Introduction
The topic of mild asthma was addressed at the 60th Annual Meeting of the
American College of Allergy, Asthma and Immunology in San Antonio,
Texas. Asthma is a disease characterized by significant variability.
Exposure to allergen or common viral respiratory tract infections may
trigger an exacerbation. These flares of symptoms will respond to
therapy or reverse spontaneously. Furthermore, there is a diurnal
variation in the intensity of asthma reflecting time of day differences
in mediator release and endogenous glucocorticoid and catecholamine
levels. The 1997 National Heart, Lung, and Blood Institute (NHLBI)
Guidelines for the Diagnosis and Management of Asthma[1]
established criteria for disease severity classification. Daytime
symptoms for patients with mild persistent asthma occur more than twice
a week but less than daily and for nighttime symptoms occur between 2
and 4 times a month. Does disease variability limit the applicability of
this classification scheme?
The Agency for Healthcare Research and Quality (AHRQ) was contracted to
perform the evidence-based review for the 2002 NHLBI guideline update.
In their discussion of disease classification, the AHRQ stated that
"asthma is a chronic disease characterized by differing frequencies of
daily symptoms, exacerbations, and remissions, (and) characterizing
disease severity is problematic."[2] AHRQ noted that disease
severity was confounded by the lack of inclusion of use of inhaled
corticosteroids or other controller medications, the duration of asthma,
or the presence of atopy. In their review, the AHRQ suggested the use of
3 classifications of persistent asthma: mild-moderate, moderate, and
severe.
Mild Asthma
Inflammatory Pathology In the first
presentation of this symposia, James Donahue, MD,[3] Chief of
Pulmonary Division and Critical Care Medicine, University of North
Carolina School of Medicine, Chapel Hill, North Carolina, presented some
of the background for this discussion. From a clinical perspective, the
difficulty with asthma is that disease severity is frequently
underestimated by both patients and healthcare workers. Patients
underreport symptoms and physicians underdiagnose disease severity.
Patients may be diagnosed as being intermittent asthmatics if symptoms
alone are assessed. When patients' medications are factored into the
disease classification, then 40% of intermittent asthmatics now appear
to have persistent disease.
Inflammation noted on biopsy is recognized in the guidelines as a common
feature of all levels of persistent asthma. Disease severity is based on
clinical assessment rather than biopsy data. Donahue next presented a
paper by Van den Toorn and colleagues[4] that demonstrated
that young adults with asthma in remission, no symptoms for greater than
1 year, still had evidence of active airway inflammation. Biopsies of
their airways looked more like patients with active asthma than
individuals who never had asthma. The asthmatics in remission had
evidence of increased major basic protein, elevated levels of exhaled
nitrous oxide, and increased collagen deposition in their subbasement
membrane, all indicating evidence of ongoing inflammation in their
airway biopsies. This study raises some very critical issues.
Clinically, these patients do not have evidence of persistent asthma,
but pathologically, their asthma is still active. How should they be
classified? Should they be treated? Even patients with milder disease
can be at risk for serious exacerbations. The question was raised as to
whether this ongoing inflammation places these patients at greater risk
for relapse. This study also suggests that children with asthma may not
outgrow their asthma.
Donahue then reviewed the study by Moore and colleagues,[5]
who performed allergen challenge in patients with both mild and moderate
persistent asthma. Patients were grouped by the impairment in lung
function and degree of airway hyperreactivity. After allergen challenge,
the authors quantitated the changes in cellular response and cytokine
and protein concentrations. These responses were the same for both mild
and moderate persistent asthmatics. Post-challenge, there were similar
increases in total cells, eosinophils, and macrophages. Cytokine and
protein concentrations increased with the same intensity in both groups
of patients and were not distinguished by disease severity. This study
confirms the difficulty in disease severity classification and
illustrates how the inflammatory process and risk of exacerbation is
similar across severity stratifications.
In a study by Louis and colleagues,[6] 3 groups of patients
with asthma were investigated. They were classified as intermittent,
mild to moderate, and severe persistent asthmatics. In this study, the
authors were able to differentiate by disease severity with greater
evidence of eosinophils and macrophages in the sputum as disease
severity increased. Tryptase levels and increased albumin in the sputum,
though, did not correlate as strongly with disease severity. What was
important in this paper is the finding of significant inflammation even
in the patients with intermittent disease. Inflammation is a potential
risk factor for severe consequences of asthma and warrants appropriate
therapy. How we classify disease severity has a direct bearing on how we
treat patients with asthma.
When Do You Treat Mild Asthma and With How Much?
Harold S. Nelson, MD,[7]
addressed the question of therapy of mild asthma. The National Asthma
Education and Prevention Program (NAEPP) presents as goals of therapy
the treatment and prevention of symptoms and exacerbations. Potential
complications of mild asthma include decreased quality of life,
exacerbations, airway remodeling, and even death. Approximately 40% of
patients have mild intermittent or persistent asthma, according to the
Asthma in America study. However, in a recent publication by Fuhlbrigge
and colleagues,[8] they explored disease classification. When
patients were assessed based on short- and long-term symptoms,
researchers found that up to 60% of patients had mild intermittent to
mild persistent disease. When the functional impact of the disease was
included in the assessment of disease severity, this number fell to 22%,
reflecting the large majority of patients now diagnosed with moderate to
severe persistent asthma.
Dr. Nelson noted that patients with asthma and normal daytime spirometry
may still have significant impact on their quality of life. In the
OPTIMA trial,[9] 33% of patients with mild asthma with normal
lung functions and mild symptoms treated with placebo had a severe
asthma exacerbation over the subsequent year. These events were severe
enough to cause a hospitalization, emergency department visit, require
prednisone, or a 25% variability in their peak flow rate on 2
consecutive days. Treatment of these patients with inhaled
corticosteroids reduced the rate of exacerbations by more than 50%. In
this trial, there was a second group of patients who were being treated
with inhaled corticosteroids at the time of enrollment. These patients
were "mildly symptomatic." When these patients were treated with the
combination of inhaled corticosteroids and a long-acting inhaled
bronchodilator, there was a further reduction in the rates of serious
exacerbations. This study describes the importance of recognizing the
patients at risk for an exacerbation and the need to use appropriate
preventive medications to reduce the risk of these flares of disease.
Several studies have demonstrated that patients with more mild asthma
are at risk for sudden death from asthma. Dr. Nelson discussed the paper
by Robertson and associates[10] that studied 51 children who
had died of asthma. This study retrospectively investigated whether
children were correctly assessed for disease severity based on medical
records and interviews. One third of the fatalities were in children
with perceived mild asthma. Whether their disease was truly mild or the
perception of their disease as mild is not as important as the fact that
these children were undertreated. Most were not on controller therapy
with inhaled corticosteroids.
Dr. Nelson next reviewed the evidence for the 2002 Update of the NAEPP
Guidelines. The Childhood Asthma Management Program[11]
demonstrated the value of using inhaled corticosteroids in the treatment
of children with a baseline forced expiratory volume in 1 second (FEV1)
of 94% who were considered mild to moderate persistent asthmatics.
Children treated with inhaled corticosteroids had a 40% to 45% reduction
in hospitalizations, emergency department visits, and prednisone use --
all significant reductions in severe exacerbations. No significant
adverse effects were noted with this treatment.
The guideline review demonstrated that use of other controller
medications as primary therapy, including theophylline, salmeterol, or
leukotriene modifiers, did not appear to be as effective as inhaled
corticosteroids. To illustrate this point, he reviewed a study by Busse
and colleagues[12] that demonstrated greater improvement in
lung function, symptom-free days, albuterol use, and nighttime
awakenings. This is one of the articles that was used in the AHRQ
evidence-based review.
Dr. Nelson concluded his presentation with 2 important questions. First
is the question of when to treat. Patients should be treated if they do
not meet the goals of the asthma guidelines, including symptoms,
pulmonary function, and prevention of exacerbations. Second is the
question of how much to treat. One may start with monotherapy with
low-dose inhaled corticosteroids but increase to add a long-acting
inhaled bronchodilator if the goals of therapy are not achieved. Mild
asthmatics are at risk for serious exacerbations and should receive
appropriate controller therapy.
The Role of Immunotherapy in Mild Asthma The third presentation at the
symposium was by Peter S. Creticos, MD,[13] of Johns Hopkins
Asthma and Allergy Center, Baltimore, Maryland. This was a discussion on
the role of immunotherapy in the treatment of mild asthma. The success
of immunotherapy in asthma is based on the proper selection of patients.
Patients with mild disease appear to be good candidates, with some
evidence demonstrating that this therapy may modify disease progression.
Caution needs to be exercised in the treatment of patients with more
severe disease because of the greater risk of side effects from the
treatment. Dr. Creticos then reviewed the literature comparing the value
of immunotherapy for various allergens. This is an area of intense
research and potential for significant change in disease pathology.
This symposium demonstrated the need for appropriate assessment of
disease severity and implementation of therapy to prevent the
consequences of untreated or under-treated asthma. The NAEPP has
developed evidence-based guidelines to address the therapy of asthma.
Disease classification is dependent on appropriate clinical assessment.
Inflammation is an important component of all persistent asthma and
potentially even intermittent asthma. The intrinsic variability of
asthma must be reflected in disease classification.
References
For more information contact:
Alan L. Wozniak, CIAQP
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