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.