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Bronchial Asthma

Diagnosis and Long-Term Treatment in Adults

Dtsch Arztebl Int 2008; 105(21): 385-94. DOI: 10.3238/arztebl.2008.0385

Ukena, D; Fishman, L; Niebling, W

Introduction: Bronchial asthma is a serious global health problem. 5% to 10% of persons of all ages suffer from this chronic airway disorder. This review article presents important considerations of diagnosis and treatment in view of the current national and international asthma guidelines.
Methods: Selective literature review, with attention to the current national and international guidelines.
Results/Discussion: Bronchial asthma is a chronic inflammatory disease of the airways characterized by bronchial hyperreactivity and a variable degree of airway obstruction. It is diagnosed on the basis of the clinical history, physical examination, and pulmonary function tests, including reversibility testing and measurement of bronchial reactivity. The goal of treatment is to control the symptoms of the disease effectively and in lasting fashion. Long-term treatment with inhaled corticosteroids is the basis of asthma treatment, alongside preventive measures and patient education. Bronchodilators such as beta-2-sympathomimetics are used for rapid symptomatic relief of acute attacks.
Dtsch Arztebl Int 2008; 105(21): A 385–94
DOI: 10.3238/arztebl.2008.0385
Key words: bronchial asthma, bronchial hyperreactivity, lung function, pharmacotherapy, inhaled corticosteroids
LNSLNS Recurrent episodes of acute shortness of breath, typically occurring at night or in the early morning hours, are the cardinal manifestation of bronchial asthma. Further symptoms include cough, wheezing, and a feeling of tightness in the chest. Asthmatic symptoms can often arise after physical exercise.

The following discussion of bronchial asthma is largely based on the German national care guidelines for asthma, on the international recommendations for asthma management of the Global Initiative for Asthma (GINA, www.ginasthma.com), and on the recommendations of the German Airway League (Deutsche Atemwegsliga) (13).

The learning objectives of this article are:

- to become acquainted with the various conditions that enter into the differential diagnosis of bronchial asthma, and
- to be able to apply the new types of treatment recommended for adult patients by the current national and international guidelines.

Depending on the severity of bronchial asthma in the individual patient, there may be phases of partial or total freedom from symptoms, alternating with periods of variably severe illness. This fact has been integrated into the definition of bronchial asthma, which is now defined as a chronic inflammatory disease of the airways characterized by bronchial hyperreactivity and a variable degree of airway obstruction (13).

Airway obstruction in bronchial asthma is mainly caused by the following four mechanisms (2):
- Contraction of bronchial smooth muscle
- Edema of the airway walls
- Mucous plugging of the bronchioles
- Irreversible changes in the lungs ("remodeling").

Bronchial asthma afflicts about 10% of children and 5% of adults. An atopic diathesis, i.e., a genetic predisposition toward the production of IgE antibodies in response to (for example) pollen, house dust mites, fungi, or animal-derived proteins, is the most important risk factor for bronchial asthma. In childhood, bronchial asthma is usually due to allergies; on the other hand, in 30% to 50% of adults with asthma, no allergy can be identified, at least not with the standard techniques. Non-allergic asthma in adults can arise, for example, after a viral infection of the lower respiratory tract. Viral infections can, in turn, promote the development of an allergic sensitization. Intrinsic asthma may reflect the simultaneous presence of sinusitis, nasal polyposis, and an intolerance to acetylsalicylic acid (ASA) or related non-steroidal anti-inflammatory drugs (NSAIDs); this is the so-called Samter’s syndrome.

Acute worsening of asthma (an asthma attack or exacerbation) can arise at any time without any prodromal symptoms and independently of the previous severity of the disease. Bronchial obstruction during an acute attack can progress, either slowly or rapidly, to life-threatening severity. The mortality due to asthma in Germany has declined by about one-third in the last decade, yet it nonetheless remains relatively high compared to that in other countries (2141 deaths due to asthma in 2004 according to the German Federal Statistical Office [Statistisches Bundesamt], 2005). The reduction in asthma-related mortality is generally attributed to the introduction of maintenance therapy with inhaled corticosteroids (ICS) (4). Around the world, however, there is little correlation between the lethality of asthma and its prevalence. The World Health Organization (WHO) estimates the number of DALYs ("disability-adjusted life years") lost to asthma at 15 million per year, which corresponds to 1% of the global loss of DALYs due to illness.

Diagnostic assessment
Airway obstruction is measured objectively with pulmonary function tests. The most important such test is spirometry, which measures the forced expiratory volume in one second (FEV1), the forced vital capacity (FVC), and the Tiffeneau parameters (FEV1/VC). Normal pulmonary function values do not rule out disease if they have been obtained during a symptom-free interval. Further aspects of the basic diagnostic assessment of bronchial asthma, including history-taking, symptoms, and physical findings, are summarized in box 1 (gif ppt) (13).

The practical value of peak expiratory flow (PEF) measurement lies in the determination of circadian variability, which is a suitable parameter for self-monitoring of asthma in outpatient follow-up. "Min % Max" is the minimal value of PEF expressed as a percentage of the maximal value, i.e., the lowest value in the morning prior to the administration of a bronchodilator drug as a percentage of the current best value. A circadian variability greater than 20% is typical of inadequately treated asthma (2, 5).

Standards and individualized norms exist for both PEF measurement and spirometry (2, 3).

Whole-body plethysmographic pulmonary function analysis provides further information, e.g., for the demonstration of obstruction (airway resistance, Raw) or overdistention (intrathoracic gas volume, ITGV). Objective criteria for the confirmation of the diagnosis of bronchial asthma are given in box 2 (gif ppt). An algorithm for the diagnostic assessment of asthma is shown in figure 1 (gif ppt).

Further diagnostic studies include, for example, bronchial provocation testing for the determination of bronchial reactivity; this kind of test is highly sensitive, but not very specific (6). Stepwise allergological testing includes skin-prick testing, the measurement of specific IgE in serum, and an allergen-specific nasal or bronchial provocation test. The use of non-invasive markers of airway inflammation, such as the nitrous oxide (NO) concentration in exhaled air or sputum eosinophilia, has not been prospectively validated for the establishment of the diagnosis of bronchial asthma, but can be helpful in therapeutic follow-up (7, 8). The indications for arterial blood gas analysis, determination of diffusion capacity, and radiological examination of the thoracic organs are determined individually, particularly for the purposes of differential diagnosis.

Differential diagnosis
The following entities should be considered in the differential diagnosis of bronchial asthma because of their frequency and clinical significance (1, 3):

- Chronic obstructive pulmonary disease (COPD)
- Hyperventilation
- Aspiration
- Laryngeal changes/vocal cord dysfunction
- Pneumothorax
- Cystic fibrosis (CF)
- Cardiac diseases, e.g., left heart failure
- Pulmonary embolism
- Gastroesophageal reflux disorder.

In as many as 10% to 20% of cases, a clear-cut distinction between asthma and COPD cannot be drawn.

The definition of controlled asthma
A four-part, multilevel treatment plan was previously recommended for the long-term treatment of bronchial asthma, based on a classification of disease severity by the clinical findings and the results of pulmonary function testing (1, 3). In the current "Global Strategy for Asthma Management and Prevention" issued by the Global Initiative for Asthma (GINA), however, the classification system is based on the degree of clinical control that has been achieved, ranging from "controlled" to "partly controlled" to "uncontrolled" (table 1 gif ppt) (2). This new classification is meant to emphasize the point that the severity of asthma depends not just on the severity of the underlying illness itself, but also on its response to treatment. Furthermore, the severity of asthma can fluctuate considerably over a period of months to years.

GINA's Global Strategy defines clinically controlled asthma as follows (2):

- No daytime symptoms at all, or at most two times per week
- No limitation of the activities of everyday living, including physical exercise
- No symptoms at night, or no awakening because of asthma
- No need for rapidly-acting bronchodilators for symptomatic treatment ("relievers"), or at most two times per week
- Normal or nearly normal pulmonary function
- No exacerbations.

The treatment of bronchial asthma
The definitive endpoint of asthma management is the achievement of the best possible quality of life. This includes, for example (1, 3) (evidence level D):

- No limitation of physical, emotional, or intellectual development in childhood and adolescence
- No symptoms and no asthma attacks
- Normal, or the best possible, physical and social activities in everyday life
- The best possible pulmonary function.

Non-pharmacological treatments are listed in Text box 3 (gif ppt) (1, 3).
The goals of pharmacotherapy are the suppression of the inflammation of asthma and the reduction of bronchial hyperreactivity and airway obstruction. The medications used for these purposes belong to two groups:

- Relievers (medications taken for symptomatic relief as necessary) include mainly the inhaled, rapidly-acting beta2 sympathomimetic agents, e.g., the short-acting drugs salbutamol, fenoterol, and terbutaline and the long-acting drug formoterol. Inhaled anticholinergic drugs and rapidly-acting theophylline (solution or drops) play a secondary role as relievers.
- Controllers (medications used for preventive, maintenance therapy) include the inhaled corticosteroids (ICS), inhaled long-acting beta2 agonists (LABA) such as formoterol or salmeterol, montelukast, and delayed-release theophylline preparations.

Formoterol can be used as a reliever because of its rapid onset of action or as a controller in combination with corticosteroids.

The undesired adverse effects that these medications can produce are listed in the e-box (gif ppt).

The anti-asthmatic drugs have been re-evaluated in the new GINA recommendations (2), as follows:

- Inhaled long-acting beta2 sympathomimetic agents (LABA), such as formoterol and salmeterol, should not be used for asthma monotherapy, but must always be given in combination with adequate doses of ICS. The reason for this is the possible association of LABA use with asthma-related death (9, 10).
- Leukotriene antagonists (in Germany, montelukast) are now more highly valued than before as asthma controllers, especially for patients who cannot or do not want to inhale corticosteroids, who experience intolerable ICS side effects such as persistent hoarseness, or who simultaneously suffer from allergic rhinitis.
- Cromones, such as cromoglicinic acid (DNCG) or nedocromil, are not a valid alternative to monotherapy with ICS for adult asthmatics.

The current GINA recommendations propose five steps of treatment (figure 2 gif ppt) (2). Often, the treatment of a previously untreated asthmatic is begun at step 2. For patients with "uncontrolled" asthma, as defined by the GINA classification, it is recommended that treatment should be begun at step 3.

At every step of treatment, a reliever (rapidly-acting bronchodilator) is used if necessary, e.g., a short-acting beta2 sympathomimetic agent or formoterol. The need to use a reliever is a sensitive indicator of the quality of asthma control; the reduction or elimination of this need is a good indicator of successful treatment (2). The symptomatic use of a rapidly acting bronchodilator characterizes step 1 (evidence level A).

In step 2, the preferred type of controller medication consists of inhaled corticosteroids (ICS) in a low dose (e.g., fluticasone, 100 to 250 µg/day, or budesonide, 200 to 400 µg/day [table 2 gif ppt]) (evidence level A). Alternatively, montelukast can be used as a controller (evidence level A).

In step 3, a combination of an inhaled corticosteroid (ICS) at a low dose and a LABA is the recommended treatment option, either as a fixed combination or as separate components (evidence level A). No advantage of fixed ICS/LABA combinations over a free combination of these two types of medication has yet been demonstrated.

Further options in step 3 – albeit with lesser clinical effectiveness – include intermediate- to high-dose ICS monotherapy (evidence level A) and a combination of low-dose ICS with montelukast (evidence level A).

In step 4, high-dose ICS is generally used in combination with LABA and montelukast, and possibly also with theophylline (evidence level B). In step 5, anti-IgE treatment is an option if the patient suffers from allergic asthma with multiple, severe exacerbations despite daily treatment with high-dose ICS and a LABA (evidence level B) (11). Patients with persistent, severe asthma may additionally need to take oral glucocorticosteroids either intermittently or as a maintenance medication, preferably as a single dose in the morning to minimize systemic side effects (evidence level D) (13).

It should be pointed out, as a critical observation, that neither the national nor the international treatment guidelines provide any information about the absolute risk reduction or NNT (number needed to treat) associated with the treatment modalities that they recommend (13).

New therapeutic concepts
As fixed combinations of ICS with LABA have become available over the last few years, new concepts for the treatment of asthma have been developed and clinically tested, with the goal of better control of bronchial asthma. These concepts take the varying pharmacological properties of the LABA into account (e.g., the rapid onset of activity of formoterol and the delayed onset of activity of salmeterol [12]).

The so-called GOAL concept ("gaining optimal asthma control") involves treatment with relatively high doses of fluticasone and salmeterol (e.g., twice-daily inhalation of 500 µg of fluticasone and 50 µg of salmeterol) in an attempt to achieve the best possible control (evidence level A) (13). If the patient becomes entirely asymptomatic, the treatment can be de-escalated in steps.

The SMART concept ("symbicort maintenance and reliever therapy"), on the other hand, involves the use of a fixed combination of budesonide and formoterol not just as a low-dosed maintenance therapy but also for the treatment of acute symptoms (asthma treatment with an inhaler) (evidence level A) (14, 15). This therapeutic modality can be helpful, for example, to patients whose asthma is poorly controlled with inhaled corticosteroids and acute bronchodilators.

Moreover, for patients with mild, persistent bronchial asthma, the use of a fixed combination of an inhaled corticosteroid and a short-acting beta2 sympathomimetic agent for symptomatic relief has been shown to be just as effective as maintenance therapy with an inhaled corticosteroid (evidence level B) (16).

These studies, taken together, imply a future shift in asthma therapy away from the treatment of acute symptoms with a bronchodilator alone and toward their treatment with a combination of an anti-inflammatory drug (i.e., an ICS) and a bronchodilator. This, in turn, implies a reduction in the need for maintenance therapy with controllers and an intensification of acute interventions. The long-term effects of this strategy, e.g., with respect to remodeling changes in the lungs, are as yet unknown.

Inadequate treatment benefit
If the initial treatment fails to achieve adequate control of the patient's bronchial asthma after it has been given for a certain period of time, e.g., one month, various further aspects should be considered:

- Checking the patient's adherence to treatment (drug-taking compliance)
- Checking the patient's inhalation technique through direct observation by the physician
- Re-evaluating the diagnosis: other differential diagnoses that may have to be considered include, for example, chronic obstructive pulmonary disease (COPD), airway narrowing by a tumor, vasculitis, and pulmonary embolism
- Persistent exposure to toxic substances and allergens
- Aggravating factors such as gastroesophageal reflux and chronic sinusitis.

Various treatment measures whose effectiveness has been demonstrated inadequately, or not at all, are listed in box 4 (gif ppt).

Allergen-specific subcutaneous immunotherapy
Allergen-specific subcutaneous immunotherapy (SCIT), also called "desensitization," has been shown to reduce medication use and bronchial hyperreactivity, as compared with placebo, in mild to moderately severe asthma, although it does not improve pulmonary function values (evidence level A) (3, 17). This statement applies mainly to younger patients. SCIT has a markedly lower chance of success in older patients who have had asthma for a long time, whose symptoms arise independently of allergen exposure, and for whom anti-inflammatory pharmacotherapy has been less effective. SCIT is contraindicated in patients whose pulmonary function is persistently impaired with FEV1 values below 70%. Specific immunotherapy should be performed only by a physician with experience in allergology. It does not replace effective anti-asthmatic pharmacotherapy, but should rather be seen as a complementary element of asthma management. There is accumulating evidence that SCIT can help prevent the progression of allergic rhino-conjunctivitis to allergic asthma in children and adolescents (evidence level B).

No definitive recommendation can be given as yet with regard to sublingual immunotherapy (SLIT) because of a lack of pertinent data from clinical trials.

Rehabilitation measures (evidence level B)
In- or outpatient pneumological rehabilitation should be considered particularly in the following situations (1, 3):

- in severe asthma with major sequelae despite adequate medical treatment,
- when the patient's working ability and earning capacity are endangered,
- when the need for nursing care and help with the activities of everyday life appears imminent,
- or when medically indicated non-pharmacological treatment measures such as patient education or training therapy cannot be carried out on an ambulatory basis.

Coordination of care
The long-term care of the patient, in the framework of a structured treatment program, is the responsibility of the primary care physician (1). Additional treatment by a physician specialized in respiratory medicine may be medically necessary as well, for any of the following reasons:

- Recurrent, severe exacerbations
- Complicating accompanying illnesses such as COPD or gastroesophageal reflux disorder
- Inadequate therapeutic benefit despite maximal treatment
- Maintenance therapy with oral corticosteroids
- Possible occupationally induced asthma
- Worsening control of asthma during pregnancy.

Conflict of interest statement
Professor Dr. med. Dieter Ukena has received lecture fees from Altana, AstraZeneca, GlaxoSmithKline, and Boehringer Ingelheim. Ms. Liat Fishman and Prof. Dr. med. Wilhelm-Bernhard Niebeling declare no conflict of interest as defined by the guidelines of the International Committee of Medical Journal Editors.

Manuscript received on 10 July 2007, revised version accepted on 1 October 2007.

Translated from the original German by Ethan Taub, M.D.


Corresponding author
Prof. Dr. med. Dieter Ukena
Klinik für Pneumologie und Beatmungsmedizin
Interdisziplinäres Lungenzentrum
Klinikum Bremen-Ost
Züricher Str. 40
28325 Bremen, Germany
dieter.ukena@klinikum-bremen-ost.de


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1.
Ärztliches Zentrum für Qualität in der Medizin (Hrsg.): Nationale Versorgungs-Leitlinie Asthma bronchiale (www.asthma.versorgungsleitlinien.de). Dtsch Arztebl 2005, 102(40): A 2734.
2.
Bateman ED, Hurd SS, Barnes PJ et al.: Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J 2008; 31: 143–78.
3.
Buhl R, Berdel D, Criee C-P, Gillissen A, Kardos P, Kroegel C et al.: Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma. Pneumologie 2006; 60: 139–83.
4.
Suissa S, Ernst P: Inhaled corticosteroids: impact on asthma morbidity and mortality. J Allergy Clin Immunol 2001; 107: 937–44.
5.
Reddel HK, Salome CM, Peat JK, Woolcock AJ: Which index of peak expiratory flow is most useful in the management of stable asthma? Am J Respir Crit Care Med 1995; 15: 1320–5.
6.
Cockcroft DW, Murdock KY, Berscheid BA, Gore BP: Sensitivity and specificity of histamine PC20 determination in a random selection of young college students. J Allergy Clin Immuno 1992; 89: 23–30.
7.
Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P et al.: Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002; 360: 1715–21.
8.
Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR: Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 2005, 352: 2163–73.
9.
Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM: The Salmeterol Multicenter Asthma Research Trial. A comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006, 129: 15–26.
10.
Nelson HS: Is there a problem with inhaled long-acting b-adrenergic agonists? J Allergy Clin Immunol 2006, 117: 3–16.
11.
Buhl R: Anti-IgE antibodies for the treatment of asthma. Curr Opin Pulm Med 2005, 11: 27–34.
12.
Barnes PJ: Scientific rationale for using a single inhaler for asthma control. Eur Respir J 2007, 29: 587–95.
13.
Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJH, Pauwels RA et al.: Can guideline-defined asthma control be achieved? The gaining optimal asthma control study. Am J Respir Crit Care Med 2004, 170: 836–44.
14.
O`Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist, Zhu Y et al.: Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med 2005, 171: 129–36.
15.
Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG: Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbation: a randomised, double-blind study. Lancet 2006, 368: 744–53.
16.
Papi A, Canonica GW, Maestrelli P, Paggiaro P, Olivieri D, Pozzi E et al.: Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma. N Engl J Med 2007, 356: 2040–52.
17.
Bousquet J, Lockey R, Malling HJ: Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper. J Allergy Clin Immunol 1998, 102: 558–62.
Klinik für Pneumologie und Beatmungsmedizin, Interdisziplinäres Lungenzentrum, Klinikum Bremen-Ost: Prof. Dr. med. Ukena
Ärztliches Zentrum für Qualität in der Medizin (ÄZQ), Berlin: Liat Fishman
Lehrbereich Allgemeinmedizin der Albert-Ludwigs-Universität Freiburg i. Br.: Prof. Dr. med. Wilhelm-Bernhard Niebling
1. Ärztliches Zentrum für Qualität in der Medizin (Hrsg.): Nationale Versorgungs-Leitlinie Asthma bronchiale (www.asthma.versorgungsleitlinien.de). Dtsch Arztebl 2005, 102(40): A 2734.
2. Bateman ED, Hurd SS, Barnes PJ et al.: Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J 2008; 31: 143–78.
3. Buhl R, Berdel D, Criee C-P, Gillissen A, Kardos P, Kroegel C et al.: Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma. Pneumologie 2006; 60: 139–83.
4. Suissa S, Ernst P: Inhaled corticosteroids: impact on asthma morbidity and mortality. J Allergy Clin Immunol 2001; 107: 937–44.
5. Reddel HK, Salome CM, Peat JK, Woolcock AJ: Which index of peak expiratory flow is most useful in the management of stable asthma? Am J Respir Crit Care Med 1995; 15: 1320–5.
6. Cockcroft DW, Murdock KY, Berscheid BA, Gore BP: Sensitivity and specificity of histamine PC20 determination in a random selection of young college students. J Allergy Clin Immuno 1992; 89: 23–30.
7. Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P et al.: Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002; 360: 1715–21.
8. Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR: Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 2005, 352: 2163–73.
9. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM: The Salmeterol Multicenter Asthma Research Trial. A comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006, 129: 15–26.
10. Nelson HS: Is there a problem with inhaled long-acting b-adrenergic agonists? J Allergy Clin Immunol 2006, 117: 3–16.
11. Buhl R: Anti-IgE antibodies for the treatment of asthma. Curr Opin Pulm Med 2005, 11: 27–34.
12. Barnes PJ: Scientific rationale for using a single inhaler for asthma control. Eur Respir J 2007, 29: 587–95.
13. Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJH, Pauwels RA et al.: Can guideline-defined asthma control be achieved? The gaining optimal asthma control study. Am J Respir Crit Care Med 2004, 170: 836–44.
14. O`Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist, Zhu Y et al.: Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med 2005, 171: 129–36.
15. Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG: Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbation: a randomised, double-blind study. Lancet 2006, 368: 744–53.
16. Papi A, Canonica GW, Maestrelli P, Paggiaro P, Olivieri D, Pozzi E et al.: Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma. N Engl J Med 2007, 356: 2040–52.
17. Bousquet J, Lockey R, Malling HJ: Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper. J Allergy Clin Immunol 1998, 102: 558–62.