Pathophysiology

A variety of airway alterations occur in asthma, but airway inflammation is the final common pathway limiting airflow. Allergens and nonallergic stimuli (e.g., exercise; aspirin-induced and menstrual-related asthma) induce bronchoconstriction via release of mediators and metabolic products from inflammatory cells. Compared with healthy individuals, patients with asthma show bronchial hyper-reactivity (hyper-responsiveness) in response to bronchoconstricting stimuli (e.g., methacholine). Edema, inflammation, mucous production, and airway smooth muscle hypertrophy contribute to bronchoconstriction and hyper-reactivity and further airway obstruction and airflow limitation. Permanent structural airway changes (airway remodeling) may contribute to increased airway obstruction and hyper-responsiveness and decrease the response to therapy. The interaction of these features determines the clinical manifestations and severity of asthma and significantly influences the response to therapy.

Evidence that inflammation is a component of asthma physiology was initially derived from autopsy findings in patients with fatal asthma. The airways revealed infiltration by neutrophils, eosinophils, and mast cells and the presence of subbasement membrane thickening, loss of epithelial cell integrity, goblet cell hyperplasia, and mucous plugs. Antemortem bronchial biopsy findings in patients with even mild degrees of asthma also demonstrate inflammatory changes in the central and peripheral airways that correlate with disease severity.¹³ Inflammatory and chemotactic cytokines produced by both resident airway and recruited inflammatory cells are identified in bronchoalveolar lavage washings and pulmonary secretions.

Asthma has been divided into allergic and nonallergic types based on the presence or absence of immunoglobulin E (IgE) antibodies to common environmental antigens (pollen, dander, mites) and microbiologic antigens (bacteria, viruses). Immunologic responses suggest an acquired cause of asthma, whereas the absence of an immunologic response suggests an innate cause. Exposure to microbes and allergens (or lack of) during childbirth, infancy, and childhood may influence expression of the asthma phenotype later in life (the hygiene hypothesis).14–16 Trigger factors precipitating acute asthma exacerbations are typically environmental or viruses, but a specific inciting agent may not be identifiable. Regardless of an allergic or nonallergic basis, both forms of asthma are characterized by infiltration of the airways by T-helper cells that release cytokines such as interleukin (IL)-4, IL-5, and IL-13, stimulating basophil, eosinophil, mast cell, and leukocyte migration to the airways. Release of inflammatory cell mediators results in bronchospasm, mucous production, airway edema, and amplification of the inflammatory response.

Mast cells are found in airway mucosa and submucosa, and increased numbers are identified in and around airway smooth muscle and airway mucous glands. Mast cell activation occurs via cross-linking of antigen and surface-bound IgE. Nonimmunologic activation by cytokines, complement, proteases, and local hyperosmolality also occurs.¹⁷ Mast cells release histamine, prostaglandin D₂ (PGD₂), and leukotriene C₄ (LTC₄), leading to bronchospasm, mucous production, and airway edema and causing acute symptoms (the early asthmatic response). Cytokines produced by mast cells result in airway smooth muscle hyper-responsiveness, eosinophil recruitment, and IgE synthesis. Mast cells release proteases that damage airway epithelium and contribute to airway remodeling. Tumor necrosis factor alpha (TNF-α) is a potent bronchoconstrictor produced by mast cells. In chronic asthma there is evidence of persistent mast cell activation resulting in continuous mediator release, cytokine production, and amplification of airway inflammation.¹⁸ The presence of mast cells in airway smooth muscle contributes to propagation of the inflammatory response, persistent bronchoconstriction, and over time, airway smooth muscle hypertrophy that plays a role in airway remodeling.^19,20

Eosinophils are major effector cells in asthma, and their presence is evidence of the allergic nature of this disease. Increased numbers of eosinophils are found in the airways of most but not all asthmatics.²¹ Eosinophils contain granules that release inflammatory mediators, including major basic protein, eosinophil cationic protein, and eosinophil peroxidase. Major basic protein is a potent bronchoconstrictor. Eosinophil cationic protein increases airway mucous production and causes histamine release from mast cells. Leukotrienes (LTs) produced by eosinophils are bronchoconstrictors and promote the secretion of thick viscid mucus, leading to airway plugging, LTs also enhance airway vascular permeability, leading to airway edema. Platelet-activating factor, superoxides, and free radicals produced by eosinophils also cause bronchospasm and bronchial tissue injury. Eosinophilic mediators damage and cause desquamation of the airway epithelium, expose nerve endings, provide submucosal access for inflammatory cells and mediators, and negate epithelial cell regulation of the inflammatory process.

Although eosinophils appear to be important in airway allergic and inflammatory processes, eosinophilia is not universal in asthmatics. Confounding the role of the eosinophil are studies with anti–IL-5 that significantly reduced sputum and blood eosinophilia but did not significantly affect asthma control.22,23 Clinically, eosinophils are important biomarkers in predicting response to corticosteroid therapy. Steroid-naïve asthmatics with sputum eosinophilia have a good response to inhaled corticosteroid (ICS) therapy, whereas those without sputum eosinophilia do not.^24–26 Suppressing sputum eosinophilia with oral or inhaled steroids reduces the number of acute exacerbations in patients with severe asthma.^17,27

Mediator and cytokine release from mast cells, eosinophils, and other airway inflammatory cells (macrophages, lymphocytes, basophils, neutrophils) contributes to prolonged bronchial smooth muscle spasm, edema, and mucous production (the late asthmatic response). Ongoing synthesis and release of cytokines, prostaglandins (PGs), and LTs (Fig. 73-4) are responsible for propagation and intensification of airway inflammation and disruption of the airway epithelial border.²⁸ Airway epithelial cells are more than a passive barrier and are recognized to produce proinflammatory mediators. Tight junctions between airway epithelial cells are altered in asthma, which may allow access of allergens, microbes, and viruses into the airway submucosa. Inflammatory cells, mediators, and airway viruses can directly damage the epithelial barrier and stimulate airway epithelial cells to produce inflammatory mediators. Abnormal repair processes may further airway inflammation and obstruction and contribute to airway remodeling.^29,30 Nitric oxide (NO) produced by airway epithelial cells in the large and small airways and alveoli is a reflection of ongoing airway inflammation. Measurements of fractional exhaled nitric oxide (FENO) may prove useful for monitoring the response to asthma therapy.³¹

Airway remodeling refers to the persistent structural changes in airways seen in patients with asthma and is caused by the presence of repetitive or chronic airway inflammation. Microscopic remodeling features include epithelial thickening, subepithelial fibrosis, mucous gland metaplasia, increases in airway smooth muscle, angiogenesis, and loss of cartilage integrity.³² Airway remodeling occurs very early in asthma (childhood) and may precede clinical symptoms.^14,33 Remodeling features are prominent in patients with severe asthma.³⁴ Basement membrane thickening may be protective by preventing inflammatory cells and proteins from entering the airway submucosa through a damaged epithelium; simultaneously, this process may be counterproductive by reducing the elasticity of the small airways. Airway remodeling may explain the resistance to therapy observed in patients with prolonged asthma histories and the decline in pulmonary function noted with age. Airway remodeling induced by chronic inflammation may lead to the development of chronic irreversible airflow limitation and increased asthma mortality.

The clinical implications of the immune and inflammatory nature of the early and late asthmatic responses are crucial because therapy may be directed differently toward each phase. Mast cell stabilizers (e.g., beta-agonists) are more effective in the early asthmatic response but are of less use later in the course of an exacerbation. Anti-inflammatory therapy (e.g., corticosteroids, LT antagonists) is more effective in the late asthmatic response. Interference with or inhibition of cytokine activities, suppression of chronic inflammation, and modulation of airway remodeling are potential therapeutic targets.

Pathology

The pathology of the asthmatic airway reflects the inflammatory process described earlier. Mucous gland hyperplasia and viscous mucous plugs in the smaller airways are present. Airway secretions reveal increased numbers of inflammatory cells. Airway epithelial damage and remodeling are evident. In contrast to patients with mild to moderate asthma, patients with acute severe asthma have extensive mucous hyperplasia, subepithelial thickening, and infiltration of inflammatory cells (particularly eosinophils).⁵³

Necropsies of patients with status asthmaticus reveal grossly inflated lungs that may fail to collapse on opening of the pleural cavities. Histologic examination reveals luminal plugs consisting of inflammatory cells, desquamated epithelial cells, and mucus. Marked thickening of the airway basement membrane, submucosal inflammatory cells, increased deposition of connective tissue, mucous gland hyperplasia, and hypertrophy of airway smooth muscle are also observed. Reports of slow-onset asthma fatalities reveal greater bronchial eosinophilia and basement membrane thickening when compared with rapid-onset fatal asthma.54,55 Reports of rapid-onset fatal asthma describe less mucus in the airway lumens, suggesting that terminal events may be dominated by bronchoconstriction without excessive luminal plugging; however, an alternative view is that “dry airways” are more reflective of postmortem tissue processing.⁵⁵

National and International Guidelines for the Diagnosis and Management of Asthma

In response to the increasing prevalence of asthma, many countries publish guidelines. Some of these, including NAEPP (National Institutes of Health [NIH]) Expert Panel Report 3 (EPR-3), devote specific portions to the management of acute exacerbations of asthma.¹ A task force of physicians representing the American Academy of Asthma, Allergy and Immunology, the American Academy of Emergency Medicine, and the American Thoracic Society (ATS) have summarized the aspects of the EPR-3 that are relevant for the ED and have developed evidence-based recommendations for acute care gaps in the NIH national guidelines. These include (1) use of noninvasive ventilation, (2) use of intubation and mechanical ventilation, (3) appropriate discharge medications, and (4) techniques for ensuring proper follow-up after an ED visit. These additional acute care recommendations were simultaneously published in 2009 in supplemental issues of Journal of Allergy and Clinical Immunology (volume 124, issue 2), Journal of Emergency Medicine (volume 37, issue 2), and Proceedings of the American Thoracic Society (volume 6, issue 4). The EPR-3 and task force recommendations are graded from levels A through D based on the strength of the scientific evidence.

ED concordance with the EPR-3 treatment recommendations is reported as moderate, with significant regional variations in quality of care.⁵⁶ In addition, ED overcrowding is associated with longer lengths of stay for acute asthma exacerbations.⁵⁷

Symptoms

Most patients with acute asthma have a constellation of symptoms, including cough, dyspnea, and wheezing. Cough often begins early in the attack, may be the sole manifestation of the disease in cough-variant asthma and elder patients, can be associated with sputum production, and is probably the result of subepithelial vagal stimulation. Nocturnal worsening is common, with most patients reporting cough or wheeze at least once per week. Nighttime mortality is higher than in the general population.

Although increased airway resistance, diminished flow rates, and increased bronchial hyperactivity are contributing factors, asthmatic patients who come to the ED with nocturnal asthma attacks have disease severity similar to that of other asthmatics. Up to 40% of asthmatic women experience premenstrual worsening of symptoms, which peak 2 to 3 days before menses and are associated with more severe disease; ED visits increase during the preovulatory and perimenstrual intervals.⁵⁸

There are interindividual differences in the dyspnea perceived by asthmatic subjects for the same level of airway narrowing. This difference results in poor correlation of symptoms with airway obstruction as determined by pulmonary function testing (PFT), both chronically and on presentation to the ED. Patients with a blunted perception of dyspnea (the “poor perceivers”) have more ED visits, hospitalizations, and near-fatal and fatal asthma attacks.⁵⁹

Wheezing reflects air movement velocity and turbulence, and its intensity varies according to the radius of the bronchi. With severe airway obstruction, it decreases or vanishes because air movement velocity is insufficient to produce sound.

Many asthmatics report symptoms of gastroesophageal reflux that may cause airway narrowing through a vagally mediated pathway or microaspiration. Proton pump inhibitor therapy decreases asthma symptoms in these patients. Approximately 80% of patients with asthma have symptoms of rhinitis. Approximately 5 to 15% of patients with perennial rhinitis have asthma, and control of sinonasal inflammation can lead to asthma improvement. Overweight (body mass index [BMI] of 25 kg/m² or higher) asthmatics have poorer asthma control, higher admission rates, and a greater risk of complications, possibly secondary to a difference in the perception of dyspnea or in response to asthma controller agents.60,61 In addition, obese patients have different bronchial and systemic inflammatory characteristics and a specific pattern of pulmonary function changes, suggesting a different asthma phenotype.⁶²

One third of patients who come to the ED with acute asthma are current cigarette smokers, and these patients have poorer asthma control and greater acute care needs than lifelong nonsmokers or former smokers.63,64 African Americans with acute asthma have lower flow rates and more potentially life-threatening episodes than whites, but they respond equally well to albuterol.⁶⁵ There are no racial disparities in inpatient asthma care when comparing whites, blacks, and Hispanics.⁶⁶

Lastly, as asthma can appear at any age, including the ninth decade, wheezing and dyspnea may be misascribed by both patients and physicians to heart failure, bronchitis, chronic obstructive pulmonary disease (COPD), occupational lung disease, or poor exercise capacity.

Historical Components

Slow-onset asthma with progressive deterioration over a period of at least 6 hours (usually days) occurs in over 80% of cases. This type has a female predominance, is triggered by upper respiratory tract infections, and has an airflow inflammation mechanism that results in a slower response to treatment. Sudden-onset asthma with rapid deterioration in less than 6 hours occurs in less than 20% of cases. This type has a male predominance, is triggered by respiratory allergens, exercise, and psychosocial stress, and has a bronchospastic cause resulting in more severe airway obstruction with a faster response to therapy.⁶⁷

Risk factors for death from asthma are important to determine and are listed in Box 73-1.^1,68–71 In urban areas, heroin and cocaine abuse are commonly associated with life-threatening asthma requiring noninvasive positive-pressure ventilation (NIPPV) or intubation in the ED.^70,71

The brief history pertinent to the current exacerbation should include onset and possible triggers, severity of symptoms especially as compared with previous exacerbations, and other comorbidities (especially those that may be worsened by systemic corticosteroids such as diabetes, peptic ulcer, hypertension, and psychosis). In addition, all current asthma medications should be noted, including times and amounts recently used, and any potential asthma exacerbators such as aspirin or NSAIDs, beta-blockers (including topical agents used for glaucoma), and angiotensin-converting enzyme inhibitors. Cardioselective and nonselective beta-blocker use increases hospitalizations and ED visits.⁷²

Physical Assessment

Patients with mild acute asthma usually speak in sentences, those moderate asthma in phrases, and those with severe asthma in words. Although alterations in mentation indicate severe asthma, restlessness and agitation do not reliably indicate hypoxia or hypercapnia. Patients who sit upright have severe airway obstruction; cyanosis is uncommon because of the left shift of the oxyhemoglobin dissociation curve produced by respiratory alkalosis. Diaphoresis can be seen secondary to the work of breathing, but if profound may be preterminal.

Tachypnea and tachycardia are associated with severe obstruction, but a lower rate does not rule out severe asthma. The respiratory rate correlates poorly with PFT and indicates severe obstruction if it is higher than 40 breaths/min.

A pulsus paradoxus or inspiratory fall in systolic blood pressure greater than 10 mm Hg usually signifies severe disease, but its absence does not exclude severe disease. Its use predates bedside pulmonary function tests, which are more accurate and reliable. When pulsus paradoxus is present, it may disappear with minimal improvement in airflow through larger airways. Similarly, use of accessory muscles of respiration (sternocleidomastoid and scalenus muscles) is not prognostic.

Wheezing does not designate the presence, severity, or duration of asthma. It correlates poorly with the degree of functional derangement and may be absent when maximal effort produces minimal airflow. Physical examination may help to identify such complications of asthma as pneumonia, pneumothorax, or pneumomediastinum.

Pulmonary Function Studies

The severity of airflow obstruction cannot be accurately assessed from symptoms and physical examination alone.⁷³ Physicians initially tend to underestimate the degree of airway obstruction in acute asthma. Therefore routine PFT should be part of ED assessment and monitoring. The forced expiratory volume in 1 second from maximal inspiration (FEV₁) or the PEFR in liters per second, starting with fully inflated lungs and sustained for at least 10 msec, may be used. Both measurements require the patient’s cooperation for maximal effort and are effort dependent. Whenever possible, the best of three consecutive values should be recorded. Any patient not able to perform a pulmonary function study should be considered to have severe airway obstruction.

Although FEV₁ can be adequately measured in most acutely ill asthmatics to meet modified ATS performance goals,⁷³ most assessments in the ED use single-patient-use portable peak flow meters because PEFR is easier to measure. The identical device should be used to assess then reassess an individual patient, and different portable meters should not be used interchangeably. Lastly, the FEV₁ and PEFR measurements are not interchangeable in assessing acute airway obstruction, which is not addressed in all management guidelines. Although absolute PFT measurements can be used, percentage of predicted performance (% predicted) values are preferable to account for age (now to age 85), sex, and height.

Arterial Blood Gas Analysis

Equilibration of oxyhemoglobin saturation occurs within 3 to 4 minutes of initiation or alteration of supplemental oxygen during an acute asthma attack. Stimulated hyperventilation leads to a modest fall in the partial pressure of carbon dioxide in arterial blood (PaCO₂). As airway obstruction increases, the PaCO₂ normalizes (PFT values 15-25% predicted) and then increases (PFT values <15% predicted) with worsening hypoxemia. Because neither pretreatment nor post-treatment arterial blood gases (ABGs) correlate with PFTs or predict clinical outcome, ABG determination is rarely clinically useful in acute asthma exacerbations unless oxygen saturation cannot be obtained reliably via pulse oximetry.

ABG sampling should be limited to a subset of patients with predicted PFT values of less than 30%, whose clinical course is perplexing, and for whom capnography is not available. Occasionally, despite improvement in PFT values with bronchodilator therapy, some patients have a transient fall in the partial pressure of oxygen in arterial blood (PaO₂) secondary to pulmonary vasodilatation and worsening ventilation-perfusion mismatch.⁷⁴ The assessment of ventilation may be simplified because there is a high concordance between end-tidal partial pressure of CO₂ (PCO₂) measured by capnography and the PaCO₂ obtained with ABG measurements.⁷⁵ Also, capnographic waveform analysis can indicate improvements in airway diameter in acute asthma and has the advantages of being effort independent and providing continuous monitoring.⁷⁶

Other Blood Testing

Laboratory studies rarely are helpful in evaluating the patient with an acute asthma attack. Leukocytosis is common with acute asthma exacerbation but is not of discriminatory value in detecting acute superimposed pulmonary infection. Corticosteroids and catecholamines demarginate polymorphonuclear leukocytes after 1 to 2 hours, and patients on chronic steroid therapy may have normal or significantly elevated white blood cell (WBC) counts.

Serum electrolytes are not primarily altered unless the patient is taking corticosteroids or diuretics or has cardiovascular disease and is receiving aggressive beta₂-agonist therapy. Frequent albuterol treatments can cause transient hypokalemia, hypomagnesemia, and hypophosphatemia, but this is rarely of clinical significance. The rare asthmatics undergoing chronic theophylline therapy should be assessed for possible toxicity. In the older asthmatic with cardiovascular comorbidities, measurement of the B-type natriuretic peptide (BNP) level may reveal unrecognized congestive heart failure.

Radiology Studies

A chest radiograph is of little value in most acute asthma exacerbations and should be restricted to patients with a complicating cardiopulmonary process, such as pneumonia, pneumothorax, pneumomediastinum, or congestive heart failure. Also, patients who do not respond to optimal therapy and require hospital admission have a higher likelihood of radiographically identifiable, unsuspected, clinically significant pulmonary complications of asthma (15% of cases).

Electrocardiogram and Cardiac Monitoring

The electrocardiogram (ECG) is selectively helpful in assessing patients with chest pain or a history of significant cardiovascular disease, in whom the asthma attack may be a physiologic stress test. In patients with severe asthma, the ECG may show a right ventricular strain pattern that reverses with improvement in airflow. Older patients, especially those with coexistent heart disease or with severe exacerbation, could require continuous cardiac monitoring to detect dysrhythmias. All patients with severe hypoxemia, and those for whom intubation is contemplated, should receive continuous cardiac monitoring.

Future Monitoring Strategies

Noninvasive monitoring of bronchial inflammation may customize the ED assessment of acute asthma. This may include measurement of biologic biomarkers, such as cytokine profiles in the blood, evaluation of LTE₄ in the urine, and the monitoring of exhaled pentane, hydrogen peroxide, NO, or carbon monoxide levels. Of these measurements, exhaled NO, a marker of airway inflammation, shows the most promise, as studies show that FENO can be measured in the ED with good reproducibility, and levels measured after 6 hours of care are associated with better asthma control after discharge.77,78

Assessment Summary

The severity of airflow obstruction cannot be accurately judged by patients’ symptoms, physical examination findings, and laboratory test results. Serial measurements of airflow obstruction (FEV₁ or PEFR) are key components of disease assessment and response to therapy (Table 73-1).