Asthma

Asthma affects up to 15 million Americans and is the most common chronic disease of childhood. It accounts for more than 100 million days of missed school or work, results in 470 000 hospitalizations a year, and causes more than 500 deaths annually. Mortality rates have increased during the past 10 years, despite new treatments, and African-American persons suffer disproportionately high mortality.

Second National Heart, Lung, and Blood Institute Guidelines Were Issued

Guidelines for the Diagnosis and Management of Asthma: Expert Panel Report 2. Bethesda, MD: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute; 1997. NIH publication no. 97-4051.

The National Heart, Lung, and Blood Institute's National Asthma Education and Prevention Program convened two expert panels to prepare guidelines that provide physicians and other health care professionals with recommendations, based on scientific evidence, to aid in the diagnosis and management of asthma. Their reports were issued in 1991 and 1997. A summary of the 1997 recommendations follows.

It is now known that asthma is a chronic inflammatory disorder of the airways whose symptoms and signs result from a complex interaction of many cells and their components. These include mast cells, eosinophils, T lymphocytes, neutrophils, and epithelial cells. This inflammation causes an increase in bronchial hyperresponsiveness to a variety of specific and nonspecific stimuli. The diagnosis may be established when at least partially reversible episodic symptoms of airflow obstruction are present and alternative diagnoses are excluded (Table 1).

In the 1991 guidelines, asthma was classified as mild, moderate, and severe; in the 1997 guidelines, the classifications were changed to mild intermittent, mild persistent, moderate persistent, and severe persistent. The panel stressed that patients at any level of disease severity may experience a severe exacerbation (Table 2).

The 1997 report emphasizes the importance of using objective measures of disease severity and the fact that physicians who care for patients with asthma need to follow patient progress with spirometry for the purpose of diagnosis and office monitoring. In selected patients, peak expiratory flow rates may be monitored to determine diurnal variation as well as variation over time. Decreases in peak expiratory flow rates to less than 80% of a patient's personal best rate generally indicate a need for additional medication, and decreases to less than 50% of a patient's personal best rate indicate a severe exacerbation.

The panel recommends that, at a minimum, allergens that may contribute to asthma be identified in patients requiring daily medication, with appropriate avoidance advice and, in selected cases, allergen immunotherapy. Avoidance of allergens identified by skin testing is important in the overall treatment plan of patients with allergen-induced asthma. Although valuable, the clinical history alone is not a reliable method of determining all relevant allergen triggers (Table 3).

Panel recommendations for pharmacotherapy include a stepwise program beginning with as-needed use of ß₂ agonists for mild intermittent asthma and progressing to a multifaceted program for severe persistent asthma. Table 4 lists the steps in asthma management.

Daily Late Afternoon Steroid Dosing Is as Effective as Four-Times-Daily Dosing

Pincus DJ, Humeston TR, Martin RJ. Further studies on the chronotherapy of asthma with inhaled steroids: the effect of dosage timing on drug efficacy. J Allergy Clin Immunol. 1997; 100(6 Pt 1):771-4.

Adrenal glucocorticoid production is greatest near dawn, and several studies have shown varying effects of inhaled and oral glucocorticoids when the drugs were used at various times during the day. In this three-part study, Pincus and colleagues gave 800 µg of inhaled triamcinolone to 60 patients with documented asthma. The three regimens were 200 µg four times daily, 800 µg given at 8 a.m., and 800 µg given at 5:30 p.m. The results showed that morning peak expiratory flow rate improved 14% in the four-times-daily group, improved 4% in the 5:30 p.m. group, and did not change in the 8 a.m. group. Evening peak expiratory flow rate improved 4% in the four-times-daily group, 5% in the 5:30 p.m. group, and 2% in the 8 a.m. group. Although morning improvements in peak expiratory flow rates were smaller with once-daily than with four-times-daily dosing, the former regimen could be considered in patients for whom compliance is a problem.

Long-Acting ß₂ Agonists Were Superior to Short-Acting ß (₂) Agonists in Milder Asthma

Boulet LP, Laviolette M, Boucher S, et al. A twelve-week comparison of salmeterol and salbutamol in the treatment of mild-to-moderate asthma: a Canadian multicenter study. J Allergy Clin Immunol. 1997; 99:13-21.

The National Heart, Lung, and Blood Institute guidelines emphasize the use of long-acting inhaled ß₂ agonists for moderate to severe persistent asthma. Less emphasis is placed on such treatment for milder asthma, but Boulet and colleagues sought to determine the effects of long-acting ß₂ agonists in patients with this type of asthma.

In a multicenter clinical trial, 228 patients with mild to moderate asthma (mean FEV₁, 66% of predicted) were randomly assigned to receive either salbutamol, 200 µg four times daily, or salmeterol, 50 µg twice daily, for 3 months. Salbutamol is similar to albuterol and has clinical activity for 4 to 6 hours; the activity of salmeterol averages about 12 hours. Patients were assessed at 3 to 6 hours and 10 to 12 hours after treatment to ensure that dose effects were minimized.

The FEV₁ improved more substantially in the salmeterol group. The initial effect of salbutamol was equal to that of salmeterol, but FEV₁ dwindled steadily to near-baseline values by the time a second dose was required. Patients taking the longer-acting drug experienced no valleys in effect. Morning peak expiratory flow rate, days without symptoms, and absence of nighttime awakening were all superior among those taking salmeterol.

Thus, it seems that a second-line drug for patients with mild to moderate disease should probably be a long-acting ß₂ agonist such as salmeterol, usually used with an inhaled anti-inflammatory agent. First-line treatment remains anti-inflammatory therapy if short-acting bronchodilators are needed more than two to three times per week (Table 4).

Role of Leukotriene Antagonists Is Still Being Clarified

O'Byrne PM, Israel E, Drazen JM. Antileukotrienes in the treatment of asthma. Ann Intern Med. 1997; 127:472-80.

A major pathway of inflammation is the arachidonic acid cascade, which has a cyclooxygenase pathway and a leukotriene pathway. The latter results in at least four leukotrienes, at least three of which have been associated with asthma. Several leukotriene antagonists are now clinically available, but their ideal place in asthma treatment remains unclear.

In a systematic review of the evidence indicating that leukotriene antagonists are safe and efficacious in patients with asthma, O'Byrne and colleagues synthesized data from clinical trials reported through 1996. Published data revealed sound evidence that leukotriene antagonists were clinically active in patients with exercise-induced, cold air hyperventilation-induced, allergen-induced, and aspirin-induced bronchoconstriction and that these effects were additive to those caused by ß₂ agonists. Measures of efficacy have included asthma symptom scores, airflow obstruction, and use of rescue ß₂ agonists. Leukotriene antagonists have occasionally been associated with elevated hepatic enzyme levels, although hepatic failure is extremely rare. Case reports have also suggested a rare association between leukotriene antagonists and eosinophilic pneumonia.

The data reviewed are helpful, but further work is needed to establish the ideal role of leukotriene antagonists in asthma treatment. These agents seem particularly helpful in patients with "triad asthma" (asthma, nasal polyps, and aspirin sensitivity). Their role in managing severe asthma may increase as more data become available.

Asthma Mortality Was Usually a Result of Inappropriate Treatment

McFadden ER Jr, Warren EL. Observations on asthma mortality. Ann Intern Med. 1997; 127:142-7.

Despite the increasingly aggressive treatment of asthma, rates of death from asthma have increased (although the mortality rate in the United States is lower than that in most developed countries). In this paper, McFadden and Warren reviewed what is known about asthma mortality.

During the past 30 years, U.S. and Canadian case-fatality rates have remained a little less than 2 deaths per 100 000 patients. In the past decade, however, the U.S. case-fatality rate has increased from 1.3 to 1.9 per 100 000, a 46% increase but still a small number of deaths compared with the mortality rate of many other pulmonary diseases (for example, lung cancer kills more than 30 times as many persons annually). Of note, whereas most asthma deaths occur in patients with known severe disease, deaths occur even among those with asthma that had been considered very mild. Risk factors for death are shown in Table 5.

Mortality rates vary markedly among regions and ethnic groups. New York and Cook County, Illinois, accounted for 21% of all asthma deaths in the United States. Other cities with high populations of poor and minority citizens had disproportionately high numbers of deaths. The highest death rates are in African-American men.

Most patients die in the hospital, and evidence shows that the greatest threat to life is inappropriate or delayed treatment. Little evidence supports other potential causes of death, including medication side effects, tachyphylaxis to inhalers, and ß₂ agonist-associated cardiac arrhythmias. Harbingers of impending disaster are a pretreatment arterial oxygen saturation of less than 90%, normal or elevated PCO₂ levels after treatment, persistent metabolic acidosis, and severe obstruction that does not improve by at least 30% to 40% after treatment with sympathomimetic agents.

The prognosis after a near-fatal asthma episode is poor. About 10% of such patients die in the year after such an event. Given these trends, as well as the lack of early accurate predictors of potentially fatal asthma episodes, all exacerbations of asthma should be viewed as potentially fatal if they last longer than a few days or are particularly severe.

Rhinitis and Inhalant Allergens

Allergic rhinitis is the most common allergic disorder, affecting about 20% of the population. Worldwide surveys suggest that allergic rhinitis is becoming more common, with the steepest increase in incidence occurring in industrialized countries. Symptoms may be seasonal but are more commonly perennial. In addition, allergic rhinitis may lead to such complications as sinusitis and sleep disturbance, and it is associated with otitis media, nasal polyposis, and exacerbations of asthma.

Pathophysiology of Rhinitis Was Described

Baraniuk JN. Pathogenesis of allergic rhinitis. J Allergy Clin Immunol. 1997; 99:S763-72.

The most common conditions in clinical allergy and immunology involve the respiratory tract. In recent years, great advances have been made toward understanding the immune response, especially inflammation. This has not only helped researchers but has prompted the development of new drugs to treat both rhinitis and asthma. In this review, Baranuik summarized current concepts about the pathogenesis of allergic rhinitis.

The respiratory mucosa is constantly assailed by countless antigens, including pollen grains, animal dander, airborne molds, and dust mite fecal particles. These allergens, which deposit on the respiratory mucosa, are thought to be processed by Langerhans cells and, possibly, other antigen-presenting cells. The allergens are then cleaved into smaller amino acid chains, which may bind to MHC class II molecules. Reflecting their genetically discrete hosts, the various types of MHC class II molecules help determine whether the immune system will mount a response to that peptide. Antigen-presenting cells then make their way to lymphoid tissue and subsequently (at an unknown location) present antigens to naive Th0 lymphocytes from the thymus. Numerous cellular interactions then occur, and cytokines may be exchanged between the two cells. This peptide-specific Th0 cell then differentiates into a Th2 lymphocyte, which is committed to release a characteristic combination of cytokines capable of maintaining a pro-atopy environment, stimulating induction of IgE-producing B cells, and inhibiting competing immune responses (such as the development of Th1 delayed-type hypersensitivity responses).

B cells bearing IgM that recognize antigen to which a person has been sensitized undergo heavy-chain switching to produce IgE. Continued antigenic exposure leads to higher-avidity IgE molecules. This IgE may circulate, with some remaining unbound and some binding to Fc receptors on the surface of mast cells and basophils. Degranulation of mast cells is the primary initiating event responsible for the production of allergic symptoms. Histamine, tryptase, prostaglandins PGD-2 and PGF-2, and bradykinin are released rapidly by the mast cell during the immediate allergic response. Mast cells and eosinophils also preferentially generate the peptidyl leukotrienes LTC-4, LTD-4, and LTE-4. These substances interact with LTD-4 receptors to increase vascular permeability, induce glandular exocytosis, and contribute to increased airway mucosal hyperresponsiveness. Pharmaceutical antagonists active in the leukotriene pathway are now available commercially or experimentally; these include 5-lipoxygenase inhibitors (for example, zileuton), 5-lipoxygenase activating protein inhibitors, LTB-4 antagonists, and cysteinyl leukotriene antagonists (for example, zafirlukast, pranlukast, and verlukast).

Histamine is critical in the production of allergic symptoms, accounting for about half of the symptoms seen in allergic rhinitis. This substance is released by mast cells in the immediate phase and by basophils in the late phase, which occurs 4 to 6 hours later. Histamine is now also known to bind to H₁ receptors on nociceptive type C nerves, which are extensively present in the mucosa and submucosa. Depolarization of these nerves may lead to release of neurotransmitters, such as substance P. The role of neurogenic inflammation in the production of human allergic symptoms is still under investigation.

After the immediate allergic response, the mucosa ushers in inflammatory cells to produce the late allergic response, which is accompanied by the recruitment of inflammatory granulocytes: eosinophils, basophils, and neutrophils.

An intriguing new chapter in our understanding of this process has been the ongoing elucidation of the role of cellular adhesion molecules in cellular recruitment. Endothelial cell glycoproteins called selectins may interact with leukocyte glycoproteins to contribute to tissue-specific homing of various T-cell subsets. Other adhesion molecules in the immunoglobulin gene superfamily include intercellular adhesion molecules 1 and 2, platelet endothelial cell adhesion molecule 1, and vascular cell adhesion molecule 1. These molecules may interact with cell surface molecules on various inflammatory cells to allow these cells to zero in on the site of inflammatory action. Allergic inflammatory cytokines, viral infections, and, possibly, allergen immunotherapy affect the concentration of these adhesion molecules.

Once attracted to the site of inflammation, such as the nasal or bronchial mucosa, the eosinophil is a major villain responsible for mucosal airway inflammation and production of symptoms. Highly charged eosinophil granules comprise major basic protein, eosinophil cationic protein, eosinophil-derived neurotoxin, and eosinophil peroxidase. These may bind to basement-membrane proteoglycans and hyaluronan and cause cellular disaggregation and epithelial desquamation. The goal of treatment is to mitigate this inflammation. Future therapy will increasingly target specific inflammatory processes.

Management of Rhinitis Begins with Allergen Avoidance

Naclerio R, Solomon W. Rhinitis and inhalant allergens. JAMA. 1997; 278:1842-8.

In this clinical review, Naclerio and Solomon discuss the background, clinical presentation, and treatment considerations of allergic rhinitis. Aeroallergens, usually 5 to 70 µm in diameter, are commonly associated with allergic rhinitis. These include tree, grass, and ragweed pollens; indoor and outdoor fungi; animal allergens; and, perhaps most important, dust mites and their droppings. Dust mites are fairly ubiquitous and are about 150 µm in size. They live in bedding, carpets, and upholstery. Tree pollen peaks in the spring, grass pollen in midsummer, and weed pollen in the autumn, and fungi are abundant from spring to mid-winter. Among animals, different substances are important. For example, rat urine is highly allergenic, as are proteins from cat saliva, urine, and dander.

Symptoms of allergic rhinitis may include congestion, rhinorrhea, postnasal drip, sneezing, itchy nose, watery eyes, headaches over parasinus areas, and loss of smell and taste. These symptoms are nonspecific, however, and can be induced by many causes other than rhinitis. Itching of mucous membranes and repetitive sneezing are more specific symptoms of allergic rhinitis, but the most specific symptom is correlation of any of the above symptoms with allergen exposure. Physical examination may show pale, boggy mucosa, but this finding is also nonspecific. Therefore, the best tests to diagnose allergic rhinitis are an exacting history and allergen testing.

Allergen skin testing is very sensitive. Therefore, it is critical that historical findings be matched with skin test results. Radioallergosorbent tests (RAST) and enzyme-linked immunosorbent assays can detect IgE antibodies in serum, but these tests are not as sensitive as and are more expensive than skin testing.

The gold standard of treatment is allergen avoidance. Because reducing moisture is key to minimizing both fungi growth and dust mite propagation, decreasing indoor humidity is helpful. Encasing mattresses and pillows in dust-proof covers, washing bedding in hot water weekly, and using dust masks while vacuuming are also excellent ways to avoid dust mite exposure. Removal of carpets has also been shown to help [1]. Pollens are difficult to avoid, although air conditioning can be beneficial. Animal allergens from pets are extremely difficult to avoid, and even frequent bathing of pets may not substantially decrease allergen production.

Antihistamines control itching, sneezing, rhinorrhea, and eye irritation but are not generally effective for nasal congestion. Nonsedating antihistamines are generally preferred. Terfenadine (which has been removed from the U.S. market) and astemizole have been linked to electrocardiographic prolongation of the Q-T interval and to serious ventricular arrhythmias. These rare events seem to occur primarily in patients with elevated drug levels, which can occur when these drugs are given with macrolide antibiotics and imidazole antifungal agents.

Oral decongestants help patients with nasal congestion but may also exacerbate hypertension, thyrotoxicosis, and glaucoma. Topical nasal decongestants rarely have a role in the treatment of nasal allergy, although they may be helpful for brief periods (2 to 5 days) in the treatment of severe nasal congestion accompanying an upper respiratory tract infection or acute sinusitis.

Intranasal steroids are effective in the treatment of allergic rhinitis, especially when used prophylactically. They may decrease the speed of nasal polyp development and may retard the recurrence of these polyps after surgical removal. Orally inhaled and nasal topical steroid preparations may have an additive systemic effect, albeit a small one. These agents should be used with caution, if at all, in patients with glaucoma. A common adverse effect is epistaxis, which occurs when the steroid is too effective at drying the nasal mucosa. If epistaxis develops, many physicians will halt therapy with the medication, use saline sprays until epistaxis episodes end, and restart nasal steroid therapy at about half the previous dose. If epistaxis recurs, alternative therapy should be used.

Systemic steroid treatment, especially depot injections, was once given at the onset of a patient's allergy season. Depot injection is cost-effective, and patients may like the convenience. However, it has many problems. First, it has been associated with subcutaneous atrophy and, with prolonged use, osteoporosis. Second, absorption of depot preparations is not completely predictable. Third, the advent of effective topical steroid therapy has decreased the necessity of using systemic steroid therapy for allergic rhinitis.

Nasal ipratropium bromide helps relieve rhinorrhea but is generally not effective for other nasal symptoms, such as congestion and sneezing. Allergen immunotherapy may be used when symptoms are prolonged during the year, are excessively severe or incapacitating, or are not adequately controlled by pharmacotherapy. The effectiveness of allergen immunotherapy in allergic rhinitis, directed against dust mites, molds, pollens, and animal danders, has been clearly documented. Potential systemic reactions are highly unlikely with careful dose titration and monitoring in the hands of physicians familiar with its use.

Recent data also suggest that indoor allergen levels are important in the sensitization to common allergens, such as cat dander and dust mites. Furthermore, in persons with an allergic disposition (for example, those with a strong family history of allergic disease), allergen avoidance early in life may prevent sensitization. Allergen immunotherapy has also been shown to alter the natural course of allergy in children by helping to prevent the development of new sensitizations to other allergens [2]. Altering the natural course of allergic disease and asthma is an exciting new area of research. As our understanding of the impact of immunotherapy on various aspects of the allergic inflammatory process becomes clearer (for example, effects on adhesion molecule expression and eosinophil recruitment), we should expect to move closer to that goal.

Rhinitis Was Linked to Asthma

Corren J. Allergic rhinitis and asthma: how important is the link? J Allergy Clin Immunol. 1997; 99:S781-6.

Many practicing allergists and primary care physicians recognize that patients often have both allergic rhinitis and asthma. Corren synthesized the current knowledge of this association and the implications for treatment and research.

Epidemiologic studies show that up to 78% of patients with asthma also have rhinitis symptoms, and up to 38% of patients with allergic rhinitis have asthma symptoms. The studies have also shown a temporal relation between the two conditions. Rhinitis tends to predate asthma in most patients, and ongoing exposure to an allergen may increase the risk for subsequently developing asthma. The observation that treatment of allergic rhinitis may also alleviate asthma symptoms has increased interest in the associations between these two respiratory disorders. The administration of intranasal steroids during the pollen season can prevent the increases in nonspecific bronchial hyperresponsiveness normally seen during that season. In patients with perennial rhinitis, intranasal steroid therapy reduces daily asthma symptoms, exercise-induced bronchospasm, and bronchial responsiveness to methacholine. The mechanisms underlying these observations are not clear.

Nasal allergen provocation may also increase lower-airway reactivity within 30 minutes, suggesting a possible neural reflex. Improvements in lower-airway function after treatment of upper-airway symptoms may result from improved warming and humidification of inspired air, decreased inhalation of inspired allergens, a decreased nasal-bronchial reflex, or other mechanisms. Postnasal drainage of inflammatory cells during sleep may also affect the responsiveness of the lower airways. Future research is needed to determine the extent to which treatment of upper-airway allergy alters the natural history of asthma.

Other conditions have strong associations with allergic rhinitis [3]. These include chronic sinusitis and otitis media, both of which respond to treatment of the rhinitis; upper respiratory tract infections; and nasal polyposis.

Latex Sensitivity

Immediate IgE-mediated allergic reactions to latex products have become increasingly recognized in medical workers and others who have begun to use rubber latex gloves more routinely. Latex gloves are the largest single source of exposure to these allergens, which may trigger reactions ranging from symptoms of mild allergic rhinitis to severe anaphylaxis resulting in death. In most cases, sensitization to latex proteins is related to exposure to latex-glove allergens. Exposure may occur through direct contact with an offending device or through inhalation of the latex allergen, which may be "carried" by the cornstarch powder used in most powdered latex gloves. Ongoing exposure to latex proteins may also result in occupational asthma to the latex proteins. If exposure continues, asthma may progress to the point of persistent impairment or disability.

Guideline Sought To Minimize Health Care Workers' Exposure to Latex

AAAAI and ACAAI Joint Statement concerning the use of powdered and non-powdered natural rubber latex gloves. Ann Allergy Asthma Immunol. 1997; 79:487.

More than 5% of hospital workers develop clinical allergies to latex and continue to remain in contact with latex proteins [4]. Dental students and faculty are also at high risk for latex sensitization [5]. An increasing duration of exposure correlates with an increasing risk for sensitization and development of latex allergy.

In late 1997, the American Academy of Allergy, Asthma, and Immunology and the American College of Allergy, Asthma, and Immunology issued a joint statement regarding this increasingly common problem. The guidelines propose that latex gloves should be used only as mandated by accepted universal precautions. The routine use of latex gloves by personnel in low-risk situations (food preparation, housekeeping, patient transport, and routine physical examination) should be discouraged.

When these gloves are necessary, the statement proposes that only low-allergen, powder-free latex gloves be worn. This practice will reduce the reaction rate among persons who are already sensitized and may reduce the rate of sensitization. Using powder-free latex gloves will decrease the airborne levels of latex allergen and should also decrease the risk for both sensitization and reactions in those already sensitized.

Summary

Top Summary Author & Article Info References

Internal medicine has witnessed astounding developments in our understanding of the immune system's role in the pathophysiology of many diseases. The present challenge is to harness this knowledge to develop more effective therapies for immune-related illness. Guidelines for the care of common illnesses such as asthma may encourage appropriate clinical application of advances in our armamentarium against immune disease.

Dr. Roberts (Series Editor): Madrona Medical Group, 3199 Steller Court, Bellingham, WA 98226.