stimulation of the irritant receptors.

Respiratory tract infection

Respiratory tract infection is an exacerbating factor for patients with either nonallergic or allergic asthma. Viral infections are the most common causes in this category, but bacterial infections of the tracheobronchial tree also can be implicated. The mechanism by which respiratory infections precipitate bronchoconstriction in persons with asthma is not entirely clear but is likely related to epithelial damage and airway inflammation. Potential consequences of epithelial injury include release of mediators from inflammatory cells, stimulation of irritant receptors, and nonspecific bronchial hyperresponsiveness.

Exercise

Exercise can frequently provoke bronchoconstriction in patients with hyperreactive airways. The crucial factor in the pathogenesis appears to be heat movement from the airway wall, resulting in cooling and drying of the airway. During exercise, individuals have a high minute ventilation, and the large amounts of relatively cool and dry inspired air must be warmed and humidified by the tracheobronchial mucosa. When the air is warmed and humidified, water evaporates from the epithelial surface, resulting in cooling and drying of the airway epithelium. The phenomenon of exercise-induced bronchoconstriction can be reproduced by having a person with asthma voluntarily breathe cold dry air at a high minute ventilation. Inhalation of warm saturated air at the same minute ventilation does not produce a similar effect. The mechanism that links airway cooling and drying with bronchoconstriction is less clear. Alteration of the ionic environment after drying of the mucosa, mediator release, hyperemia of the mucosa following airway rewarming, and stimulation of irritant receptors have all been proposed as mechanisms, but none is universally accepted.

Airway cooling and drying are important in exercise-induced bronchoconstriction.

As might be expected from the description of exercise-induced bronchoconstriction, inhalation of cold air during the winter months can cause asthma exacerbations or worsening of symptoms in selected patients. The mechanism of airway narrowing in these patients following inhalation of cold air is also believed to be due to airway cooling and drying and is therefore analogous to the mechanism of exerciseinduced bronchoconstriction.

Pathology

Pathologic findings in asthma traditionally have been described from autopsy studies and thus represent the consequences of particularly severe disease. In these cases, marked overdistention of the lungs is seen, and the airways are occluded by thick, tenacious mucous plugs. However, information regarding the histologic appearance of airways in patients with stable mild disease more recently has become available. Examination of the airways by microscopy demonstrates the following findings of variable severity that are apparent in both mild and more severe disease:

1.Edema and cellular infiltrates within the bronchial wall, especially with eosinophils and lymphocytes

2.Epithelial damage, with a “fragile” appearance of the epithelium and detachment of surface epithelial cells from basal cells

3.Hypertrophy and hyperplasia of the smooth muscle layer

4.Increased deposition of collagen in a layer beneath the epithelium (referred to in the past as

which may be greater than 200% of the predicted value. The increase in RV is believed to be due to premature small airway closure with expiration as a result of smooth muscle constriction, mucous plugs, and inflammatory changes of the mucosa.

FRC, the resting point of the lungs at the end of expiration, is increased in the setting of an asthma flare due to air trapping. In addition, patients may experience dynamic hyperinflation because more time is required for expiration when airways are obstructed, and patients may not have sufficient time before the next breath to fully exhale the volume from the previous breath. Dynamic hyperinflation is a particular problem when the person with asthma is breathing at a rapid respiratory rate. During an asthma exacerbation, it is also hypothesized that patients have persistent activity of the inspiratory muscles during expiration, maintaining lung volume at a level higher than expected throughout expiration. A physiologic advantage to breathing at higher-than-normal lung volumes is having airways held open at a greater diameter. A disadvantage is increased work of breathing due to reduced compliance of the respiratory system at higher lung volumes (see Fig. 1.3C) and a mechanical disadvantage for diaphragmatic function when the diaphragm is lower and flatter (see Mechanisms of Abnormal Gas Exchange in Chapter 6).

The focus so far has been on pulmonary function and physiologic abnormalities seen with a typical asthmatic attack. Between attacks, pulmonary function, as measured by FEV1 and FVC, often returns to normal. However, even when a person is not having an acute attack, subtle abnormalities in pulmonary function may be present, such as a decrease in maximal midexpiratory flow rate and a mild increase in RV. These abnormalities may reflect some residual disease in the small airways of the lung, frequently the last region to become normal after an attack.

A subgroup of persons with asthma, generally those with long-standing disease, have pulmonary function that does not return fully to normal. Instead, they have demonstrable physiologic abnormalities (e.g., abnormal FEV1 and FVC) that persist between attacks. Even though asthma is generally characterized by reversible episodes of airflow obstruction, these individuals also appear to have a component of irreversible disease, particularly after decades with asthma. Nevertheless, they still generally experience episodes of reversible airflow obstruction and worsening of expiratory flow rates superimposed upon whatever irreversible disease is present.

The increased resistance to airflow in asthma exerts a toll on gas exchange, which is generally disturbed during acute attacks. The most common pattern of arterial blood gases consists of a low PO2 accompanied by a low PCO2 (respiratory alkalosis). The mechanism for the hypoxemia is ventilationperfusion mismatch. The increased airway resistance in asthma is not evenly distributed, such that some airways are affected more than others. Therefore, inspired air is not distributed evenly but tends to go to less diseased areas. However, blood flow remains relatively preserved in the regions that are ventilating poorly due to the suppression of normal hypoxic vasoconstriction by inflammatory mediators. The regions

of low ventilation-perfusion ( ) ratio contribute blood with a low PO2 that cannot be compensated for

by increases in the ratio from other regions of the lung (see Chapter 1).

Patients are typically able to hyperventilate if an acute asthma attack is not too severe, and PCO2 is usually low. The stimulus or mechanism for the hyperventilation is not clear. During an acute attack, activation of irritant receptors may stimulate ventilation, or other reflexes originating in the airways, lung, or chest wall may stimulate ventilation. PCO2 that increases to either a normal or a frankly elevated level often indicates worsening airflow obstruction or fatigue of the respiratory muscles in a tiring individual who is no longer able to maintain normal or high minute ventilation in the face of significant airflow obstruction. Thus, the clinician should view a normal or high PCO2 as a potentially serious warning sign of progressive respiratory failure.

may require assisted ventilation, and may even die as a result of the acute attack.

The overall severity of an individual’s asthma can be characterized based on the frequency of exacerbations, nocturnal symptoms, and magnitude of abnormality and variability in pulmonary function. The features used to define four categories of severity (intermittent asthma, mild persistent asthma, moderate persistent asthma, and severe persistent asthma) are listed in Table 5.3.

TABLE 5.3

Classification of Asthma by Severity: Clinical Aspects and Treatment