Asthma and Other Allergic Disorders
From WiserWiki
[edit] Asthma and Other Allergic Disorders
Richard M. Effros
Jack Kaufman
[edit] BRONCHIAL ASTHMA
Bronchial asthma is a clinical disorder in which the airways are hyperreactive to a variety of stimuli. After exposure to these stimuli, airway resistance increases because of smooth muscle contraction, increased secretions, and inflammation of the bronchial walls. In contrast to the relatively fixed airway obstruction encountered in emphysema, increased airway resistance in asthma is episodic and improves between attacks. During remissions the patient may be essentially asymptomatic, but in more severe forms of the disease, some bronchospasm may persist even between attacks. No evidence indicates that asthma shortens life span, although later onset and concomitant chronic obstructive pulmonary disease appear to shorten survival.[1][2]
[edit] Pathogenesis
Although asthma was once thought to result from an abnormal immune response of the lungs, multiple inflammatory factors are now known to play a role in its etiology[3] (Fig. 72-1). The primary immune mechanism of asthma involves the association of antigen with immunoglobulin E (IgE) bound to the cell surfaces, which triggers the release of histamine and a variety of other factors that promote both bronchospasm and local inflammation. Histamine increases leakage of protein and fluid from venules, increases airway secretions, and can stimulate irritant receptors in the airway walls. This in turn leads to reflex vagal release of acetylcholine near smooth muscles, promoting further bronchoconstriction. Although antihistamines are useful in the treatment of other allergic disorders such as allergic rhinitis, they are not helpful in asthma.
Many factors besides histamine participate in the pathogenesis of bronchial asthma, including the lipoxygenase products of arachidonate, the leukotrienes (formerly known as slow-reacting substance of anaphylaxis). Other mediators that may play a role in bronchospasm include platelet activating factor, bradykinin, substance P, oxidants, complement fragments, and a variety of other substances. Agents that inhibit the synthesis of leukotrienes or their receptors have proved helpful in some patients with asthma. The intensity of the eosinophilia observed in patients with asthma appears to be correlated with the severity of airflow obstruction, and eosinophil counts are increased in bronchoalveolar lavage fluid from asthmatic patients. Response to steroids is marked by a decrease in both airway resistance and eosinophil counts. Mast cells within the lung tissues of patients appear to be activated and probably play an important role in the early events preceding an asthmatic attack. Bronchospasm can be induced by cholinergic nerves that travel in the vagus nerve and may release acetylcholine reflexively when irritant receptors in the airways are stimulated. Stimulation of these same receptors is also responsible for cough. Although not as effective as β-adrenergic agents, anticholinergic drugs can relieve airway obstruction in some asthmatic patients.
[edit] Epidemiology
Bronchial asthma is a common clinical problem in the United States, affecting about 10 million people, or about 4% of the population. The economic cost of this disease in the United States was estimated at $6.2 billion in 1990,[4] and the incidence may be increasing in the general population.[5] Males predominate over females by a factor of 1.5 to 2.0 under age 10 years, but the incidence is approximately equal by age 30, after which incidence in women becomes greater. Black children have a higher incidence of asthma than other children. Airway hyperresponsiveness, as judged by methacholine challenges, is almost always present in asthmatic persons, but this observation is also seen in many asymptomatic subjects. Perhaps 20% of those with asymptomatic airway hyperreactivity eventually develop clinical asthma. Approximately half of those with asthma have a familial history of asthma, rhinitis, eczematous dermatitis, or urticaria. The onset of asthma is frequently associated with viral upper respiratory tract infections (e.g., respiratory syncytial virus disease in infancy, rhinovirus or influenza in older children and adults). Air pollutants such as ozone, nitrogen dioxide, and sulfur dioxide can initiate attacks in asthmatic persons and probably contribute to the incidence. Both active and passive smoking may predispose to the development of asthma.
About 50% of children with asthma improve or become symptom free on reaching early adulthood, but a very early onset of disease is associated with a less favorable prognosis. Mortality is uncommon in the United States, averaging 3000 per year. Despite the introduction of newer modes of therapy, the mortality rate for asthma has not declined, and some are concerned that mortality in the United States and elsewhere may be increasing.
[edit] Agents and Circumstances That Induce Asthma
Many patients with asthma tend to produce IgE to one or more antigens in the environment (designated as allergens) and are therefore referred to as atopic. Atopy may also be associated with eczema and hay fever. This form is sometimes referred to as extrinsic asthma, whereas the type unrelated to an atopic predisposition or to specific environmental antigens is designated as intrinsic asthma. Patients with extrinsic asthma generally contract their illness at a younger age. Pollens, molds, house dust, and animal dander are common antigens. Because the pollens are too large to reach the bronchi or reactive cells (mast cells), fragments of the pollens apparently are responsible for asthmatic attacks. Antigens associated with the skin mites Dermatophagoides pteronyssinus, especially the feces of these arthropods, are the principal allergenic factors in house dust. Cockroaches are a common cause of asthma, particularly in high-density inner-city apartments. An important antigen associated with cats is produced by the sebaceous glands, and many patients are allergic to dogs.
True asthmatic attacks related to foods are much less common than those induced by inhaled antigens, but exposure to specific foods and additives such as metabisulfites (sometimes used as a preservative for salads) can induce serious attacks. Reactions to foods are usually associated with either gastrointestinal symptoms or rashes. Gastroesophageal reflux is common in asthmatic patients, and treatment of this problem can relieve the asthma's severity.
A careful occupational history is essential in the evaluation of adults with bronchial asthma.[6] Substances that can cause asthma in the workplace can be divided into low-molecular- weight substances and proteins. Toluene diisocyanate (TDI), is an important ingredient of polyurethane foams that can foster asthma in workers who may have had no previous reaction to the substance over many months. Platinum salts and a variety of anhydrides may cause development of both IgE antibodies and asthma. Proteins that can cause asthma include enzymes used in detergents, which may result in hypersensitivity in approximately one fourth of workers exposed. A variety of wood dusts, particularly western red cedar, can also cause occupational asthma. Electricians may contract asthma from inhalation of fumes released during soldering. Exposure to cotton and other organic fibers can provoke bronchospasm by stimulating release of histamine, a condition referred to as byssinosis (see Chapter 76 ). Although formaldehyde appears to have been responsible for asthma in a few workers exposed to heavy concentrations, evidence regarding the small amounts released from fiberboard or foam in homes is not considered persuasive.
A single, direct exposure to high concentrations of toxic fumes (e.g., ammonia, bleach, TDI) can result in the onset of asthma in patients without previous airway disease.[7] This condition is referred to as reactive airway dysfunction syndrome (RADS). Patients with RADS characteristically become acutely ill and require medical attention during the first 24 hours after exposure. After recovery, airway hyperreactivity may be present, with asthmatic symptoms persisting indefinitely, or airway hyperreactivity may gradually decline over months. The hyperreactivity of the airways of asthmatic patients extends to a variety of nonspecific stimuli, including cold air, perfume, smoke, and sulfur dioxide. Vigorous exercise may be followed by bronchospasm, and hyperventilation (voluntary or associated with laughing and crying) can initiate an asthmatic attack. Exercise-induced asthma can be avoided by prior inhalation of cromolyn, nedocromil, or a β-adrenergic agent. Other nonspecific contributing factors are esophageal reflux and chronic sinus disease.
Drugs are responsible for approximately 10% of acute asthmatic attacks. Nonsteroidal antiinflammatory drugs (NSAIDs), particularly aspirin preparations, have been implicated in more than half these cases. Hypersensitivity to aspirin and other NSAIDs typically appears in the third and fourth decades of life and does not seem to be inherited. Intense vasomotor rhinitis frequently precedes asthmatic symptoms, and nasal polyps and sinusitis are common. Within several hours of ingesting aspirin, patients experience rhinitis and wheezing and may develop nausea, vomiting, facial edema, angioedema, and life-threatening anaphylaxis. The action of these drugs appears to be related to their ability to inhibit cyclooxygenase. Drugs that do not inhibit cyclooxygenase, such as salicylamide and sodium salicylate, are considered safe. Acetaminophen and dextropropoxyphene are also relatively safe in the great majority of these patients. Desensitization with daily administration of aspirin has been recommended but should be undertaken by an experienced allergist. Leukotriene receptor inhibitors may also be useful.
β-Adrenergic inhibitors, including those used in ophthalmic preparations and even those that enter the milk of nursing mothers, may induce asthmatic attacks. Because the lung, like the heart, contains some β1-receptors as well as β2-receptors, the physician must ensure that the action of these drugs is restricted to the heart. Many antibiotics and iodinated dyes may result in severe asthmatic responses, which can be ameliorated by prior treatment with antihistamines and steroids. Cocaine and a variety of anesthetic agents have also been associated with asthmatic attacks. Any of the angiotensin-converting enzyme inhibitors may cause a persistent cough that begins soon after administration or as late as 1 year after initiating therapy; however, these reactions are rarely associated with bronchospasm or changes in bronchial hyperreactivity and are relieved within weeks after the drug is discontinued. Rarely, they have been associated with acute angioedema, which may affect the mouth, tongue, and larynx, causing acute upper airway obstruction, which may require administration of epinephrine.
[edit] Patient Evaluation
[edit] History.
More than in any other respiratory disease, the history plays a crucial diagnostic role in bronchial asthma. The patient usually gives a history of dyspnea with recurrences and remissions. Often the dyspnea worsens at night and may be initiated by viral infections or exposure to irritants or antigens, such as those already listed. Although intrathoracic obstruction leads to greater resistance during expiration, patients typically complain more of inspiratory distress. Fatigue of the inspiratory muscles probably occurs because they remain tonically contracted throughout the respiratory cycle and are disadvantaged by the high maintenance volumes in the lungs. Wheezing is apparent to both patient and physician but may disappear when tidal volumes become sufficiently compromised in severe asthma. Cough is a common manifestation of asthma and may be the only complaint; response to bronchodilators may reveal the cause. Frequently a cough productive of intrabronchial plugs may herald relief during an attack. Symptoms of asthma usually occur within 10 to 30 minutes of exposure to an irritant or antigen. Late responses are also common, however, occurring several hours after exposure. Usually an early response precedes the late response, but some patients with occupational asthma may have no early phase. Whereas the early response appears to be caused by bronchospasm, edema, and vascular congestion, the late response is associated with the appearance of inflammatory cells in the tissues.
[edit] Physical Examination.
Wheezing is the most common physical finding in asthma and generally is audible during both inspiration and expiration rather than just expiration. If these sounds are audible only during inspiration, extrathoracic obstruction with stridor is probably present rather than intrathoracic obstruction from bronchial asthma. The time required for airway sounds to disappear over the trachea during expiration is characteristically increased to as long as 6 seconds in patients experiencing bronchospasm. In a severe attack the patient strains to inspire, often using both scalenus and sternocleidomastoid muscles, and then expires slowly, frequently against pursed lips, contracting abdominal muscles to force the diaphragm upward. Marked variation of intrathoracic pressures results in pulsus paradoxus, with systolic pressures falling by more than 15 mm Hg during inspiration. Pulsus paradoxus may become less prominent, however, if the patient tires; again, wheezing may disappear in severe attacks as tidal volume decreases.
[edit] Laboratory Studies and Diagnostic Procedures
Increases in airway resistance associated with bronchial asthma can be readily detected by spirometry. Forced vital capacity (FVC) maneuvers reveal decreased flow rates, forced expiratory volume in 1 second (FEV1) and peak expiratory flow rate (PEFR) are most often used to assess alterations in airway obstruction. It is common practice to determine responsiveness to bronchodilators during the evaluation of pulmonary function. Failure to document a response is not particularly helpful, however, since patients who show no improvement in the laboratory may respond outside the laboratory; a clinical trial of bronchodilator therapy should generally be given regardless of the laboratory response. It is important to assess the FEV1/FVC ratio, since a reduction of this ratio from expected values is specific for obstructive rather than restrictive disease. The severity of asthma can be judged on the basis of both pulmonary function studies and clinical presentation (Table 72-1).[8][9]
Table 72-1 Therapeutic Staging for Acute Bronchial Asthma Exacerbations in Adults
| Stage | Symptoms | FEV1 or PEFR✢ | Treatment |
|---|---|---|---|
| Mild | Mild wheeze, cough, dyspnea on exercise | >80% | Use metered-dose inhaler or nebulizer up to three times an hour; oral steroids if no response. |
| Administer oxygen (O2) to keep saturation at 90% or higher. | |||
| Moderate | Wheeze, cough, moderate dyspnea at rest | 50%-80% | As above, with repeat bronchodilators every hour; if no response, call physician. |
| In emergency room (ER), intravenous steroids and inhaled anticholinergic agent; admit to hospital if poor response. | |||
| Severe | Severe dyspnea at rest, accessory muscle use, retraction, difficulty talking, wheeze may disappear | <50% | As above, and go to ER; if no response, admit to hospital. |
| If impending respiratory arrest, intubate and place on 100% O2. |
✢PEFR, Percentage of predicted peak expiratory flow rate;FEV1, percentage of personal-best forced expiratory volume in 1 second.
Differentiation between intrathoracic and extrathoracic obstruction is facilitated by obtaining a flow-volume loop. The total lung capacity and, during remission, the carbon monoxide diffusion test are frequently increased in asthmatic patients. Between bronchospastic episodes, pulmonary function may be completely normal; bronchoprovocation studies are then conducted, generally by having the patient inhale an aerosol containing methacholine. Patients with hyperreactive airways experience a decrease in airflow with very low methacholine concentrations. Documentation of a normal challenge test argues against bronchial asthma, but many normal subjects who have airway hyperreactivity on bronchoprovocation tests may have no history of asthma, and these tests may become abnormal for several months after a viral infection in nonasthmatic individuals.
Arterial blood gases must be carefully followed in patients with severe asthma. Mild hypoxia and hypocapnia are usually observed in mild and moderate asthma. With more severe episodes, hypoxia worsens and carbon dioxide pressure (Pco2) may rise to normal or greater levels, resulting in respiratory acidosis. If oxygen delivery to the tissues becomes inadequate, lactic acidosis ensues. If Pco2 increases to normal or elevated levels in a patient in distress, respiratory failure may be present, and mechanical ventilation may become mandatory.
Eosinophilia is common in all forms of allergic diseases, including asthma, drug reactions, allergic rhinitis, angioedema, and eczema. As noted, the number of eosinophils tends to reflect the severity of asthma and may indicate whether steroid therapy is adequate.
The lungs are characteristically hyperinflated on radiographs. Chest films should be obtained in patients with severe asthma, since they may reveal unexpected findings (e.g., pneumothorax, atelectasis, pneumonia) that require immediate attention. The detection of central bronchiectasis with mucous plugs strongly suggests bronchopulmonary aspergillosis, which is usually accompanied by asthmatic symptoms.
[edit] Complications
Status asthmaticus, generally defined as life-threatening asthma that does not respond to standard medication, is one of the most serious complications in asthmatic patients. A patient who shows signs of respiratory failure with severe hypoxia and rising Pco2 must be admitted to an intensive care unit, where mechanical ventilation can be properly managed (see Chapter 77 ). Other complications of acute asthma include pneumothorax, pneumomediastinum, and atelectasis from bronchial plugging.
[edit] Differential Diagnosis
Many clinical disorders can mimic bronchial asthma (Box 72-1). Manifestations of extrathoracic obstruction caused by lesions of the upper airways may be confused with those of intrathoracic obstruction caused by asthma. Because of injuries sustained to the larynx and trachea during intubation and tracheostomies, extrathoracic obstruction is increasingly common in general practice. Careful examination should allow detection of inspiratory stridor, which is loudest over the larynx and trachea. In some cases, laryngeal "dysfunction" may be a manifestation of psychiatric disorders. Patients with this disorder characteristically narrow their glottis during inspiration and expiration but do not have increases in alveolar-arterial oxygen differences. Wheezing is also often associated with early congestive heart failure (CHF) with edema of the airways, and CHF may cause a cough that worsens when the patient is recumbent. CHF patients have an increased incidence of bronchial hyperreactivity. Bronchial asthma must also be distinguished from hypersensitivity pneumonitis, which is related to inhalation of fungi or proteins. Unlike bronchial asthma, this condition is more often manifested by rales than wheezing, is frequently associated with pulmonary infiltrates and fever, and recurrent exposure may lead to chronic pulmonary fibrosis. Children who have had bronchopulmonary dysplasia or cystic fibrosis may develop airway obstruction that may be confused with bronchial asthma.
| Box 72-1 - Disorders and Diseases Associated with or Mimicking Bronchial Asthma |
|
Bronchiolitis is a common disease in infants frequently associated with respiratory syncytial virus infections. It is also seen in adults after viral infections and may present with chronic cough and wheezing, which subside over weeks or months. Bronchiolitis obliterans is a more serious form of small-airway obstruction in which granulation tissue fills the smaller bronchioles. This disease may be idiopathic or may be caused by toxic fume exposure, connective tissue disorders (e.g., rheumatoid arthritis), and bone or organ transplantation (e.g., graft-vs.-host disease). Early inspiratory crackles are common, and chest radiographs may be normal or show patchy overinflation. Bronchiolitis obliterans with organizing pneumonia (BOOP) is characterized by small-airway obstruction with plugs of granulation tissue and accumulation of fibrinous exudates and foamy macrophages in inflamed alveoli. Patchy infiltrates are visible in chest radiographs, and BOOP frequently responds to steroid therapy.
[edit] Management
Although considerable effort has been devoted to development of more effective treatment of asthma, progress has been slow, and many drugs represent variants of agents used for centuries. The complexity of the inflammatory events responsible for hyperreactive airways suggests that it is necessary to block multiple mediators and effectors to prevent and treat asthma more effectively. Many of the more effective drugs tend to have multiple biologic actions. Treatment should be graded in accordance with the severity and chronicity of the disorder (Table 72-2).[8][9] Asthma can be unpredictable, and the physician must use ingenuity in designing individualized regimens. Evidence indicates that frequency of hospitalization can be reduced if asthmatic patients are closely followed by their physicians, are instructed carefully in the use of their medications, and, in more labile patients, are taught to keep a record of their own pulmonary function with a peak flowmeter.
Table 72-2 Stepwise Management of Chronic Bronchial Asthma in Adults and Children over 5 Years Old
| Step | Frequency (day/night) | PEFR or FEV1✢ | Daily medications† | ||
|---|---|---|---|---|---|
| Day | Night | Value | Variability | ||
| 1: mild intermittent | ≤2/week | ≤2/month | ≥80% | <20% | None |
| 2: mild persistent | 3-6/week | 3-4/month | ≥80% | 20%-30% | Inhaled steroid: low dose; cromolyn, nedocromil, theophylline, or anti-leukotriene agent |
| 3: moderate persistent | Daily | ≥5/month | 60%-80% | >30% | Inhaled steroid: medium dose plus step 2; sustained-release β2-agonist |
| 4: severe persistent | Continual | Frequent | ≤60% | >30% | Inhaled steroid: high dose plus step 3; oral steroids with attempts to reduce |
✢PEFR, Percentage of predicted peak expiratory flow rate;FEV1, percentage of personal-best forced expiratory volume in 1 second.
†Short-acting β2-agonist (2-4 puffs) is used for acute symptoms, regardless of step.
[edit] Sympathomimetic Agents.
The recognition that different adrenergic receptors exist in different tissues has led to the development of β-adrenergic drugs that are more specific in their action to promote bronchodilation and less likely to be associated with side effects. α-Agonists cause vasoconstriction, whereas β1-adrenergic agents increase cardiac contractility and heart rate, which is undesirable in patients undergoing therapy for asthma. In addition to promoting bronchodilation, β2-adrenergic agents also increase secretion of electrolytes by the airways and enhance mucociliary activity. Protein kinase A levels increase within the smooth muscle cells, resulting in inhibition of myosin phosphorylation and smooth muscle cell relaxation. β2-Agonists are not free from side effects, such as skeletal muscle tremor, hyperglycemia, and hypokalemia, as well as dilation of the vasculature of skeletal muscles. A transient decrease in oxygen saturation is sometimes observed after administration of these agents. This paradoxic effect is related to the effect of increased cardiac output, which can result in perfusion of underventilated regions of the lungs and is not a contraindication to continued use of these drugs.
Epinephrine was introduced in 1910 and continues to be administered subcutaneously, and less frequently by intravenous injections, in the treatment of severe asthmatic or anaphylactic attacks (see Anaphylaxis). Cardiac necrosis has been described after administration of parenteral epinephrine, and if at all possible, such injections should be avoided in older patients and those with history of coronary artery disease. Because epinephrine is the only aerosolized agent available without prescription, many patients continue to use it. However, epinephrine is associated with potent α-adrenergic and nonspecific β-adrenergic activity and has a very limited half-life; its use in aerosols has been largely replaced by newer, more specific agents. Ephedrine, an oral drug with weak properties similar to those of epinephrine, is of largely historic interest, since it was used for millennia in herbal form and was popular in various proprietary combinations for many years. Isoproterenol became popular after its introduction in the 1940s because it lacked α-adrenergic activity. Unfortunately, it is relatively nonspecific for β1-adrenergic and β2-adrenergic effects, and the former may have been responsible for an increased incidence of sudden death when it was widely used as a metered aerosol. Isoproterenol is still occasionally used intravenously in children with status asthmaticus to avoid the need for intubation and ventilation, but terbutaline is safer for this purpose.
Metered-dose inhalers (MDIs) containing β2-agonists are widely available on the American market, including terbutaline (oral and subcutaneous forms), albuterol (aerosol and oral administration but not parenteral therapy), bitolterol, and pirbuterol. These drugs remain active for relatively longer periods than the earlier preparations and are less likely to cause unwanted cardiovascular effects. Salmeterol has a particularly long duration of action and is useful for preventing nocturnal bronchospasm. The onset of bronchodilation is also delayed, however, and salmeterol should not be used to treat acute bronchospasm. β2-Adrenergic agents are best prescribed in aerosol form because much higher concentrations can be reached locally within the lungs than with oral and parenteral administration, and systemic effects can be minimized. The latter routes, however, may permit the drug to reach areas of the lung that are inaccessible to aerosols because of severe bronchoconstriction and mucous plugging, and oral and occasionally parenteral administration may be helpful. Studies suggest that MDIs are just as effective as aerosol generators, particularly if the patients are properly trained in inhaling during release of medication from the inhaler. For those who have difficulty with the MDI inspiratory maneuver, spacers can be used to permit administration of medication during tidal breathing. Considerably more medication is delivered with the aerosol generators, however, and they continue to be popular for patients with episodes of very severe asthma unresponsive to the MDIs.
Concern still exists that patients tend to develop tachyphylaxis to β-adrenergic therapy. Although laboratory models can show this phenomenon, the clinical significance of tachyphylaxis is not clear. Nevertheless, the physician must be alerted if the patient finds it necessary to use the medication more frequently, since this may signal worsening of the disease and mandate additional therapy. The usual recommendation has been that β-adrenergic aerosols should be used regularly (e.g., two breaths four times a day), but with concern about increased cardiac events or tachyphylaxis, the recommendation now is that patients with relatively mild asthma can use MDIs less frequently and as needed. Administration of aerosols is often increased to every 15 minutes for patients in the emergency room, but chronic administration of high doses should probably be avoided, since an increase in asthma mortality may be related to overuse of these agents.
[edit] Corticosteroids.
The beneficial and deleterious effects of the glucocorticoids in asthma treatment are related in part to the specific cytoplasmic receptors for these agents in both inflammatory cells and many parenchymal cells, including those of the lungs. Subsequent activity requires interaction with regulatory elements of DNA, so the antiinflammatory actions of corticosteroids are not seen for 6 to 12 hours. Chronic administration can reduce nonspecific airway hyperresponsiveness, and single doses inhibit the late, inflammatory response to antigen exposure.
Parenteral administration is particularly valuable in patients with severe episodes of asthma (Table 72-3). Because the effects of these agents may not be clinically evident for as long as 12 hours and the course of the illness is so unpredictable, these drugs are administered as early as possible to patients who require hospitalization. High dosages of steroids may be continued in oral form until flow returns toward baseline levels, and then tapering may proceed over 1 or 2 weeks, with adjustment if peak flows begin to deteriorate (Table 72-4). Concomitant use of steroid aerosols is recommended both during and after tapering (see following discussion). Oral glucocorticoids can be used for recurrences in the home environment with appropriate tapering schedules. In a minority of patients, oral steroids must be used on a chronic basis with attempts at as slow a taper as possible. Longer exposure entails increased risk of side effects. Administration of more than the physiologic levels of glucocorticoids (7.5 to 10 mg/day of prednisone) leads to suppression of the hypothalamic-pituitary-adrenal (HPA) axis. This effect can be reduced by administering all the medication in the morning, when adrenocorticotropic hormone (ACTH) levels are maximal, rather than in multiple doses throughout the day. Alternate-day dosing is even more effective in preventing HPA axis suppression and, by allowing recovery of some inflammatory function, may reduce the incidence of infection; however, controlling asthmatic symptoms in many patients is difficult with this regimen. After prolonged glucocorticoid administration, weaning should be done slowly (e.g., by decreasing dosage by 1 mg/day for a month). Hypothalamic-pituitary function may remain suppressed for as long as a year, and the patient should keep steroids on hand for stressful circumstances and carry a card indicating possible need for steroid administration if stress or surgery occurs during the year after discontinuation of steroids.
Table 72-3 Parenteral Agents Used to Treat Asthma
| Agent | Form/patient | Dose |
|---|---|---|
| β-Adrenergics | ||
| Epinephrine | 1:1000 solution | 0.3-0.5 mg every 20 min×3 |
| Sus-Phrine | 1:200 suspension | 0.1-0.3 mg every 6 hr or more often |
| Terbutaline | 1 mg/ml solution | 0.25 mg every 20 min×3 |
| Theophylline | ||
| Loading dose | Not receiving therapy | 5 mg/kg IV in 20 min |
| Receiving therapy | 2.5 mg/kg IV in 20 min | |
| Maintenance | Young smoker | 0.7 mg/kg/hr |
| Nonsmoking adult | 0.43 mg/kg/hr | |
| Older adult, cor pulmonale | 0.26 mg/kg/hr | |
| Corticosteroids | ||
| Methylprednisolone | Acute | 40-120 mg q 4-6 hr |
| Prednisone | Exacerbation | 100-400 mg q 4-6 hr |
Table 72-4 Oral Agents Used to Treat Asthma
| Agent | Available tablets | Dose |
|---|---|---|
| β-Adrenergics | ||
| Metaproterenol | 10 and 20 mg | 10-20 mg every 6 hr |
| Terbutaline | 2.5 and 5 mg | 2.5-5.0 mg every 6-8 hr |
| Albuterol | 2 and 4 mg | 2-4 mg every 6-8 hr |
| Leukotriene Modifiers | ||
| Zafirlukast (Accolate) | 20 mg | 1 tab twice daily between meals |
| Montelukast (Singulair) | 10 mg | 1 tab each evening |
| Zileuton (Zyflo) | 600 mg | 1 tab four times daily |
| Theophylline | ||
| Sustained release (once or twice daily forms) | 100, 200, 300, 400 and 600 mg | Initial: 100-300 mg/day |
| Maximum: 800 mg/day | ||
| Routine serum levels: 5-15 μg/ml | ||
| Prednisone | 1, 2.5, 5, 10, 20, 50 mg | 1-2 mg/kg/day |
| See text regarding taper | ||
| Methylprednisolone | 2, 4, 8, 16, 24, 32 mg | 0.8 mg/kg/day |
| See text regarding taper | ||
Aerosolized steroids have gained considerable popularity in the treatment of asthma. These have been designed to exert maximal local activity while minimizing absorption and systemic effects. They can assist in withdrawal of chronic oral steroid therapy and may reduce dependence on β2-adrenergic agents and the incidence of exercise dyspnea. Oropharyngeal candidiasis can be ameliorated or avoided by thoroughly rinsing the mouth after administration of aerosolized steroids. Dysphonia, manifested as hoarseness, is usually related to the effect of the drugs on the skeletal muscles of the larynx. It may respond to less frequent administration or use of spacers to improve more distal delivery of medication.
High dosages of inhaled steroids may have systemic effects, such as suppression of the HPA axis and bone formation, and the incidence of cataracts and glaucoma may be increased. Use of a spacer can decrease absorption through the membranes of the mouth and upper airways; patients should rinse their mouths after administration. It should be emphasized to patients that these aerosolized steroids do not provide immediate relief and must be taken on a regular basis for some weeks before improvement may occur and some months before maximal effect is observed (Table 72-5).
Table 72-5 Inhaled Steroids Used to Treat Asthma
| Agent steroid | Daily dose (puffs) | ||
|---|---|---|---|
| Low | Medium | High | |
| Beclomethasone (Vanceril, Beclovent) | |||
| 42 μg/puff | 4-12 | 12-20 | >20 |
| 84 μg/puff | 2-6 | 6-10 | >10 |
| Budenoside (Pulmicort Turbuhaler) | 1-2✢ | 2-3✢ | >3✢ |
| Flunisolide (AeroBid) | 2-4 | 4-8 | >8 |
| Fluticasone (Flovent) | |||
| 44 μg/puff | 2-6 | ||
| 110 μg/puff | 2-6 | ||
| 220 μg/puff | >3 | ||
| Triamcinolone (Azmacort) | 4-8 | 8-12 | >12 |
✢Inhalations.
[edit] Methylxanthines.
The popularity of methylxanthines for the treatment of asthma has waxed and waned dramatically. Although they cannot be considered primary drugs for asthma treatment because of a less favorable benefits/complications ratio than aerosolized β2-adrenergic agents, they can be beneficial as ancillary therapy in many patients. Of the three most common derivatives of methylxanthine (theophylline, caffeine, theobromine), only theophylline is used to treat asthma. Theophylline is frequently formulated with ethylenediamine (aminophylline) to improve solubility by making the diluent solution more alkaline. Although the actions of methylxanthines were thought to be mediated by inhibition of phosphodiesterases, this requires concentrations much greater than those encountered clinically. In addition to bronchodilation, theophylline appears to increase diaphragmatic contractility, decrease pulmonary artery resistance, and act as a respiratory stimulant.
During acute attacks, aminophylline is often administered intravenously at a rate to maintain blood levels at 5 to 15 μg/ml. Lower blood levels are less effective but may help patients who cannot tolerate higher concentrations. Chronic therapy is generally administered with sustained-release oral medication. As blood concentrations increase, patients develop anorexia, nausea, and vomiting because of the central action of theophylline. The patient may also develop more serious symptoms, such as cardiovascular toxicity with tachycardia, tachyarrhythmias, and hypotension. Nervousness, insomnia, headache, and refractory seizures are central nervous system manifestations of toxicity. Drugs, illnesses, and smoking can have a profound effect on blood levels, complicating therapy. Dosage should be reduced by one third when a patient is given ciprofloxacin or erythromycin and by one half when fever develops or the patient is given cimetidine or oral contraceptives. Dosage should also be decreased in patients receiving zileuton or zafirlukast (see next section). Blood levels should be determined after the onset of therapy or a change in dosage and when bronchospasm worsens or symptoms are consistent with toxicity. Patients should be advised to refrain from taking their next dose and to contact their physicians when these symptoms appear. Theophylline is often recommended in patients with nocturnal asthma resistant to bedtime β-adrenergic agonists.
[edit] Leukotriene Inhibitors.
Agents that inhibit the synthesis of leukotrienes (zileuton) or block leukotriene receptors (zafirlukast, montelukast) offer a new approach to treating mild or moderate bronchial asthma (see Table 72-4). Zileuton has been associated with elevations in liver enzymes, however, and patients should be monitored periodically for this complication. Also, zileuton should be avoided in patients with preexistent liver disease or alcoholism. Both zileuton and zafirlukast may elevate prothrombin times of patients receiving coumadin and may increase levels of theophylline if taken concomitantly. Churg-Strauss syndrome has occurred in patients taking zafirlukast who were withdrawn from steroids, but the drug has proved to be very safe. Current guidelines suggest that leukotriene inhibitors can replace inhaled steroids, nedocromil, or cromolyn in mild to moderate asthma, using inhaled β-agonists as needed.
[edit] Other Medications (Table 72-6).
Cromolyn (disodium cromoglycate) helps prevent immediate and delayed bronchoconstriction after exposure to antigens. Although its exact mode of action is unclear, cromolyn inhibits release of mediators (e.g., histamine, leukotrienes) from mast cells and has other antiinflammatory properties. The liquid aerosol is less irritating than the powder formerly used. Cromolyn is particularly helpful in children and adults with asthma related to specific allergic responses. It is effective in airway challenges from exposure to animals and substances at work. Cromolyn is less effective than β2-adrenergic agonists in preventing bronchospasm induced by exercise or exposure to cold. Response may take up to 2 months, and cromolyn provides no relief in an acute asthmatic attack. Cromolyn can prevent bronchospasm, however, if given just before exposure to exercise or a known offending agent. Side effects are rare but include local irritation, cough, hoarseness, and minor complications (dermatitis, myositis, gastroenteritis).
Table 72-6 Inhaled Drugs Other Than Steroids Used to Treat Asthma
| Agent | Dose (puffs) |
|---|---|
| Short-actingβ-agonists | |
| Albuterol | 2 qid |
| Bitolterol (Tornalate) | 1-3 qid✢ |
| Pirbuterol (Maxair) | 2 qid |
| Terbutaline | 2 qid✢ |
| Long-actingβ-agonist | |
| Salmeterol (Serevent) | 2 bid |
| Anticholinergic | |
| Ipratropium (Atrovent) | 2 qid |
| Cromolyn and nedocromil | |
| Cromolyn (Intal) | 2-4 qid |
| Nedocromil (Tilade) | 2 qid |
| Combination | |
| Albuterol/ipratropium (Combivent) | 2 qid |
| qid, Four times daily; bid, twice daily. | |
✢Puffs separated by 1 to 3 minutes.
Nedocromil is an alternate agent that may have antiinflammatory effects in the airways and may also inhibit reflex reactions to exercise and cold. Although aerosolized anticholinergic drugs have been used primarily for chronic obstructive disease, some asthmatic patients respond to ipratropium, which has a slower onset of action than the β-agonists and requires 30 to 60 minutes before maximal effects are achieved. Antibiotics are indicated only if bacterial infection is associated with asthma. Desensitization may have a role in the treatment of asthma related to specific pollens and to mites if patients do not respond adequately to routine pharmacotherapy, but it is more effective in the treatment of allergic rhinitis. Magnesium, gold, methotrexate, and cyclosporin have been used to treat asthma but are potentially toxic and must be considered experimental at this time. Bronchoalveolar lavage for status asthmaticus can worsen bronchospasm and probably should be avoided.[10]
[edit] ANAPHYLAXIS
[edit] Pathophysiology
Anaphylaxis is the most dreaded complication of immediate hypersensitivity. As with other disorders of immediate hypersensitivity, anaphylaxis is initiated by binding of antigen to IgE attached to the surfaces of mast cells, with the subsequent release of agents that mediate vascular leak of protein, smooth muscle contraction, and mobilization of inflammatory cells. The relationship of anaphylaxis to prior atopy remains unclear; the incidence of anaphylactic reactions to both penicillin and bee stings is no more common in subjects with than without atopy. Antigenic substances include proteins and smaller solutes that combine with proteins. The offending agents range from foods, pollens, insect bites, and drugs to latex and ethylene oxide. Some drugs (e.g., NSAIDs) cause anaphylactic-like reactions that may result from direct effects on mast cells rather than from IgE-mediated events.
[edit] Etiology
Stings of bees, yellow jackets, wasps, and hornets (all of which are members of the order Hymenoptera) can induce reactions varying from local cutaneous symptoms to the characteristic manifestations of anaphylactic shock. Penicillin is the most common cause of drug-related anaphylaxis, and cross-reaction with cephalosporins is common. Other antibiotics, local anesthetics, and specific foods, such as eggs, seafood, nuts, beans, and chocolate, can also be associated with anaphylaxis. Blood products can cause anaphylactic reactions as well as more common complications such as hemolysis. Patients with an inherited absence of immunoglobulin A may develop severe anaphylaxis after administration of blood or plasma containing this protein.
[edit] Patient Evaluation
Within seconds to minutes after exposure (e.g., sting, ingestion, injection) the patient may experience symptoms related to both upper and lower airway obstruction, with hoarseness, stridor, chest tightness, wheezing, and shortness of breath. Pruritic, raised, and erythematous urticaria typically appears in a local or diffuse distribution over the skin. Angioneurotic edema is also common, with localized swelling that does not pit and may or may not be accompanied by local burning or stinging. Angioedema of the larynx and epiglottis may result in asphyxiation. Mucosal swelling, intense bronchospasm, and bronchial edema are found at autopsy with secondary emphysematous overdistention of the lungs. The patient may experience severe hypotension and syncope.
[edit] Laboratory Studies and Diagnostic Procedures
Skin tests and radioallergoabsorbent tests are available for both bee stings and penicillin allergies.
[edit] Management
Subcutaneous injection of epinephrine (0.2 to 0.5 ml of 1:1000 solution, repeated twice at 20-to 30-minute intervals if needed) remains the cornerstone for immediate treatment of anaphylaxis and should be given as early as possible. Antihistamines and steroids seem to have relatively little effect in the acute episode. Aerosolized bronchodilation and theophylline may be needed as well as oxygen if the patient is hypoxic. If the patient is in profound shock, 5 ml of 1:10,000 epinephrine should be administered intravenously every 5 minutes as needed; if no response is observed, 2 to 50 μg/kg of dopamine is indicated. Patients should wear bracelets indicating agents to which they are allergic; if drug therapy is essential, desensitization with increasing doses of medication administered intradermally, subcutaneously, and then intramuscularly can be tried with an allergist. Immunotherapy is particularly effective in preventing anaphylactic reactions to insect stings but may need to be continued indefinitely if the skin test remains positive. Allergic patients should carry kits for self-administration of epinephrine if they are not receiving immunotherapy.
[edit] ALLERGIC RHINITIS
[edit] Etiology and Epidemiology
IgE on mast cells and basophils in the nasal mucosa interacting with antigens causes allergic rhinitis, which affects at least 15 million Americans. Pollens are the most common antigens involved, and the disease is frequently seasonal. Many antigens causing asthma can also cause allergic rhinitis. However, many patients have perennial symptoms or vasomotor rhinitis unrelated to specific antigens but aggravated by changes in temperature, humidity, spicy foods, and inhaled irritants.
[edit] Patient Evaluation
The cardinal manifestations of allergic rhinitis are nasal obstruction and secretions, sneezing, and itching of the mucous membranes of the nose, eyes, posterior pharynx, and conjunctivae. When symptoms are severe, patients complain of fatigue, loss of appetite, and irritability. The nasal mucous membranes may appear blue with swollen turbinates, and the conjunctivae are injected. Nasal polyps are uncommon unless the patient has aspirin-type allergy, but serious otitis media is common and may lead to hearing defects, especially in young children. Chronic sinusitis may result in throbbing pain over the sinus areas.
[edit] Diagnostic Procedures
If negative, scratch, prick, and intradermal skin tests argue against allergic rhinitis. Radioallergoabsorbent and other in vitro tests also are available.
[edit] Management
Antigens (e.g., those associated with animals) can frequently be avoided, and levels of pollens can be decreased by remaining indoors and using electrostatic precipitators. The histamine (H1) receptors can be blocked with a variety of antagonists. Many older agents crossed the blood-brain barrier and caused sleepiness. Loratidine, cetirizine, and fexofenadine are less likely to cause sedation and are not associated with the arrhythmias that were observed with terfenamide and astemizole (which are no longer available in the United States). Antihistamines should be given regularly because they are more effective if administered before than after exposure. Short-acting and long-acting α-adrenergic agents are effective when applied to the nasal mucosa. Continued use for more than a few days, however, results in rebound nasal congestion and reliance on the medication (rhinitis medicamentosa). Oral preparations are also effective but have systemic effects. Nasal steroid aerosols effectively treat allergic rhinitis, although they may not relieve ocular symptoms. Nasal cromolyn can be effective for both prevention and treatment, although a beneficial response may require weeks. Ipratropium nasal aerosol can effectively treat some patients with vasomotor rhinitis. Immunotherapy, using increasing doses of the offending antigen, can also help but requires prolonged therapy. Administration of antigen is believed to result in the development of IgG antibody, which binds to the antigen and limits access to IgE, but other mechanisms have also been proposed.
[edit] URTICARIA AND ANGIOEDEMA
Hives (urticaria) are often encountered in primary care practice and may or may not be a manifestation of an allergic reaction. These pruritic, raised lesions are caused by local vasodilation and accumulation of fluid in the superficial skin layers. Fluid entering the deeper tissues causes a nonpitting edema with erythema over a more diffuse area and is referred to as angioedema. Angioedema and urticaria may appear together or independently and more frequently affect young adults. Interaction of IgE on cutaneous mast cells with antigens causes the allergic forms of these disorders. Histamine is released from the mast cells and interacts with receptors in the venules, which dilate and leak fluid and inflammatory cells. If the symptoms persist for more than 6 weeks, the disorder is considered to be chronic. In the great majority of patients, no cause is ever found for chronic urticaria-angioedema. In addition to recurrent reactions to defined antigens, urticaria may be initiated by physical stimuli such as cold exposure or exercise (either of which can result in life-threatening anaphylaxis), heat, stroking (dermatographism), vibration, sun exposure, and pressure. Inherited and acquired deficiencies in the inhibitor (CINH) of the activated form of the first component of complement (C1) can result in angioedema not associated with urticaria. Urticaria can also be seen in some forms of vasculitis. Antihistamine therapy may be of some help in treating patients with these disorders, and steroids are also effective in some patients (see Chapter 95 ).
[edit] REFERENCES
- ↑ RF LemanskeJr, WW Busse: Asthma. JAMA 1997; 278:1855.
- ↑ MD Silverstein, CE Reed, EJ O'Connell,et al.: Long-term survival of a cohort of community residents with asthma. N Engl J Med 1994; 331:1537.
- ↑ R Djukanovic, WR Roche, JW Wilson,et al.: Mucosal inflammation in asthma. Am Rev Respir Dis 1990; 142:434.
- ↑ KB Weiss, PJ Gergen, TA Hodgson: An economic evaluation of asthma in the United States. N Engl J Med 1992; 326:862.
- ↑ AS Buist: Is asthma mortality increasing?. Chest 1988; 93:449.
- ↑ KM Venables, M Chan-Yeung: Occupational asthma. Lancet 1997; 349:1465.
- ↑ SM Brookes, MA Weiss, K Bernstein: Reactive airways dysfunction syndrome (RADS): persistent asthma syndrome after high level irritant exposures. Chest 1985; 88:376.
- ↑ 8.0 8.1 Guidelines for the diagnosis and management of asthma. NIH Pub No 97-4051 Bethesda, Md: National Institutes of Health; 1997:
- ↑ 9.0 9.1 Practical guide for diagnosis and management of asthma. NIH Pub No 97-4053 Bethesda, Md: National Institutes of Health; 1997:
- ↑ PJ Barnes, IW Rodger, NC Thomson: Asthma: basic mechanisms and clinical management ed 3. Philadelphia: Academic Press; 1998:
