathy, cranial and other isolated nerve palsies, cerebrovascular accidents, abdominal pain, bloody diarrhea, and, occasionally, intestinal perforation. Renal disease is uncommon, but cardiac involvement can occur and is a serious complication potentially leading to heart failure and sudden death. These manifestations of disease may develop over a short period, emphasizing the importance of a prompt diagnosis. The differential diagnosis clearly depends on the specific manifestation of Churg-Strauss syndrome occurring in the individual patient, but pulmonary manifestations may need differentiating from allergic bronchopulmonary aspergillosis, other pulmonary eosinophilias, pulmonary sarcoidosis, Wegener granulomatosis, microscopic polyangiitis, and polyarteritis nodosa.

Figure 39-10 Histopathologic features of Churg-Strauss syndrome (CSS). This photomicrograph shows a combination of parenchymal necrosis and focally marked tissue eosinophilia in CSS. The inflammatory infiltrate includes a combination of eosinophils and variable numbers of epithelioid histocytes in a vaguely granulomatous appearance.

(From Partridge MR: Asthma: clinical features, diagnosis, and treatment. In Albert RK, Spiro SG, Jett JR, editors: Clinical respiratory medicine, ed 3, Philadelphia, Mosby, 2008.)

In many cases, the response to steroids alone may be very good, and it is possible to achieve long-term control with low-dose prednisolone. With more aggressive disease, additional treatment with cyclophosphamide is necessary. Prognosis reflects the degree of severity of the disease and its manifestations, with the worst outcomes in patients with cardiac decompensation or cerebrovascular manifestations. The association of Churg-Strauss syndrome with the use of leukotriene antagonists has recently attracted attention. Although theoretically any drug may potentially induce a hypersensitivity vasculitis, the most likely reason for development of relevant problems after initiation of leukotriene antagonist is that improved control of the patient’s asthma has led to a reduction in oral steroid dose with subsequent unmasking of a previously silent systemic condition.

Aspergillus-Associated Asthma

The fungus Aspergillus is globally distributed and found in soil and decaying leaf mold and vegetable matter. Fungal spores are dispersed by the wind, and peak levels are found during the autumn and winter. Some patients with asthma develop an IgE- and IgG-mediated response to Aspergillus and other molds on repeated exposure. Patients who are highly atopic, have long-standing disease, and exhibit evidence of airway damage are at particular risk. Some develop the arbitrarily defined condition allergic bronchopulmonary aspergillosis (ABPA), which features, in addition to asthma and Aspergillus sensitivity, pulmonary eosinophilia and infiltration with an intense allergic reaction in the proximal airways. This reactivity can result in bronchial occlusion, which may give rise to segmental or lobar collapse and, especially if untreated, significant bronchial wall damage and development of bronchiectasis of the proximal airways (Figure 39-11). It is becoming clear that less well-developed forms of this condition are common, and the term Aspergillus-associated asthma is preferred. Up to 40% of patients with severe asthma have Aspergillus sensitization, and many grow Aspergillus in their sputum when this organism is looked for specifically.

Figure 39-11 Computed tomography scan of the thorax of a patient with bronchopulmonary aspergillosis. Significant proximal airway bronchiectasis is evident.

(From Partridge MR: Asthma: clinical features, diagnosis, and treatment. In Albert RK, Spiro SG, Jett JR, editors: Clinical respiratory medicine, ed 3, Philadelphia, Mosby, 2008.)

The following features should alert the clinician to the possibility of Aspergillus-associated asthma:

The combination of Aspergillus sensitization and colonization may be an important and potentially modifiable factor responsible for airway damage and the development of fixed airflow obstruction, and there is increasing interest in screening for this condition in patients with more severe disease. The acute syndrome associated with pulmonary infiltration is undoubtedly helped by oral corticosteroid therapy, and a maintenance regimen of inhaled steroids between attacks probably prevents recurrent attacks and preserves lung function. Long-term maintenance oral corticosteroid therapy may be necessary. Increasing evidence suggests that antifungal drugs (e.g., itraconazole 200 mg twice daily for 4 months) are effective in patients with aspergillus-associated asthma.

Occupational Asthma

Approximately 15% of patients with adult-onset asthma are thought to have occupational asthma. The causes, diagnosis, investigation, and management of occupational asthma are discussed in more detail in Chapter 40. The key point in the history is that symptoms are worse at work and better away from work, particularly with prolonged work absence during holidays. It should be possible to document this work effect objectively with PEF measurements done at work and away from work. A computerized analysis system is available online (see under “Web Resources”); this has been shown to be a valid means of diagnosing occupational asthma provided accurate and frequent (i.e., every 2 hours during waking hours) PEF readings are available. Occupational asthma results in considerable expense to the patient as a result of lost productivity, estimated to be in the order of £13 million in the United Kingdom over the course of his or her lifetime. Society contributes a similar amount, so reducing the incidence of occupational asthma is an important priority.

Work can aggravate preexisting asthma because of exposure to irritant stimuli (e.g., cold air) or can cause new-onset disease because the worker becomes sensitized to an occupational high- or low-molecular-weight sensitizer. Occupational asthma due to exposure to a sensitizer often occurs after the worker has been exposed for some time and is classically preceded by work-related rhinitis. This latent period is not seen with work-aggravated asthma. If the condition is recognized early, then removal of the worker from the occupational sensitizer can lead to complete remission; cessation of exposure is an important priority even if complete remission is not achieved. Environmental control with appropriate management of underlying asthma often is all that is needed in work-aggravated asthma. Asthma also can develop after sudden accidental exposure to a high concentration of toxic fumes, resulting in the so-called reactive airway dysfunction syndrome (RADS).

Asthma in Athletes

A high proportion of endurance athletes report symptoms suggesting asthma and have abnormalities of airway function consistent with this condition. Up to 50% of Olympics-standard swimmers and winter sport athletes report use of asthma treatment. The prevalence may be highest in athletes participating in these sports, because endurance exercise occurs in challenging environments. The pathophysiologic basis of airway dysfunction is incompletely understood but the injurious effect of pollution and cold air on the airway mucosa is likely to be important. Athletes with asthma tend to have noneosinophilic airway inflammation and respond poorly to inhaled corticosteroid treatment.

Asthma in Pregnancy

Asthma may worsen, stay the same, or improve during pregnancy. The pattern may be repetitive in subsequent pregnancies. For women who experience a worsening of asthma, this is likeliest in the second and third trimesters; problems during labor are extremely unusual. Treatment for asthma should be the same during pregnancy as in the nonpregnant state, except that leukotriene antagonists should not be initiated during pregnancy. In the absence of appropriate advice, those with asthma may stop their medication on discovering they are pregnant, and it is important that pregnant women are reassured as to the safety of usual asthma treatment. After delivery, breast-feeding should be encouraged; none of the commonly used asthma medications are secreted in breast milk to the degree that any alteration in treatment is necessary.

Asthma Attacks

Asthma attacks are the third leading cause of preventable admissions to the hospital, and are responsible for more than 5000 deaths per year in the United States and 1500 deaths per year in the United Kingdom. Attacks are often not acute. In around half of patients the asthma attack has often been developing for days or weeks and there have been many opportunities to alter their treatment to prevent deterioration to crisis levels. Thus, undertreatment or inappropriate therapy is an important contributor to asthma morbidity and mortality.

People who have asthma die because they, their loved ones, or their doctors underestimate the severity, because of delays in seeking medical treatment, and because of underuse of oxygen and corticosteroid tablets. The severity of an exacerbation must therefore be carefully assessed, and the outcome determines the therapy given and the optimal treatment setting. Box 39-7 and Table 39-2 show features associated with exacerbations of asthma of mild, moderate, severe, or critical nature. All but the mildest attacks require treatment with bronchodilators, corticosteroids, and oxygen, with careful follow-up and assessment of responses to each intervention (Figure 39-12). Non–life-threatening asthma can be treated initially with four to six puffs of salbutamol from a pressurized metered dose inhaler (pMDI) with a large-volume spacer plus ipratropium, four puffs from a pMDI with large-volume spacer, both repeated as necessary every 10 to 15 minutes. A good response with symptom relief and an improvement in PEF to greater than 80% of the patient’s best is followed by continuing regular β-agonists every 4 hours for 24 to 48 hours, a four-fold increased dose of inhaled corticosteroids for at least 7 days, and careful review of the patient’s disease control status within days.

Figure 39-12 Algorithm for management of patient with acute severe asthma presenting for emergency care. IV, intravenous.

(From Partridge MR: Asthma: clinical features, diagnosis, and treatment. In Albert RK, Spiro SG, Jett JR, editors: Clinical respiratory medicine, ed 3, Philadelphia, Mosby, 2008.)

In life-threatening asthma, bronchodilators (albuterol [salbutamol] 5 to 10 mg and ipratropium bromide 0.5 mg) are administered by a nebulizer. All patients with life-threatening asthma and patients with non–life-threatening asthma who have an incomplete response (PEF 50% to 80% of predicted or best) with persistent symptoms require continuation of β-agonists every 2 to 4 hours and prompt addition of oral corticosteroids (prednisolone 30 to 40 mg once daily for 7 to 14 days). Either hospitalization is arranged or the patient is seen again urgently (the same day or the next morning).

A chest radiograph is indicated and should be performed if there is suspicion of additional intrathoracic pathology such as a pneumothorax or infective consolidation that will require additional therapeutic measures, if the patient fails to respond or deteriorates after initial therapy, or if the asthma attack is life-threatening or mechanical ventilation is being considered. If the blood oxygen saturation (SaO₂) does not reach 92% with the patient breathing room air or if the PEF is less than 100 L/min, arterial blood gas analysis is indicated. Patients with features of severe disease (see Table 39-2) should be referred urgently for intensive care monitoring. The first warning of this level of acuteness may be a normal or raised arterial partial pressure of carbon dioxide (PaCO₂) on blood gas sampling. Repeat blood gas sampling should be done in patients who are not clearly improving or appear to be deteriorating.

A single dose of magnesium sulfate (1.2 to 2 g intravenous infusion over 20 minutes) has also been shown to be safe and effective in severe asthma attacks and there is preliminary evidence that inhaled magnesium can be helpful when added to nebulized salbutamol. Intravenous aminophylline, 250 mg given slowly over 20 minutes followed by an infusion of 0.5 mg/kg/hour, is widely used if the patient is not taking regular oral theophyllines, although this practice is not strongly evidence-based.

Once clinical recovery has been achieved, the following criteria for successful management should be ascertained at discharge of the patient from the hospital:

The reason(s) for the exacerbation and admission must be determined and details sent to the primary care physician, together with a discharge plan and potential best PEF. Patients need to be given clear advice on how long to continue corticosteroid tablets, which should be continued in full dose until clinical stability is achieved and then either stopped suddenly (if the patient was not previously on corticosteroids and has taken them for less than 2 weeks) or tapered off.

Every attack of severe asthma and every hospital admission or emergency department visit must be regarded as a sign of failure of that patient’s previous asthma management. Patients presenting with acute severe asthma are at high risk for recurrent attacks and have a poor prognosis, often reflecting poor self-management skills. After successful medical management of the attack, a full review of the lessons that can be learned from the attack is warranted, and a self-management plan for the future should be formulated and communicated to the primary care physician. The most important elements of the management plan are illustrated in Figure 39-7.