ENTRY CRITERIA

1
Decline in Asthmatics' Personal Best FEV1 Is Not
Associated with Progressive Obstruction as
Measured by Spirometry D. Kaelber, J.A. Nelson,
L.F. Strauss, E. West, I.A. Gilbert. Medical
College of Wisconsin, Milwaukee, WI Case Western
Reserve University, Cleveland, OH
Results
Methods
Decline in Asthmatics' Personal Best FEV1 Is Not
Associated with Progressive Obstruction as
Measured by SpirometryD. Kaelber, J.A. Nelson,
L.F. Strauss, E. West, I.A. Gilbert. Medical
College of Wisconsin, Milwaukee, WI Case
Western Reserve University, Cleveland,
OHRATIONALE Asthmatics may show an enhanced
loss of FEV1 but little data exist as to whether
this is due to worsening of underlying
obstruction, stiffening of the lungs from airway
scarring, and/or changes in inhaled steroid use.
METHODS We analyzed spirometry for 125 patients
(72 women 47/- 1 yrs old 18/-1 yrs with
asthma) enrolled in a subspecialty clinic for at
least 30 months with 9 prospective determinations
of clinical and functional status. RESULTS
Initial pre-bronchodilator FEV12.11/-.08L,
78/-2 FVC2.95/-.10L, 90/-2 predicted 81
moderate to severe persistent symptoms and 42
on no inhaled steroids. By 6 months, 22 moderate
to severe persistent symptoms, averaged
pre-bronchodilator FEV1 and FVC increased to
2.25/-.07 and 3.08/-.08L, and 99 on inhaled
steroids, p less than .001,with no changes
subsequently. Personal best FEV1 and FVC rose by
6 months, but declined, thereafter (6month FEV1
and FVC2.62/-.07 and 3.48/-.09 30
month2.44/-.07 and 3.25/-.08L, p less than
.01). FEV1/FVC ratio did not change for either
averaged or personal best indices. 61 had
inhaled steroids decreased after 18months without
worsening in symptoms or averaged lung function.
However, personal best FEV1 and FVC fell in this
group, p less than .05. CONCLUSIONS Loss of lung
function was not totally accounted for by
worsening obstruction and may represent scarring
leading to restriction. Even when symptoms and
pre-bronchodilator spirometry are stable,
decreases in inhaled steroids may be associated
with declines in personal best lung function.
This abstract is funded by HL03320
Asthma outcomes
Personal best lung function
ENTRY CRITERIA All patients presenting to a
Guidelines- directed, inner-city, asthma clinical
management and education program from 1996-2000
eligible for inclusion Diagnosis of asthma
confirmed by compatible symptoms and physical
examination and demonstration of reversible
airflow obstruction Smoking history lt15 pack
years lifetime No concurrent cardiopulmonary
illnesses other than hypertension Compliance with
clinical visits, patient education curriculum,
and pharmacotherapy for no less than 30 months
and 9 program encounters SUBJECTS (N
125) Mean (SEM) Age 47 (1) years 72 Female,
28 Male 50 African American, 30 Caucasian, 20
Hispanic Age of Onset of Asthma 28 (2) Years
with Asthma 18(1) 64 Lifetime Nonsmokers 25
Past and 11 Current Smokers 2(.5) pack
years Length of Program Enrollment 39 (1)
months Number of Program Encounters 17
(1) LUNG FUNCTION MEASUREMENTS Spirometry
performed pre and post bronchodilator at each
clinic encounter Predicted values age, sex,
height, weight, and race corrected Knudson,
1983 PROSPECTIVE OUTCOME MEASURES Symptom
Severity Classification as per the NAEPP
Guidelines (Mild Intermittent or Mild, Moderate,
or Severe Persistent) FVC, FEV1, and FEV1/FVC
ratio pre and post bronchodilator as determined
by spirometry (at program entry, averaged over
each 6 month interval, and personal best for each
6 month period) Level of Inhaled Corticosteroid
use as per the EPR 2, 2002 comparability
classifications STATISTICAL
ANALYSIS Data were analyzed by paired and
unpaired t-tests and Pearsons chi-square
test. Minimal significance at the .05 level after
the Bonferroni correction when indicated
Months from program entry
Averaged Asthma Symptom Severity Class and Pre-
Bronchodilator Lung Function as a function of
Months from Program Entry The graph at the left
depicts the averaged symptom severity score and
the graph at the right averaged
pre-bronchodilator lung function at entry (0
months) and over 0-6 (6), 6-12 (12), 12-18 (18),
18 to 24 (24), and 24 to 30 (30) months. The
data points are mean values and the brackets
represent one standard error of the mean.
Symptom severity decreased significantly from
entry through 6 months, with the maximum
decrement occurring by 12 months. Thereafter, no
significant changes were observed. Averaged
pre-bronchodilator forced vital capacity and one
second forced expiratory volume improved
significantly and maximally from program entry to
6 months, with no significant changes occurring
thereafter. Not shown, the one- second forced
expiratory volume to forced vital capacity ratio
did not change at any point in the observation
period - .72 (.01), 87 (1) of predicted at
entry.
Months from program entry
Personal best lung function with respect to
Months from Program Entry The graph at the left
depicts the maximum forced vital capacity and
one- second forced expiratory volume recorded
during each period of observation. Both
parameters rose significantly over the first 6
months of program entry, but thereafter fell.
Not shown, there were no changes at any point in
time in the one-second forced expiratory volume
to forced vital capacity ratio - .73 (.01), 88
(1) of predicted at program entry. The graph
at the right illustrates the observed and
predicted (Lange, 1998) changes in personal best
one second forced expiratory volume over the 1st
year following optimization (6 to 18 months
period) in which there were no significant
changes in inhaled steroid dose and the 2nd year
(18 to 30 months period) in which levels
declined. The white bars represent the decline
in one- second forced expiratory volume for the
group as a whole, the yellow bars the stable dose
of inhaled steroid patients, the green bars the
decreased dose patients, the black bar the yearly
predicted fall for normal individuals, and the
blue bar the yearly predicted fall for
asthmatics. From 6 to 18 months, all 3-subject
groups demonstrated an equivalent decline in
maximum achievable one-second forced expiratory
volume that exceeded the predicted yearly
declines for both normal and asthmatic
individuals. From 18 to 30 months, the rates of
decline in personal best one- second forced
expiratory volume decreased, but for the group as
a whole and the decreased inhaled steroid
asthmatics, the falls in this parameter continued
to exceed both predicted values and were greater
than for the stable inhaled steroid dose
patients. Of note, their were no significant
differences between the stable and decreased
inhaled steroid dose patients with respect to
age, gender, race or ethnicity, age of onset of
asthma, years with asthma, smoking history, or
measured personal best one-second forced
expiratory volume throughout the first 18 months
of program participation.
Background and Objectives
Change in inhaled steroid use

• BACKGROUND
• Loss of lung function over time has been found to
  occur in asthmatics at an accelerated rate
  compared to non-asthmatics (Lange et al, 1998)
  and may be due to inadequate control of airway
  inflammation leading to irreversible airway
  remodeling.
• The National Asthma Education and Prevention
  Program Guidelines recommend instituting the use
  of inhaled steroids early and at levels in
  concordance with or one step higher than
  objective measures of symptom severity and lung
  function, with subsequent tapering once
  optimization has occurred.
• Histologic studies have shown that following
  measures of bronchial reactivity may be more
  effective at minimizing airway inflammation and
  guiding therapy than clinical and functional
  indices of asthma severity (Sont et al. 1999) and
  that even mild to moderate asthmatics require
  high doses of inhaled steroids to reduce
  submucosal vascularity and basement membrane
  thickness (Chetta et al, 2003).
• Little data exist as to whether progressive loss
  of lung function differs in asthmatics that
  remain on high doses of inhaled steroids despite
  clinical and functional optimization compared to
  those whose anti-inflammatory therapy is tapered
  as per the recommendations of the Guidelines.
• OBJECTIVES
• Delineate the natural history of lung function in
  otherwise healthy asthmatics that are
  prospectively managed and monitored according to
  the principles of the EPR 2, 2002
• Retrospectively analyze if tapering inhaled
  corticosteroids according to clinical and
  functional severity impacts upon spirometric
  indices of airway obstruction

Conclusions

• Improvements in averaged level of symptom
  severity and pre-bronchodilator lung function can
  be achieved and maintained for demographically
  high risk, inner city asthmatics undergoing
  Guidelines- directed management, including the
  tapering of inhaled steroids commensurately with
  these disease severity indices.
• Once clinically and functionally optimized,
  asthmatics personal best one- second forced
  expiratory volume shows an early and accelerated
  rate of decline, even when anti-inflammatory
  therapy is held constant and clinical and
  pre-bronchodilator lung function appear stable.
• Retrospective analysis of pharmacotherapy use
  indicates that subsequent loss of personal best
  lung function may be mitigated if asthmatics do
  not undergo a decrease in their level of inhaled
  corticosteroids.
• The observed changes in personal best lung
  function over time were not characterized by a
  decline in the one second forced expiratory
  volume to forced vital capacity ratio, indicating
  that these deficits may not be due to progressive
  bronchial obstructive but to scarring and
  stiffening of the airways associated with
  uncontrolled airway inflammation and remodeling.
• COMMENT
• Although pharmacotherapeutic regimens that take
  into account serial assessments of airway
  hyper-reactivity in addition to clinical severity
  and pre-bronchodilator lung function have been
  shown to enhance asthma control and alleviate
  airway inflammation, such an approach is not
  practical for most physicians and patients.
• Further prospective studies need to be undertaken
  to explore the effectiveness of utilizing
  personal best one- second forced expiratory
  volume as a guide for tapering inhaled steroids
  and whether remaining on higher levels of
  anti-inflammatory therapy can attenuate loss of
  lung function in asthmatics.

Months from program entry
Inhaled Corticosteroid Use as a function of
Months from Program Entry The graph at the left
depicts the averaged level of Inhaled Steroids
Used for the group as a whole (white), for the
61 of patients whose inhaled steroid dose was
decreased by at least 25 over the last year of
observation (green), and for the remaining
patients whose inhaled steroid level remained
stable (yellow -75 or more of the averaged 6 to
18 month level). For the group as a whole, the
Level of Inhaled Steroid Used increased
significantly from entry to 6 months, with a
maximum level of utilization occurring by 12
months. No changes were observed from 12 to 18
months but thereafter, significant tapering
occurred for the 24 and 30 months periods. At
the 24 and 30 months time periods, steroid levels
were higher for the stable (yellow) verses
decreased dose (green) asthmatics. The heights of
the bars in the graph at the right depict the
percentages of patients in the stable and
decreased dose of inhaled steroid groups who
utilized high dose therapy over the 6 to 12 (red
bars) and 24 to 30 (blue bars) month observation
periods. By 12 months, 39 and 41 of the stable
and decreased dose groups, respectively, required
high dose therapy. At the 24 to 30 months
period, significantly less decreased dose
patients were on high dose therapy.
Asthma outcomes and change in inhaled steroid use
Months from program entry
Asthma outcomes as a function of change in
Inhaled Steroid Use The graph at the left depicts
the percentages of patients in the stable
(yellow) and decreased inhaled steroid dose
(green) groups whose Averaged Symptom Severity
Classification for the 6 to 12 and 24 to 30
months observation periods were Mild Intermittent
or Mild Persistent. The graph at the right shows
similar data for Averaged Pre-bronchodilator Lung
Function, as measured by percent of predicted one
second forced expiratory volume. For both indices
there were no significant differences found with
respect to time period of observation or change
in inhaled steroid dose.