Similarity and differences in elderly patients with fixed airflow obstruction by asthma and by chronic obstructive pulmonary disease.

Abstract

Epidemiologic studies have demonstrated that elderly patients with fixed airflow obstruction can be affected by asthma or chronic obstructive pulmonary disease (COPD).
We studied 49 consecutive elderly outpatients, presenting fixed airflow obstruction, by clinical history (smoking), pulmonary function tests, blood gas analysis, and induced sputum.
The age was not different in patients with COPD (n=28) and asthma (n=21) (70.2+/-3.9 years vs. 69.6+/-3.7 years), also the degree of fixed airflow obstruction was similar (FEV1: 58.3+/-1.5% vs. 59.0+/-1.4% of predicted). Patients with asthma had significantly more eosinophils in peripheral blood (0.43+/-0.05x10(-3)microL vs. 0.27+/-0.1x10(-3)microL, P<0.0001), and in induced sputum (5.0% [(p25th and p75th) 5.0-6.0%] vs. 1.0% [(p25th and p75th) 0.01-1.0%]; P<0.0001), as well as serum ECP (18.6+/-4.9ng/mL vs. 7.7+/-4.7ng/mL, P<0.0001) and ECP in the induced sputum (31.6+/-2.9ng/mL vs. 5.6+/-4.9ng/mL, P<0.0001). Finally, in induced sputum the eosinophils EG2+ were higher in patients with asthma than in patients with COPD (40.5 [(p25th and p75th) 39.3-44.3] MFI vs. 3.9 [(p25th and p75th) 0-11.4] MFI, P<0.0001). They also had significantly higher diffusing capacity, and a greater reversibility to steroids, after 14-day course of therapy, whereas the reversibility to 400microg of salbutamol was similar.
Despite similar fixed airflow obstruction, elderly patients with asthma have distinct characteristics compared with patients with COPD.

Full text

Page 1

Similarity and differences in elderly patients with
fixed airflow obstruction by asthma and by chronic
obstructive pulmonary disease
Gabriele Di Lorenzoa,?, Pasquale Mansuetoa, Vito Dittaa,
Maria Esposito-Pellitteria, Claudia Lo Biancoa, Maria S. Leto-Baronea,
Alberto D’Alcamoa, Cristina Farinaa, Gaetana Di Fedeb, Francesco Gervasic,
Calogero Carusod, GiovamBattista Rinia
aDipartimento di Medicina Clinica e delle Patologie Emergenti, Universita ` degli Studi di Palermo, Italy
bDipartimento di Discipline Chirurgiche ed Oncologiche, Universita ` degli Studi di Palermo, Italy
cU.O. Ematologia con T.M.O., ARNAS Civico, Di Cristina, Ascoli di Palermo, Italy
dDipartimento di Biopatologia e di Metodologie Biomediche, Universita ` degli Studi di Palermo, Italy
Received 12 July 2007; accepted 18 September 2007
KEYWORDS
Elderly;
Asthma;
Chronic obstructive
pulmonary disease;
Eosinophils;
Neutrophils
Summary
Background: Epidemiologic studies have demonstrated that elderly patients with fixed
airflow obstruction can be affected by asthma or chronic obstructive pulmonary disease
(COPD).
Methods: We studied 49 consecutive elderly outpatients, presenting fixed airflow
obstruction, by clinical history (smoking), pulmonary function tests, blood gas analysis,
and induced sputum.
Results: The age was not different in patients with COPD (n ¼ 28) and asthma (n ¼ 21)
(70.273.9 years vs. 69.673.7 years), also the degree of fixed airflow obstruction was
similar (FEV1: 58.371.5% vs. 59.071.4% of predicted). Patients with asthma had
significantly more eosinophils in peripheral blood (0.4370.05?10?3mL vs. 0.277
0.1?10?3mL, Po0.0001), and in induced sputum (5.0% [(p25th and p75th) 5.0–6.0%]
vs. 1.0% [(p25th and p75th) 0.01–1.0%]; Po0.0001), as well as serum ECP (18.674.9ng/mL
vs. 7.774.7ng/mL, Po0.0001) and ECP in the induced sputum (31.672.9ng/mL vs.
5.674.9ng/mL, Po0.0001). Finally, in induced sputum the eosinophils EG2
patients with asthma than in patients with COPD (40.5 [(p25th and p75th) 39.3–44.3] MFI
vs. 3.9 [(p25th and p75th) 0–11.4] MFI, Po0.0001). They also had significantly higher
+were higher in
ARTICLE IN PRESS
0954-6111/$-see front matter & 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.rmed.2007.09.007
Abbreviations: COPD, chronic obstructive pulmonary disease; ROC, receiver operating characteristic; FEV1, forced expiratory volume in 1s;
FVC, forced vital capacity; DLCO, diffusing capacity of carbon monoxide; PO2(mmHg), partial oxygen pressure; PCO2(mmHg), partial carbon
oxide pressure; SaO2(%), saturation of oxygen; ECP, eosinophil cationic protein; EG2, monoclonal antibody (mAb) anti-ECP
?Corresponding author. Fax: +390916552987.
E-mail address: dilo601@unipa.it (G. Di Lorenzo).
Respiratory Medicine (]]]]) ], ]]]–]]]
Please cite this article as: Di Lorenzo G, et al. Similarity and differences in elderly patients with fixed airflow obstruction by asthma and by
chronic obstructive pulmonary disease. Respir Med (2007), doi:10.1016/j.rmed.2007.09.007

Page 2

diffusing capacity, and a greater reversibility to steroids, after 14-day course of therapy,
whereas the reversibility to 400mg of salbutamol was similar.
Conclusion: Despite similar fixed airflow obstruction, elderly patients with asthma have
distinct characteristics compared with patients with COPD.
& 2007 Elsevier Ltd. All rights reserved.
Introduction
Airway diseases are a significant problem for older subjects.
They cause a large burden of illness in the community, and,
in primary settings, they present particular problems for
diagnosis and management. Despite this, much of what we
already know and do for asthma in older subjects is based on
studies conducted in young people with asthma.
Lung function is not routinely measured and airflow
obstruction is largely underestimated, particularly in the
elderly.1–3However, distinguishing between asthma and
chronic obstructive pulmonary disease (COPD) is difficult
and may be impossible in some older patients, specially in
those with fixed airflow obstruction.4,5Many elderly patients
are often diagnosed as having COPD, even if the differential
diagnosis between asthma and COPD, in patients with fixed
airflow obstruction, may be important as the responses to
treatment are different, depending on whether fixed airflow
obstruction is due to asthma or COPD.6,7Epidemiologic
studies have demonstrated that up to 30% of patients with
fixed airflow limitation have a history of asthma.8
The goals of treatment are similar in asthma and COPD: to
reduce symptoms, maintain lung function and normal
activity, prevent exacerbation, and minimize the adverse
effects of treatment.9,10Asthma is usually treated with anti-
inflammatory medications, and bronchodilators are used as
needed.9COPD is usually treated with bronchodilators,
which provide small symptomatic benefits, and inhaled
corticosteroids, which can reduce exacerbations and im-
prove quality of life.10,11
We planned this study to investigate if fixed airflow
obstruction in elderly subjects, by asthma or by COPD, can
be differentiated through clinical and functional character-
istics or through the evaluation of the cells in induced
sputum, or both.
Methods
Patients
From January 2000 to December 2004, we evaluated 80
patients, older than 64 years, who consecutively presented
at Dipartimento di Medicina Clinica e delle Patologie
Emergenti of the University of Palermo (Italy), with fixed
airflow obstruction.
Fixed airflow obstruction was defined as post-bronchodi-
lator (salbutamol) FEV1/FVC less than 70%.12
None of the patients received regular anti-inflammatory
treatment at the time of the sampling. Smoking status was
checked during patient interview.13
We excluded patients who had an exacerbation requiring
pharmacologic treatment in the 6 months before the study.
The number and severity of exacerbations before the
months preceding the study were not recorded.
Flow-volume curves were assessed at baseline and after
400mg salbutamol by metered-dose inhaler, and diffusing
capacity (diffusing capacity of carbon monoxide [DLCO]),
and carbon monoxide transfer coefficient [KCO]) was
measured. Equipment: Gould 2400 automated system
(Bilthoven, Netherlands), and SensorMedics Vmax 229
V6200 Autobox Bodypletismograph with DLCO (Yorbalinda,
CA, USA).
Atopic status was assessed by skin prick test (SPT) for
pneumo-allergens in the Palermo area14(allergens used: Alk
Abello `, Milan, Italy). The panel included the following
extracts: pollens (grass [Phleum pratense], mugwort [Arte-
misia vulgaris], wall pellitory [Parietaria judaica], and trees
[Olea europea and Cupressus]), house dust mites (Dermato-
phagoides pteronyssinus and farinae), molds (Alternaria
alternata and Aspergillus fumigatus), animal danders (cat
and dog), a negative (glycerinated saline), and a positive
control (histamine, 10mg/mL). A positive response was
defined as any wheal with a diameter 3mm greater than the
negative control, 15min after the application.15
Each patient also performed arterial blood gases analysis,
eosinophils blood count, serum total IgE and ECP in serum
and in induced sputum, according to the manufacturer’s
instructions. Equipment: pH/Blood Gas Analyzer, Instrumen-
tation Laboratory 1306 (Lexington, MA, USA), Technicon-H1
blood cell counter (Bayer Leverkusen, Germany), and CAPTM
SYSTEM (Phadia Diagnostics, Uppsala, Sweden).
In all patients were controlled the reversibility to
corticosteroids (14-day course
50mg/day).
Authorization of the study was not required according to
our institutional policy and the ethical committees of our
institution. However, written informed consent to the study
was obtained from every patient, in compliance with our
institutional policy.
All the measurements and clinical data collections were
performed during the first visit.
withoralprednisone,
Sputum induction and processing
After baseline FEV1and FVC measurements, salbutamol was
given by inhalation (200mg by metered-dose inhaler), and
subjects then inhaled hypertonic (4.5%) saline nebulized
solution for periods of progressively increasing length (1, 2,
4, 8, and 16min). FEV1 was measured 1min after each
inhalation. The hypertonic saline solution was administered
with a MEFAR nebulizer (Markos, Monza, Italy). The collected
sputum samples were examined within 2h. Selected portions
of the sputum sample originating from the lower respiratory
tract were chosen through examination with an inverted
ARTICLE IN PRESS
G. Di Lorenzo et al.2
Please cite this article as: Di Lorenzo G, et al. Similarity and differences in elderly patients with fixed airflow obstruction by asthma and by
chronic obstructive pulmonary disease. Respir Med (2007), doi:10.1016/j.rmed.2007.09.007

Page 3

microscope, were weighed, and then, processed using 1%
dithiothreitol (Sigma Chemicals, Poole, UK). Total cell count
and viability (Trypan blue exclusion method) were deter-
mined with a Burkers chamber hemocytometer. The cell
suspension was placed in a Shandon cytocentrifuge (Shandon
Southern Ltd., Runcorn, UK) and cytospin preparations were
made at 450rpm for 6min. Cytospin slides were fixed with
methanol, stained with May-Grunwald-Giemsa for an overall
differential cell count of 500 nucleate nonsquamous cells,
and examined, under oil immersion by light microscopy, at
magnification of 400?, by an observer unaware of the
clinical characteristics of the subjects. Only samples with a
cell viability 450% and o20% squamous cell contamination
were considered.16
EG2
+cells in induced sputum
A flow cytometric technique, based on fixation with
formaldehyde and permeabilization with octyl-glucopyrano-
side of eosinophils from induced sputum, was used according
to Hallden et al. with minor modifications, previous
described.17,18The results were expressed as mean fluores-
cence intensity (MFI) ratio of positive cell populations.17–19
Statistical analysis
Data have been presented as mean7S.D. and as median and
25–75th percentile, and analyzed with Student’s test for
unpaired data, or with Mann–Whitney U-test, on the basis of
the distribution of the data. For statistical analyses a value
of Po0.05 was considered statistically significant.
Receiver operating characteristic (ROC) curve analysis
was performed for all the functional/pathologic parameters
that were thought to define the capability/power of each
variable (predictive value) to recognize patients with a
history of asthma within our study population. The area
under the ROC curves was determined, and a value above
0.80 was considered a good discrimination.20ROC curve
analysis also allowed (sensitivity vs. one minus specificity)
selection of the best cut-off point of each variable for
discriminating between the two groups.
Results
On the whole, the subjects were elderly, with fixed airflow
obstruction. From the 80 patients recruited, we report the
results obtained in the 49 patients who agreed to participate
in the study. Each patient was characterized by medical
history and physical examination. Of the 49 patients
studied, 21 had a history of asthma and 28 had a history of
COPD.
All asthma patients had a clear clinical history of
recurrent wheezing or breathlessness episodes that reversed
spontaneously or after treatment, and a familial history of
asthma.9None of these patients was a smoker. All patients
with COPD had a clear history of smoking, with more than 20
pack-years, chronic productive cough or sputum, no history
of asthma, even in their familial, and no reported allergic
diseases.10
In Table 1, we have been reported gender, age, duration
of disease (years), smoking (pack-years), previous treat-
ments, total serum IgE, and rate of SPT positivity. The
patients with history of asthma differed from patients with
history of COPD for smoking (no asthmatic was a smoker),
previous treatments, total serum IgE (209kU/L [162–331] vs.
36kU/L [27.5–63.0], Po0.0001), and rate of SPT positivity
(47.6 vs. 7.1, P ¼ 0.001).
In Table 2, we reported the pulmonary function and
diffusing capacity. FEV1, FVC, and FEV1/FVC have been
reported as value obtained and as percentage of theoretical
value. These parameters did not differ between the 21
patients with asthma and the 28 patients with COPD.
Patients with asthma had higher diffusing capacity (DLCO
ARTICLE IN PRESS
Table 1
Demographic and clinical features of patients.
Asthma group (n ¼ 21)
10/11
70.273.9
11.973.7
COPD group (n ¼ 28)
16/12
69.673.7
11.774.3
P-value
Gender (M/F)
Age (years)?
Duration of disease (years)?
0.5
0.6
0.9
Previous treatments
Inhaled steroid (%)
b2-short-acting (%)
b2-long-acting (%)
Oral steroids (%)
Cromones (%)
Anticholinergic (%)
Mucolytic (%)
Antileukotrienes (%)
Ketotifen (%)
71.4
100
61.9
100
52.0
14.2
9.5
66.6
33.3
60.7
100
46.4
100
3.5
42.8
100.0
42.8
7.1
0.4
0.2
o0.0001
0.03
o0.0001
0.1
0.02
Serum total IgE (kU/L)y
Rate of skin prick test positivity (%)
209 (162–331)
47.6
36 (27.5–63)
7.1
o0.0001
0.001
?Data have been reported as mean7S.D.
yData have been reported as median with lower quartile (25th) and higher quartile (75th) shown in parentheses.
Similarity and differences in elderly patients with asthma and COPD3
Please cite this article as: Di Lorenzo G, et al. Similarity and differences in elderly patients with fixed airflow obstruction by asthma and by
chronic obstructive pulmonary disease. Respir Med (2007), doi:10.1016/j.rmed.2007.09.007

Page 4

and KCO). However, the patients with asthma differed from
patients with COPD only for an increasing FEV1after steroids
(14-day course), considered as D % of FEV1(13.175.0 vs.
10.773.0, P ¼ 0.04).
In Table 3, have been shown the results of ABG analysis.
Both PO2(86.971.2mmHg vs. 85.572.0mmHg, P ¼ 0.006)
and SaO2(94.971.9% vs. 93.576%, P ¼ 0.01) significantly
differed in patients with COPD respect to patients with
asthma.
ECP in the serum (18.674.9ng/mL vs. 7.774.7ng/mL,
Po0.0001) and in the induced sputum (31.672.9ng/mL vs.
5.674.9ng/mL, Po0.0001) was higher in patients with
asthma than in patients with COPD.
Also the number of eosinophils in the blood was higher in
patientswith asthmathan
(0.4370.05?10?3mL vs. 0.2770.1?10?3mL, Po0.0001).
Compared with the patients with COPD, patients with
asthma had more eosinophils (5.0% [(p25th and p75th)
5.0–6.0%]vs.1.0%[(p25th
Po0.0001), and fewer neutrophils in the induced sputum
in patientswithCOPD
andp75th)0.01–1.0%];
ARTICLE IN PRESS
Table 2
Pulmonary function of patients.
Parameters Asthma group
(n ¼ 21)
23.271.5
4.170.2
1.2970.23
58.371.5
2.1370.37
76.072.3
60.572.1
1.4070.24
106.4716.5
8.371.2
1.4770.05
165.8752.9.5
13.175.0
COPD group
(n ¼ 28)
15.771.5
3.370.2
1.3770.21
59.071.4
2.2370.35
76.772.8
61.374.1
1.4870.22
112.5716.8
8.371.6
1.5170.04
144.6734.5
10.773.0
P-value
DLCO (mL/min/mmHg)
KCO (mL/min/mmHg/L)
FEV1(L)
FEV1(%)
FVC (L)
FVC (%)
FEV1/FVC (%)
FEV1after bronchodilator (400mg of salbutamol) (L)
Increasing of FEV1(mL) after bronchodilator (400mg of salbutamol)
D % of FEV1after bronchodilator (400mg of salbutamol)
FEV1after steroid (50 mg of prednisone) (L)
Increasing of FEV1(mL) after steroid (50mg of prednisone)
D % of FEV1after steroid (50mg of prednisone)
o0.0001
o0.0001
0.1
0.1
0.2
0.09
0.9
0.2
0.09
0.7
0.4
0.1
0.04
Data have been reported as mean7S.D. D ¼ change.
Table 3
The results of arterial blood gas analysis.
Parameters AsthmaCOPD
P-value
pH
PO2(mmHg)
PCo2(mmHg)
SaO2(%)
7.4370.02
86.971.2
38.470.6
94.971.9
7.4370.01
85.572.0
38.570.7
93.576.0
0.7
0.006
0.9
0.01
Data have been reported as mean7S.D.
Figure 1
patients with fixed airflow obstruction by COPD and asthma.
The best cut-off points to discriminate between the two groups
are 42.0% eosinophils in induced sputum.
Percentage of eosinophils in induced sputum in
Figure 2
patients with fixed airflow obstruction by COPD and asthma.
The best cut-off points to discriminate between the two groups
are p21.0% neutrophils in induced sputum.
Percentage of neutrophils in induced sputum in
G. Di Lorenzo et al.4
Please cite this article as: Di Lorenzo G, et al. Similarity and differences in elderly patients with fixed airflow obstruction by asthma and by
chronic obstructive pulmonary disease. Respir Med (2007), doi:10.1016/j.rmed.2007.09.007

Page 5

(9.0% [(p25th and p75th) 8.0–11.0] vs. 36.0% [(p25th and
p75th) 32.0–40.0]; Po0.0001) (Figures 1 and 2). No
difference was found between patients with asthma (33.0%
[(p25th and p75th) 26.0–36.0]) and COPD (34.0% [(p25th and
p75th) 28.0–36.0], P ¼ 0.8) as regards to percentage of
macrophages. Finally, in the induced sputum, the MFI of
eosinophils EG2
patients with COPD (40.5 [(p25th and p75th) 39.3–44.3] vs.
3.9 [(p25th and p75th) 0–11.4], Po0.0001) (Table 4).
+was higher in patients with asthma than in
ROC curve analysis
None of the functional pulmonary parameters were able to
recognize patients with asthma among subjects with fixed
airflow obstruction due to asthma or COPD. The values of
the area under the ROC curves (0.53 for reversibility to
bronchodilators, 0.55 for reversibility to steroids, 0.59 for
KCO, 0.70 for SaO2, and 0.71 for PO2) were below 0.80,
suggesting that these parameters are poor predictors of the
diagnosis of asthma.
In contrast, the percentage of eosinophils in sputum was
good predictors of asthma, whereas the percentage of
neutrophils in sputum was good predictors of COPD. The
area under the ROC curve was 0.99 (CI 95%, 0.92–1.00) for
the percentage of eosinophils in sputum. For sputum
eosinophils, the best cut-off point was 2.0% [(with a
sensitivity of 1.00 (CI 95% 0.83–1.00) and a specificity of
0.92 (CI 95% 0.75–0.98)], indicating that values higher to
3.0% predicted asthma, whereas values lower than 2%
predicted COPD, among subjects with fixed airflow obstruc-
tion. The area under the ROC curve was 0.99 (CI 95%,
0.89–0.99) for the percentage of neutrophils in sputum. For
sputum neutrophils, the best cut-off point was p21% [(with
a sensitivity of 1.00 (CI 95% 0.83–1.00) and a specificity of
92.9 (CI 95% 0.75–0.98)], indicating that values lower or
equal to 21% predicted asthma, whereas value higher than
21% predicted COPD, among subjects with fixed airflow
obstruction.
Discussion
In this study, we showed that, within a group of elderly
patients with fixed airflow obstruction, those with asthma
have distinct airway inflammation as compared with those
with COPD and history of smoking-induced airway disease.
This finding suggests that asthmatic airway inflammation
does not change with the development of fixed airflow
obstruction and thus does not become similar to the airway
inflammation characteristic of COPD. Therefore, our results
indicate that, even when fixed airflow obstruction is
present, asthma should be diagnosed as asthma and not as
COPD.
Previous studies have compared airway inflammation in
asthma and COPD.21,22All those studies compared young
patients with asthma, who had variable airflow obstruction,
with older COPD patients, who had fixed airflow obstruction.
Thus, they did not address whether the issue of the
pathology of asthma changes with the development of fixed
airflow obstruction and becomes similar to that character-
istic of COPD. In another study, the authors compared 27
patients with late-onset asthma and 24 patients with COPD.
The reported values for FEV1(%), FVC(%), and FEV1/FVC(%),
in their patients with COPD (43.79720.08, 59.54718.21,
and 56.08714.36, respectively), were lower that the values
of our patients with COPD (59.071.4, 76.772.8, and
61.374.1, respectively). Moreover, the characteristics of
the asthmatic patients were different between the studies:
their asthmatic patients were smoker, and the comparisons
between patients with asthma and patients with COPD were
statistical significant for FEV1%, FVC%, and FEV1/FVC(%). On
the contrary, our asthmatic patients were never smoker and
we found no differences between FEV1(%), FVC(%), and
FEV1/FVC(%) between asthmatic patients and patients with
COPD.23
Indeed, in this study, the patients examined were clearly
identified as suffering from COPD, and the differential
diagnosis with asthma has not been even previously
considered.24,25
In this study, we investigated the characteristics of airway
inflammation in elderly patients of similar age and similar
degree of fixed airflow obstruction, but with a different
clinical history, asthma or COPD.
The relationship between airway inflammation and air-
flow obstruction is poorly understood, both in asthma and in
COPD. The increased number of eosinophils in asthma and
neutrophils in COPD seems to be the major determinant of
airflow obstruction, therefore it may be a marker of two
different inflammatory cascades for two diseases, asthma
and COPD, that result in the same functional abnormality,
i.e. fixed airflow obstruction. One limitation of our study is
that no patients have been submitted to bronchial biopsies.
Our Ethic Committee did not consider ethical performing
bronchial biopsies in elderly subjects with the diagnosis of
asthma or COPD.
The differential diagnosis between fixed airflow obstruc-
tion due to asthma or COPD is important in clinical practice,
because the response to treatment of the two diseases are
different.26The results of our study show that measurement
of lung volumes, responsiveness to steroids, and even
ARTICLE IN PRESS
Table 4
Inflammatory cells in the induced sputum in patients with fixed airflow obstruction.
Asthma group (n ¼ 21)
33.0 (26.0–36.0)
9.0 (8.0–11.0)
5.0 (5.0–6.0)
40.5 (39.3–44.3)
COPD group (n ¼ 28)
34.0 (28.0–36.0)
36.0 (32.0–40.0)
1.0 (0–1.0)
3.9 (0–11.4)
P-value
Macrophages (%)
Neutrophils (%)
Eosinophils (%)
Eosinophils EG2
0.8
o0.0001
o0.0001
o0.0001
+(MFI)
Data have been expressed as median with lower quartile (25th) and higher quartile (75th) shown in parentheses.
Similarity and differences in elderly patients with asthma and COPD5
Please cite this article as: Di Lorenzo G, et al. Similarity and differences in elderly patients with fixed airflow obstruction by asthma and by
chronic obstructive pulmonary disease. Respir Med (2007), doi:10.1016/j.rmed.2007.09.007