Respiratory Medicine (2009) 103, 1878e1884

available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/rmed

High sensitivity C-reactive protein: Its correlation

with sputum cell counts in bronchial asthma
Mona Hashem Allam a, Azza Farag Said a,*, Ahmed Abd El Samie Omran b,
Dalia Mohammed Abd El-Reheim c, Ahmed Hussein Kasem a
a

Department of Chest Diseases, Faculty of Medicine, Minia University, Egypt

Department of Clinical Pathology, Faculty of Medicine, Minia University, Egypt
c
Department of Pathology, Faculty of Medicine, Minia University, Egypt
b

Received 20 May 2008; accepted 19 June 2009

KEYWORDS
High sensitivity e
C-reactive protein;
Bronchial asthma;
Pulmonary function
tests;
Sputum cell counts

Summary
Background: Two major acute-phase proteins were identified in human, C-reactive protein and
serum amyloid A. There are 3 types of C-reactive protein assays: conventional C-reactive protein,
high sensitivity C-reactive protein and cardiac C-reactive protein. High sensitivity C-reactive
protein assays can detect minor inflammatory changes that could be missed by other indices of
inflammation. Induced sputum cell counts are relatively non-invasive, safe and reliable method
for identifying the presence and type of airway inflammation in asthmatic patients.
Purpose of the work: This study was designed to detect the role of serum levels of high sensitivity
C-reactive protein in asthmatic patients with or without inhaled corticosteroids treatment. Also
to determine the relationship of serum high sensitivity C-reactive protein levels to clinical indices
of asthma and inflammatory cell counts in induced sputum.
Subjects & Methods: Serum high sensitivity C-reactive protein level, pulmonary function tests,
body mass index and induced sputum cell counts were estimated in 50 asthmatic patients (26
steroid inhaled and 24 steroid nave). Fifteen healthy volunteers, who matched in age and sex
with the other groups, were used as a control group.
Results: There was an increase of high sensitivity C-reactive protein in asthmatic patients among
both steroid inhaled and steroid nave patients compared to the healthy controls. Serum high
sensitivity C-reactive protein correlated negatively with pulmonary function tests and positively
with sputum eosinophil % in both inhaled steroid and steroid nave groups.
Conclusion: High sensitivity C-reactive protein is one of the markers of systemic inflammation that
can be indirectly reflecting the degree of severity of airway inflammation in bronchial asthma.
2009 Published by Elsevier Ltd.

* Corresponding author. Tel.: 20 0862635364.

E-mail addresses: makawhiteblue@yahoo.com (M.H. Allam), azza20022@yahoo.com (A.F. Said), ahmad11@yahoo.com (A.A. El Samie
Omran), dalia_abdelrehim@hotmail.com (D.M. Abd El-Reheim), ahmed_hussein981@yahoo.com (A.H. Kasem).
0954-6111/$ - see front matter 2009 Published by Elsevier Ltd.
doi:10.1016/j.rmed.2009.06.020

High sensitivity C-reactive protein in bronchial asthma

Introduction
C-reactive protein (CRP) is the first acute-phase protein to be
described and is highly sensitive systemic marker of inflammation, infection and tissue damage.1 CRP is predominantly
produced and secreted by hepatocytes, although other cells
including alveolar macrophages may also synthesize it2 under
control of cytokines mainly interleukin-6 (IL-6). A positive CRP
may be an indicator of several conditions including rheumatoid arthritis, rheumatic fever, cancer, tuberculosis, pneumonia, heart attack and systemic lupus. There is also a high
sensitivity CRP (hs-CRP) assay in addition to the conventional
CRP test. The hs-CRP measures very low amount of CRP in the
blood (below 0.2 mg/L) and is typically used to assess risk for
heart problems3 and can be used as prognostic marker for
development of diabetes mellitus. A population based study
showed an association of increased level of serum hs-CRP with
a high frequency of airway hyper responsiveness and low
forced expiratory volume in one second FEV1 among
subjects without heart disease,4 suggesting that systemic
inflammation may be associated with respiratory impairment.
Asthma is a chronic inflammatory airway disorder characterized by airway hyper responsiveness and inflammation,
in which various cells as eosinophils, neutrophils, macrophages, T lymphocytes, cytokines and mediators play a role.
Besides local inflammation, systemic inflammation is present
in asthma as shown by increased level of plasma fibrinogen
and serum myeloid A (SAA).5 Thus hs-CRP could be a useful
tool for detecting systemic inflammation in asthma.6

Aim of the work

1879
According to the severity of asthma based on symptoms
and lung function tests; asthmatic patients were classified
into intermittent, mild persistent, moderate persistent and
severe persistent cases.7 Patients included in this study
were those of moderate persistent (pre-bronchodilator
FEV1 60e80% predicted) and severe persistent asthma
categories (pre-bronchodilator FEV1 < 60% predicted) as
they were the usual groups presenting to the outpatient
chest clinic.
Patients were divided into the following groups:
Group (A): Included (26) asthmatic patients who were on
inhaled corticosteroids (ICSve) in their usual
treatment of asthma besides bronchodilators.
This group was divided into 2 subgroups
according to asthma severity: subgroup (A1):
included 11 cases of moderate persistent
asthma and subgroup (A2): included 15 cases of
severe persistent asthma.
Group (B): Comprised (24) steroid nave asthmatic patients
(not on inhaled corticosteroids) (ICSve).This
group was further divided also into 2 subgroups
according to asthma severity: subgroup (B1)
which included 12 patients of moderate persistent asthma and subgroup (B2) which included
12 patients of severe persistent asthma.
Control group
(group C): Included 15 apparently healthy nonsmoker individuals matched in age and sex with the other 2
groups.
All the patients and healthy controls had been subjected
to the following:

The aim of this study was to detect:

1. The role of serum levels of hs-CRP in asthmatic patients
with and without inhaled corticosteroids treatment.
2. Relationship of serum hs-CRP levels to clinical indices
of asthma and inflammatory cell differential counts in
induced sputum.

Subjects and methods

Fifty cases of bronchial asthma were recruited from those
attending the outpatient Chest clinic in Minia University
hospital from January 2007 to August 2007. This study was
approved by the ethical committee of Faculty of Medicine,
Minia University and a written consent was obtained from
patients and controls. Patients were selected according to
the global initiative for asthma on the basis of symptoms
such as: episodic breathlessness, wheezing, chest tightness, seasonal variability of symptoms with or without
positive family history of asthma and post bronchodilator
increase in FEV1 (more than 12%) or increase of peak
expiratory flow (PEF) > 15%.7 Current smokers, patients
with recent respiratory tract infection or exacerbation of
less than one month prior to study were excluded. Besides,
patients with heart diseases, diabetes mellitus collagen
vascular disorder, obesity with body mass index
(BMI) > 30 kg/m2 and semi quantitative CRP > 10 mg/L
were also excluded.

- Full detailed history taking including: (age, sex, duration of bronchial asthma, patients medications and
family history of allergic diseases).
- Clinical examination, including: vital signs and BMI. The
latter is defined as weight in kilograms divided by square
of height in meters {wt in kg/(height in meter)2}.8
- Local chest examination.
- Investigations included:
1. Plain chest X-ray (PA view).
2. Complete blood count (CBC), total white blood cell
counts (WBCS) and differential cell count.
3. Electrocardiogram (ECG).
4. Pulmonary function tests (PFTs) using (Vitallograph
compact device), which is calibrated daily. Patients
maximum effort had been used in performing the
test so as to avoid any expected error in diagnosis.
Results were obtained for forced vital capacity
(FVC), FEV1, FEV1/FVC percentage and forced expiratory flow at 25e75% of FVC (FEF 25e75%).
5. Sputum induction9: Patients and controls had been
medicated with inhaled salbutamol 200 mg, in hypertonic saline 5% administered for 15 min by ultrasonic
nebulizer. Before expectoration, they were instructed
to rinse their mouth to minimize saliva and then asked
to expectorate sputum into a sterile plastic dish.
6. Sputum processing and staining: Sputum samples were
processed within two to seven hours of expectoration
as delayed processing and examination more than nine

1880

M.H. Allam et al.

3

70

2
1. 5

FEV1/FVC

Mean hs -CRP
(mg/ L)

2. 5

1
0. 5
0

Group A

Group B

50

Group C

Groups

Figure 1

60

40

Mean hs-CRP in the studied groups.

hours are associated with significant reduction in cell

viability.10 Sputum was treated with 15 ml HCl 8% and
left for two to four hours to separate sputum from
saliva.11 Sputum was put in a test tube and centrifuged
at 2000 rpm for ten minutes. The precipitate was taken
on slide and fixed with ethyl alcohol 95% in order to
preserve cell details, without distortion. Staining was
done using papanicoloau stain according to Bancroft
and Gamle protocol.12
7. Differential cell counts: The quality of induced
sputum samples was assessed according to Gibson
et al.13 which is based upon a slide quality assessment
that evaluated the presence of three parameters:
Adequate number of cells for enumeration, the
presence of pulmonary macrophages on the slide, and
the proportion of squamous epithelial cells.
Cell number was scored as (0) if there were fewer than
200 cells, (1) if there were 200e399 cells, and (2) if 400
or more cells were present. Pulmonary macrophages
were scored as present (2) or absent (1). The proportions of squamous epithelial cells were scored as (2) if
less than 20%, and (1) if 20% or greater. This gave
a quality score ranging from 0 (poor quality) to 6 (good
quality). Slides with low score <4 were excluded.
8. Measurement of serum hs-CRP: Under complete
aseptic venipuncture, three ml venous blood samples
were withdrawn, blood left to be clotted and centrifuged for ten minutes. The separated serum was kept
frozen at 20  C till assay of hs-CRP by ELISA.

Assay of hs-CRP by ELISA

Serum hs-CRP levels were measured using ultra Sensitive CRP
assay, which is enzyme immuno-assays diagnostic kits supplied
by (DiaMed eurogen company, 2300 Turnhout, Belgium) for the
quantitative determination of hs-CRP in human serum.
A separate disposable tip for each sample transfer was
used to avoid cross-contamination. All reagents were mixed
without foaming in room temperature. Processing was done
without any interruption

Statistical analysis
All obtained data were analyzed statistically by SPSS software version 14. Data were presented as range and

30
0

Figure 2

4
hs-CRP (mg/L)

Correlation of hs-CRP to FEV1/FVC in group A.

mean  SD (standard deviation) for numerical data or

number and percent (%) for categorical data. ManneWhitney U-test was used to compare means between two groups
of numerical data. Correlations between data were
analyzed using Spearman correlation test. The significance
was considered according to the level of significance (Pvalue) as follows:
P > 0.05 Z no significance (NS). P  0.05 Z significant
difference (*). P  0.01 Z high significant difference (**).
P  0.001 Z very high significant difference (***).

Results
On studying the general characteristics of all studied
subjects, it was found that there was no difference in the
mean age in group A & B (33.3  11) and (35.1  12.1)
respectively (P > 0.05). There was no difference between
both groups of bronchial asthma regarding duration of the
disease (P > 0.05). Considering BMI, there was no significant
difference in BMI among all of the asthmatic patients and
healthy control (P > 0.05).
Fig. 1 shows hs-CRP levels among the studied groups. It
was found that group B had a mean value of hs-CRP of
2.63  2.1 mg/L which was higher than that of group A and
healthy control group. The difference of hs-CRP mean value
between group A (2.35  1.66) and B (2.63  2.1) was not
significant (P > 0.05). On the other hand, the difference
between both groups A and B in comparison with control
group (0.70  0.67) showed a highly significant difference
(P < 0.01) (Fig. 1).
Correlation between age, duration of bronchial asthma,
BMI and hs-CRP using Spearman correlation was done.
There was no significant correlation of age, duration of
bronchial asthma, BMI and hs-CRP among all studied
patients and healthy controls.
Correlation of hs-CRP to pulmonary function tests using
Spearman correlation is illustrated in Table 1. Among group
A, hs-CRP had a significant negative correlation with FEV1/
FVC, PEF and FEF 25e75%. In group B, hs-CRP had

High sensitivity C-reactive protein in bronchial asthma

1881
macrophage %(r Z 0.56, P Z 0.005) and lymphocytes %
(r Z 0.55, P Z 0.006). There was no significant correlation
between hs-CRP and sputum cell counts in the control
group (Fig. 3).

Discussion

Figure 3
group B.

Correlation of hs-CRP to sputum eosinophils in

a significant negative correlation to FEV1 and high significant

negative correlation to FEV1/FVC, PEF and FEF 25e75%. In
the control group, hs-CRP had no significant correlation to
any of pulmonary function test parameters (Fig. 2).
Table 2 shows range and means  SD of sputum cell
counts among studied groups. The mean value of sputum
macrophage % was higher among healthy control group. The
difference between this value with groups A & B showed
a very highly significant difference (P < 0.001). The mean
value of neutrophils was very highly significant (P < 0.001)
in group A when compared with group B and healthy
controls. The mean value of sputum eosinophil % was higher
among steroid nave asthmatics (group B) than other groups
and this difference was very highly significant as compared
with group A and healthy controls (P Z 0.0001). The sputum
percentage of lymphocytes showed a very highly significant
difference between inhaled corticosteroids group (group A)
and steroid nave asthmatics (group B) vs. healthy control
group (P Z 0.0001).
Correlation of hs-CRP to sputum cell counts is shown in
(Table 3). It was found that in group A, hs-CRP had no
significant correlation to macrophages, neutrophils, and
lymphocyte %, while it had a significant positive correlation
to eosinophil % in induced sputum(r Z 0.44, P Z 0.025). In
group B, hs-CRP had a very highly significant positive
correlation to eosinophil % in induced sputum (r Z 0.66,
P Z 0.001), highly significant positive correlation to

Table 1

CRP production is part of the nonspecific acute-phase

response to most forms of inflammation and infection. High
sensitivity CRP assays may be used to diagnose conditions
with low grade inflammation in apparently healthy individuals. hs-CRP value ranges between 0.3 and 8.6 mg/L in
healthy men and between 0.2and 9.1 mg/L in healthy
women not taking hormonal replacement therapy.14 A
positive relationship has been reported between raised CRP
levels and current asthma,15 respiratory impairment,16 and
bronchial hyper responsiveness.5
Asthma is characterized by inflammatory changes in the
airway mucosa.17 The importance of local inflammation in
the pathogenesis of asthma is well established. However,
only limited data is available on whether systemic inflammation is also associated with asthma or not. Sensitive
markers of systemic inflammation, particularly SAA and
fibrinogen, were positively and significantly associated with
asthma prevalence. These findings support the hypothesis
that not only local but also systemic inflammation exist in
bronchial asthma and may play a role in its pathogenesis.18
The present study was designed to detect firstly, the role
of serum levels of hs-CRP among asthmatic patients with
and without inhaled corticosteroids treatment. This study
had shown that serum levels of hs-CRP were significantly
higher in asthmatic patients than among healthy controls.
Steroid nave patients (group B) showed higher mean
value of hs-CRP than those on inhaled steroid (group A) but
the difference between group A & group B was not significant. This agrees with the results of Takemura et al.19 who
showed that patients with ICSve represented a higher
mean value of hs-CRP. On the other hand, the present study
showed that in ICSve patients, the serum hs-CRP levels
differ with high significance (P Z 0.002) from those of
healthy controls. This was different from Takemura et al.
findings who found that in ICSve patients, serum hs-CRP
levels did not differ from those of healthy controls, due to
the well characterized anti-inflammatory properties of
inhaled steroid which reduced serum hs-CRP.
In this study, the apparent controversy with Takemura
et al. study could be explained by either the non compliance of the studied patients with the use of steroid
inhalers or may be due to development of steroid resistant
form of asthma. Elevated CRP in stable asthma can be

Spearman correlation of hs-CRP to pulmonary function test.

Studied groups

Group A
Total (n Z 26)
Group B
Total (n Z 24)
Control (n Z 15)

FEV1

FEV1/FVC

PEF

FEF 25e75%

P-value

P-value

P-value

P-value

0.11
0.49
0.006

0.58
0.01*
0.98

0.48
0.67
0.01

0.01**
0.0001***
0.96

0.45
0.65
0.27

0.02*
0.001***
0.48

0.4
0.63
0.24

0.043*
0.001***
0.41

* denotes significant difference; ** denotes high significant difference; and *** denotes very high significant difference.

1882
Table 2

M.H. Allam et al.

Shows range and means  SD of sputum cell counts among the studied groups.

Main group

Macrophage %

Group A (n Z 26)
Group B (n Z 24)
Control group (n Z 15)

Neutrophil %

Lymphocyte %

Range

Mean  SD

Range

Mean  SD

Range

Mean  SD

Range

Mean  SD

0e39
1e34
40e69

13.2  9.5
6  7.6
57.06  9.01

41e88
1e84
30e60

71.8  12.2
52.5  19.5
40.73  8.50

1e22
13e78
0e6

6.8  5.2
33  14.6
1.40  2.02

2e24
1e80
0e3

8.1  5.6
8.8  16.3
1.20  1.08

explained by considering asthma as a chronic inflammatory

disease leading to a damage of lung tissue. This might
generate endogenous ligands such as fibronectin or heat
shock protein triggering direct inflammation.20 IL-6 and
interleukin-1 beta (IL-1) are secreted by activated
monocytes and macrophages. These cytokines have been
found in asthma and chronic obstructive pulmonary disease
(COPD) and are directly implicated in elevating CRP
level.21 It is also postulated that elevated CRP level in
stable asthma and COPD may be due to lung colonization in
30% of the patients with chronic obstructive airway
diseases.22
The second aim of this study was to determine the
relationship of serum hs-CRP to clinical indices of asthma
and inflammatory cell differentials in induced sputum
among asthmatic patients. It was found that there was no
significant correlation between serum hs-CRP and age of
asthmatic patients. As the mean age of ICSve and ICSve
patients was 33.3  11 and 35.1  12.1 respectively so most
of the patients of this study were in their middle age, thus
avoiding the effect of aging on hs-CRP levels. Nakamura and
Yamashita23 showed that aging and its associate atherosclerotic changes are contributing factors of elevated hsCRP. Smokers show elevation of hs-CRP levels and smoking
cessation leads to a reduction in hs-CRP level.24 For this
reason current smoker whether patients or controls were
excluded from this study.
There was no correlation between the duration of
bronchial asthma and BMI with serum hs-CRP levels in the
present study and this was consistent with Takemura
et al.19 Obese asthmatic patients with BMI > 30 kg/m2 were
excluded from this study to avoid effect of obesity on serum
hs-CRP levels. Higher BMI is associated with higher hs-CRP
values even among healthy persons, which suggests a state
of low grade systemic inflammation in over weight and
obese persons.25
In the present study, serum hs-CRP levels correlated
negatively with pulmonary function test parameters and
this negative correlation was highly significant among those
of steroid nave patients. These findings are in accordance
with Takemura et al.19 who found also that the degree of
negative correlation of hs-CRP and pulmonary function test
Table 3

Eosinophil %

parameters were more in steroid nave than in steroid

inhaled patients.
The negative correlation between pulmonary function
tests and hs-CRP in our study is consistent with previous
studies that have found a relationship between lung function and other markers of systemic inflammation. Kauffmann et al.26 found a negative association between FEV1
and haptoglobin levels in men. Also Dahl et al.27 reported
that a lower FEV1 and increased risk of chronic obstructive
pulmonary disease were associated with increased plasma
fibrinogen levels. Finally, Engstrom et al.28 showed that the
FVC was inversely associated with levels of inflammatory
markers as (fibrinogen, a1-antitrypsin, haptoglobin and
ceruloplasmin). They also showed that the levels of these
inflammatory markers partially accounted for the relationship between lung function and cardiovascular events.
The current study showed that sputum neutrophil % was
higher in asthmatic patients when compared with that of
healthy controls and that increase showed higher significant level in ICSve (group A) (71.8  12.1) patients than
ICSve (group B) (52.5  19.5). The same results were
obtained by Takeumura et al.19 Gibson et al.29 used induced
sputum to assess 56 patients with persistent asthma taking
high doses of inhaled corticosteroids and found that 59% of
patients had suppressed sputum eosinophil counts but they
showed evidence of neutrophilic inflammation. The
increase of sputum neutrophils % in bronchial asthma may
be due to the use of high doses of steroid, severity of
asthma,30 subtle sub-clinical bronchiectasis or lower
respiratory tract infections.31
Sputum lymphocyte % in the present study was significantly higher among asthmatic patients than healthy
control group. The present study showed that there was
a highly significant increase in sputum eosinophil % among
steroid inhaled and steroid nave patients compared to
healthy control group. The increase in steroid nave
patients was highly significant than steroid inhaled group.
On the other hand, Takemura et al.19 reported that the
number of sputum % of eosinophils was increased in ICSve
group than ICSve group (7.0  11.9 vs. 3.5  9.2).
In regards to the correlation of serum hs-CRP to sputum
cell %, it was found that in ICSve group there was

Spearman correlation of hs-CRP to sputum cell counts.

Studied groups

Group A
Group B
Control group

Total (n Z 26)
Total (n Z 24)
(n Z 15)

Macrophage%

Neutrophils%

Eosinophils%

Lymphocytes%

P-value

P-value

P-value

P-value

0.05
0.56
0.15

0.8
0.005*
0.57

0.11
0.18
0.154

0.6
0.4
0.58

0.44
0.66
0.08

0.025*
< 0.001**
0.78

0.38
0.55
0.04

0.06
0.006*
0.89

* denotes significant difference; ** denotes high significant difference; and *** denotes very high significant difference.

High sensitivity C-reactive protein in bronchial asthma

a significant positive correlation between serum hs-CRP and
sputum eosinophil % with no significant correlation with
other sputum inflammatory cells.
Takemura et al.19 found that there was no significant
correlation between serum hs-CRP and any sputum
inflammatory cells among ICSve group. This apparent
controversy could be explained as mentioned before, i.e.
non-compliance or inefficient utilization of inhaled steroid,
use of suboptimal doses of inhaled steroid or finally the
asthma became steroid resistant.
Regarding steroid nave patients, the current study
demonstrated a very highly significant positive correlation
between serum hs-CRP and sputum % of eosinophils,
macrophages and lymphocytes. The positive correlation
between hs-CRP and sputum % of eosinophils can reflect
the degree of severity affecting airway inflammation.
Takemura et al.19 found similar result; significant positive
correlation between hs-CRP and sputum eosinophil % and
marginally positive correlation with both of neutrophils
and macrophages % among steroid nave asthmatic
patients.

Conclusion
-

hs-CRP is a sensitive, easily measured inflammatory

marker and is a useful systemic biomarker of airway
inflammation in asthmatic patients.
It is obviously less complicated than other exhaled
biomarkers of inflammation.
Asthma has a systemic aspect of inflammation besides
the local inflammation as documented by the increase
level of hs-CRP among steroid inhaled and steroid nave
patients in comparison with the control group.
Increased eosinophil number and decreased pulmonary
function are associated with higher serum hs-CRP level
more in steroid nave patients. Therefore serum hs-CRP
can be used as one of the parameters indirectly detecting
the degree of severity affecting the airways.

Conflict of interest
The authors report no conflicts of interest. The authors
alone are responsible for the content and writing of the
paper. None of the authors had a financial support for this
paper.

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