We read with interest the recent article from Simler et al in Thorax
investigating angiogenic cytokines in patients with idiopathic
interstitial pneumonia [1]. We were surprised by their reported high
levels of plasma VEGF in the normal control group. Previously, several
other groups, including the manufacturers of the ELISA (R&D systems)
quote normal plasma VEGF levels in the range of 36-76 pg/...
We read with interest the recent article from Simler et al in Thorax
investigating angiogenic cytokines in patients with idiopathic
interstitial pneumonia [1]. We were surprised by their reported high
levels of plasma VEGF in the normal control group. Previously, several
other groups, including the manufacturers of the ELISA (R&D systems)
quote normal plasma VEGF levels in the range of 36-76 pg/ml[2, 3]. Indeed
one of the authors of the paper previously quoted normal VEGF levels as 76
pg/ml using a matched pair ELISA [4]. It is clear, therefore that the
levels quoted of 648 pg/ml for normal controls are nearly 10 fold higher
than reported previously.
One possible explanation for this finding is the low centrifugal
force used for preparation of plasma (300g for 12 minutes). The
manufacturer of the ELISA recommends 1000 g for 15 minutes as a way to
reduce platelet contamination of plasma. Platelet secretion of VEGF is the
reason for elevated serum levels of VEGF when compared to plasma and might
therefore explain the extraordinarily high levels of VEGF found in these
normal subjects [4]. Interestingly 14/49 (28.5%) of patients included were
on immunosuppressant drugs that potentially reduce platelet count. This
offers an alternative explanation as to why there was no difference
between normal patients and those with pulmonary fibrosis in contrast to
earlier reports in connective tissue disease related pulmonary fibrosis
from 1998 [5].
Although the plasma levels of VEGF correlated with fibrosis based
upon CT score it is difficult to fully appreciate the relevance of this
finding, without knowing the concentration of VEGF actually within the
lung compartment. This is because in the normal individual, epithelial
lining fluid levels of VEGF at 9-11 ng/ml are several orders of magnitude
greater than that found in the circulation [6, 7]. Furthermore, previous
investigators have reported reduced levels of alveolar VEGF in patients
with IPF [8]. Low BALF VEGF levels are also seen in patients with acute
lung injury, sarcoidosis, emphysema and the transplanted lung. Thus it
would appear that a reduced alveolar level of VEGF is a common feature of
diseases associated with alveolar epithelial damage. Indeed, in ARDS,
alveolar levels of VEGF are lowest in those with the worst lung injury.
This is probably a result of reduced epithelial cell secretion of VEGF and
increased expression of its soluble receptor sVEGFR-1, which acts as a
natural inhibitor to the bioactivity of VEGF. The trophic role of VEGF
within the lung is supported by the fact that VEGF acts as a proliferative
factor for fetal pulmonary epithelial cells (9) and because lung-targeted
VEGF inactivation leads to an emphysema phenotype in mice[10]. These
studies suggest that reduced alveolar levels of VEGF may inhibit
epithelial repair in a wide variety of lung diseases.
To summarize, we have some concerns about the
validity/reproducibility of the VEGF levels reported in this study.
Furthermore, based upon the available evidence, we believe it is
inappropriate to suggest that antagonizing VEGF would be a successful
potential therapy for patients with pulmonary fibrosis. To the contrary we
believe this would hasten epithelial cell apoptosis and promote alveolar
septal cell loss with resultant honeycombing and functional deterioration.
References
(1) Simler, N. R., P. E. Brenchley, A. W. Horrocks, S. M. Greaves, P.
S. Hasleton, and J. J. Egan. 2004. Angiogenic cytokines in patients with
idiopathic interstitial pneumonia. Thorax 59(7):581-585.
(2) Thickett, D. R., L. Armstrong, S. J. Christie, and A. B. Millar. 2001.
Vascular endothelial growth factor may contribute to increased vascular
permeability in acute respiratory distress syndrome. Am J Respir Crit Care
Med 164(9):1601-5.
(3) Himeno, W. 2001. Angiogenic growth factors in patients with cyanotic
congenital heart disease and in normal children. Kurume Med J 48(2):111-6.
(4) Webb, N. J., M. J. Bottomley, C. J. Watson, and P. E. Brenchley. 1998.
Vascular endothelial growth factor (VEGF) is released from platelets
during blood clotting: implications for measurement of circulating VEGF
levels in clinical disease. Clin Sci (Lond) 94(4):395-404.
(5) Kikuchi, K., M. Kubo, T. Kadono, N. Yazawa, H. Ihn, and K. Tamaki.
1998. Serum concentrations of vascular endothelial growth factor in
collagen diseases. Br J Dermatol 139(6):1049-51.
(6) Kaner, R. J., and R. G. Crystal. 2001. Compartmentalization of vascular
endothelial growth factor to the epithelial surface of the human lung. Mol
Med 7(4):240-6.
(7) Thickett, D. R., L. Armstrong, and A. B. Millar. 2002. A role for
vascular endothelial growth factor in acute and resolving lung injury. Am
J Respir Crit Care Med 166(10):1332-7.
(8) Koyama, S., E. Sato, M. Haniuda, H. Numanami, S. Nagai, and T. Izumi.
2002. Decreased level of vascular endothelial growth factor in
bronchoalveolar lavage fluid of normal smokers and patients with pulmonary
fibrosis. Am J Respir Crit Care Med 166(3):382-5.
(9) Brown, K. R., K. M. England, K. L. Goss, J. M. Snyder, and M. J.
Acarregui. 2001. VEGF induces airway epithelial cell proliferation in
human fetal lung in vitro. Am J Physiol Lung Cell Mol Physiol 281(4):L1001
-10.
(10) Tang, K., H. B. Rossiter, P. D. Wagner, and E. C. Breen. 2004. Lung-
targeted VEGF inactivation leads to an emphysema phenotype in mice. J Appl
Physiol.
I read the article by Janssen-Heijnen et al with interest [1]. There are
large differences in the reported survival of patients presenting with
lung cancer. Those presenting in the United states and Spain are reported
to have up to twice the chance of surviving five years when compared to
those presenting in the United Kingdom [2-4]. This may be due to differences
in disease, differences in performanc...
I read the article by Janssen-Heijnen et al with interest [1]. There are
large differences in the reported survival of patients presenting with
lung cancer. Those presenting in the United states and Spain are reported
to have up to twice the chance of surviving five years when compared to
those presenting in the United Kingdom [2-4]. This may be due to differences
in disease, differences in performance status or co-morbidity, differences
in treatment, or differences in recording, but it demands a critical
analysis of current practice. This study informs the discussion suggesting
that age and co-morbidity do not significantly alter prognosis but it
includes only those with a histologically confirmed non small cell lung
cancer. It seems likely that age and significant co-morbidity might reduce
the chances of getting histology. Do the authors know the rate of
histological confirmation in the population described and, if so, is it
influenced by age or co-morbidity? It is hard to base any conclusion on
the role of these factors in outcomes for the whole population on those
with confirmed histology without first quantifying age and co-morbidity in
those without histological confirmation.
References
(1) Janssen-Heijnen MLG. Effect of comorbidity on the treatment and prognosis of elderly patients with non-small cell lung cancer. Thorax 2004; 59: 602-607
(2) Berrino F, Capocaccia R, Estève T, et al. Survival of cancer
patients in Europe- the EUROCARE 2 Study. (IARC Scientific Publications
No. 151) International Agency for Research on Cancer (Lyon: 1999)
(3) Sikora K. Cancer survival in Britain. BMJ 1999; 319: 461-2
(4) American Cancer Society, Inc. Cancer Facts and Figures 2002.
Surveillance Research (2002)
The paper by Fitzgerald et al [1] raises important questions as to
what patients should be advised to do during periods of less well
controlled asthma. In other words, the commonly advised practice of
doubling the inhaled corticosteroid dose is not backed up by a wealth of
evidence, in turn resulting in an embarassing paucity of clear guidance
for patients.
The paper by Fitzgerald et al [1] raises important questions as to
what patients should be advised to do during periods of less well
controlled asthma. In other words, the commonly advised practice of
doubling the inhaled corticosteroid dose is not backed up by a wealth of
evidence, in turn resulting in an embarassing paucity of clear guidance
for patients.
It has become apparent in the management of chronic asthma, that
additional 2nd line controller therapy is generally more advantageous than
doubling the dose of inhaled corticosteroid. [2] In the treatment and
prevention of asthma exacerbations, a similar pharmacotherapeutic
rationale may also become the norm and be incorporated into individualised
asthma action plans. In other words, adding further 2nd line therapy for a
short period of time during deteriorating asthma control - while
maintaining the same inhaled corticosteroid dose - may be appropriate.
For example, the hybrid actions of leukotriene antagonism would
attenuate airway hyperresponsiveness and further dilate the airways, while
add on long acting ß2-agonist would maximally bronchodilate the airways
with the provision of an “airway stabilising effect”.[3] Indeed, Aalbers
et al demonstrated that the use of budesonide and eformoterol in
combination, with dose adjustment according to patients symptoms,
conferred benefit in terms of exacerbations, lung function and reliever
use. Perhaps in asthmatics already using an inhaled corticosteroid plus
long acting ß2-agonist, the addition of montelukast may be worthwhile, as
“triple therapy” has been shown to confer further benefit in terms of
surrogate inflammatory biomarkers and attenuating airway
hyperresponsiveness.[5]
In conclusion, studies evaluating the effects of “short bursts” of
leukotriene receptor antagonists or add-on long acting ß2-agonists
compared to doubling the inhaled corticosteroid dose during deteriorating
asthma control are urgently required.
Graeme P Currie
Daniel K C Lee †
Department of Respiratory Medicine, Aberdeen Royal Infirmary,
Foresterhill, Aberdeen AB25 2ZN, Scotland, United Kingdom
† Department of Respiratory Medicine, Ipswich Hospital, Heath Road,
Ipswich IP4 5PD, Suffolk, England, United Kingdom
References
1. FitzGerald JM, Becker A, Sears MR, et al. Doubling the dose of
budesonide versus maintenance treatment in asthma exacerbations. Thorax
2004;59:550–6
2. British Guideline on the Management of Asthma. Thorax 2003; 58
(Suppl 1):1-83.
3. Currie GP, Jackson CM, Ogston SA, Lipworth BJ. Airway-stabilising
effect of long-acting ß2-agonists as add-on therapy to inhaled
corticosteroids. QJM 2003;96: 435-40.
4. Aalbers R, Backer V, Kava TTK, et al. Adjustable maintenance
dosing with budesonide/formoterol compared with fixed-dose
salmeterol/fluticasone in moderate to severe asthma. Curr Med Research and
Opinion 2004; 20: 225-40.
5. Currie GP, Lee DKC, Haggart K, et al. Effects of montelukast on
surrogate inflammatory markers in corticosteroid treated patients with
asthma. Am J Respir Crit Care Med 2003; 167:1232-8.
Dr McFadden is putting forward an interpretation of the small non-
significant decrease in asthma episode contacts seen amongst those with
moderate exposure to passive smoking. In our view this is unwise. The
effect could well be due simply to the play of chance. Further we have
shown that non-clinical factors have a dominant influence on visit
frequency and that the frequency of contacts is a poor measu...
Dr McFadden is putting forward an interpretation of the small non-
significant decrease in asthma episode contacts seen amongst those with
moderate exposure to passive smoking. In our view this is unwise. The
effect could well be due simply to the play of chance. Further we have
shown that non-clinical factors have a dominant influence on visit
frequency and that the frequency of contacts is a poor measure of asthma
morbidity. In consequence our study gives no support at all to the idea
that moderate levels of tobacco smoke suppress asthma. We agree that
further research is needed both into the consequences of passive smoking
and also into the determinants of health care utilisation among children
with asthma.
Iain K Crombie, Professor
Linda Irvine, Research Fellow
Department of Epidemiology and Public Health University of Dundee, Dundee DD1 9SY, UK
We agree with Anderson that age and significant co-morbidity might
reduce the chances of getting histology. In the population of our study
the proportion of patients with a clinical diagnosis was 7%. This
proportion varied from almost 3% for patients younger than 65 to 8% for
those aged 65-79 and 22% for those aged 80 or older. In patients younger
than 65 or in those aged 80 or older this proportio...
We agree with Anderson that age and significant co-morbidity might
reduce the chances of getting histology. In the population of our study
the proportion of patients with a clinical diagnosis was 7%. This
proportion varied from almost 3% for patients younger than 65 to 8% for
those aged 65-79 and 22% for those aged 80 or older. In patients younger
than 65 or in those aged 80 or older this proportion did not decrease with
significant co-morbidity. In patients aged 65-79, however, the proportion
of patients with a clinical diagnosis increased from 5% for patients
without co-morbidity to 7% for those with one co-morbid condition, and to
10% for those with at least two co-morbid conditions.
In our study we only included patients with non-small cell lung
cancer. In those with localized disease 3-year survival significantly
decreased with age.
However, the differences in lung cancer survival within Europe cannot
entirely be explained by differences in age distribution. In the EUROCARE
study [1,2] survival rates were standardised to a common age structure.
Furthermore, the rates were adjusted for the age-specific background
mortality to keep to a minimum the effect of age and competing causes of
death on the overall comparisons. In the United Kingdom the proportion of
microscopically verified lung cancer cases was rather low (about 60%) [3].
Therefore, differences in access to diagnostic care might be responsible
for variation in lung cancer survival, rather than differences in age
distribution or the prevalence of co-morbidity. Registration procedures
might also play a role, because we do not dispose on notifications from
death certificates. This problem becomes larger when access to care is
less optimal. The number of chest physicians in the Netherlands was 2 to 3
times as high as in the UK.
References
(1) Janssen-Heijnen ML, Gatta G, Forman D, et al. Variation in survival
of patients with lung cancer in Europe, 1985-1989. EUROCARE Working Group.
Eur J Cancer 1998;34:2191-6.
(2) Sant M, Aareleid T, Berrino F, et al. EUROCARE-3: survival of
cancer patients diagnosed 1990-94-results and commentary. Ann Oncol
2003;14 Suppl 5:V61-V118.
(3) Capocaccia R, Gatta G, Roazzi P, et al. The EUROCARE-3 database:
methodology of data collection, standardisation, quality control and
statistical analysis. Ann Oncol 2003;14 Suppl 5:V14-V27.
We read with interest the recent article by Niimi et al reporting low
levels of exhaled breath condensate (EBC) pH in patients with chronic
cough [1]. We and others have described low EBC pH in association with
airway inflammation in allergic asthma, cystic fibrosis and
COPD [2][3][4]. In these studies there is a relatively close association
between inflammation and low pH which is shown by the furth...
We read with interest the recent article by Niimi et al reporting low
levels of exhaled breath condensate (EBC) pH in patients with chronic
cough [1]. We and others have described low EBC pH in association with
airway inflammation in allergic asthma, cystic fibrosis and
COPD [2][3][4]. In these studies there is a relatively close association
between inflammation and low pH which is shown by the further fall in pH
during exacerbations [2]. However in non-asthmatic chronic cough whilst
there is a low grade inflammation present in some subjects this is much
less than would be required to invoke inflammation as the major cause of
airway acidification.
It is unclear from the description of the assessment protocol how
patients were allotted their individual diagnostic categories. A positive
methacholine challenge test is not infrequently found in patients with
reflux [5] and, even in classical asthma, reflux is a common phenomenon [6].
We would suggest that there has been a significant under diagnosis of
reflux disease in this cohort because of the lack of a structured history,
the non uniform application of investigations and the failure to perform
full oesophageal assessment, particularly manometry. We have shown that
when oesophageal manometry is not performed a significant number of
patients with reflux cough will be missed [7]. Proton pump inhibitors at
conventional doses only temporarily increase the pH of gastric reflux and
do not prevent reflux per se and, unsurprisingly, only improve symptoms in
a proportion of patients with reflux cough. A failure of cough to improve
with proton pump inhibitors does not therefore adequately rule out reflux
cough.
The simplest explanation for the low airway pH observed by Niimi et
al would be that a large proportion of the subjects have laryngopharyngeal
reflux. This would also explain the otherwise surprising finding of
similar EBC pH across the authors’ diagnostic categories.
References
(1) Niimi A, Nguyen LT, Usmani O, Mann B, Chung KF. Reduced pH and
chloride levels in exhaled breath condensate of patients with chronic
cough. Thorax 2004; 59: 608-612.
(2) Ojoo JC, Mulrennan S, Kastelik JA, Morice AH, Redington AE.
Exhaled breath condensate pH and exhaled nitric oxide in allergic asthma
and in cystic fibrosis. Thorax 2004; (In Press)
(3) Kostikas K, Papatheodorou G, Ganas K, Psathakis K, Panagou P,
Loukides S. pH in expired breath condensate of patients with inflammatory
airway diseases. Am J Respir Crit Care Med. 2002; 165: 1364-1370.
(4) Tate S, MacGregor G, Davis M, Innes JA, Greening AP. Airways in
cystic fibrosis are acidified: detection by exhaled breath condensate.
Thorax 2002; 57: 926-929.
(5) Bagnato GF, Gulli S, Giacobbe O, De Pasquale R, Purello DF.
Bronchial hyperresponsiveness in subjects with gastroesophageal reflux.
Respiration 2000; 67: 507-509.
(6) Vincent D, A.M., Leport J, et al. Gastro-oesophageal reflux
prevalence and relationship with bronchial reactivity in asthma. Eur
Respir J 1997; 10: 2255-2259.
(7) Kastelik JA, Redington AE, Aziz I, et al. Abnormal oesophageal
motility in patients with chronic cough. Thorax 2003; 58: 699-702.
in a recent issue of the Journal, Gan WQ et al. published a systematic review
and meta-analysis of 14 reports which confirmed the strong association between
COPD and biological markers of systemic inflammation [1]. In 6 reports, COPD was
diagnosed according to the presence of a FEV1/FVC ratio lower than 0.7. However,
in the remaining 8 studies this measure was not available, and authors assumed
as affecte...
in a recent issue of the Journal, Gan WQ et al. published a systematic review
and meta-analysis of 14 reports which confirmed the strong association between
COPD and biological markers of systemic inflammation [1]. In 6 reports, COPD was
diagnosed according to the presence of a FEV1/FVC ratio lower than 0.7. However,
in the remaining 8 studies this measure was not available, and authors assumed
as affected by COPD all participants in the lowest quartile of FEV1% and, for
one study [2], of FVC%. In these cases, the corresponding highest quartile group
served as control. Since a COPD diagnosis based on the decreased FEV1/FVC ratio
was lacking in 8 reports, the possibility cannot be excluded that a certain
number of patients included in the meta-analysis did not have COPD, but a
restrictive ventilatory defect. This could be particularly true for participants
to the study by Engstrom [2], who were characterized only by a low FVC.
According to the current GOLD guidelines [3], only a FEV1/FVC ratio lower
than 0.7 indicates airflow obstruction, thus allowing a COPD diagnosis. Indeed,
in the absence of particular pulmonary diseases, many subjects show an
homogenous decrease of all dynamic lung volumes (FEV1, FVC, PEF), without any
alteration of FEV1/FVC ratio, and are thus considered as having “impaired lung
function”. The occurrence of respiratory symptoms [4], the systemic inflammation
[2] and the increased risk of cardiovascular disease [5] are the only features
that restrictive subjects share with COPD. In fact, whereas COPD is
characterized by a decrease in BMI and blood lipids, restrictive subjects often
have abdominal obesity, insulin-resistance and other metabolic risk factors [6].
Although we believe that most of the included patients were really affected
by COPD, the possible inclusion of restrictive patients may have altered the
statistical conclusions of the meta-analysis. In addition, the choice of
selecting patients in the lowest quartile of FEV1 or FVC hindered the authors
from confirming the absence of inflammation in mild COPD (GOLD stage I and II),
a finding previously reported by the same group in a study not included in this
meta-analysis [7].
Because the two groups of restrictive and COPD patients have different
features, the generic term ”impaired lung function” should not be used. Future
studies about the role of inflammation and other cardiovascular risk conditions
in respiratory patients, as well as those investigating the outcome of these
subjects, should clearly distinguish restrictive from COPD patients.
References
(1) Gan WQ, Man SFP, Senthilselvan A, Sin DD. Association between chronic
obstructive pulmonary disease and systemic inflammation: a systematic review and
a meta-analysis. Thorax 2004; 59: 574-580
(2) Engstrom G, Lind P, Hedblad B et
al. Lung function and cardiovascular risk. Relationship with
inflammatory-sensitive plasma protein. Circulation 2002; 106: 2555-2560
(3)
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Publication no.
2701. Bethesda, National Institute for Health, 2001 (2004 update).
(4) Mannino
DM, Ford ES, Redd SC. Obstructive and restrictive lung disease and functional
limitation: data from the Third national Health and Nutrition Examination.
Journal of Internal Medicine 2003; 254: 540-547
(5) Hole DJ, Watt GC, Davey-Smith
G et al. Impaired lung function and mortality risk in men and women: findings
from the Renfrew and Paisley prospective population study. BMJ 1996; 313:
711-715
(6) Lawlor DA, Ebrahim S, Davey-Smith G. Associations of measures of lung
function with insulin resistance and type 2 diabetes: findings from the British
Women’s heart and health Study. Diabetologia 2004; 47: 195-203
(7) Sin DD, Man SFP. Why are patients with obstructive pulmonary disease at increased risk of
cardiovascular diseases? The potential role of systemic inflammation in Chronic
Obstructive Pulmonary Disease. Circulation 2003; 107: 1514-1519
We thank Professor Morice and his colleagues for their interest and
for the issues raised vis-a-vis our manuscript.
The main issue raised concerns the possibility that we may have
missed gastrooesophageal disorders such as reflux and dysmotility in our
cohort of chronic cough patients. In our assessment protocol, we state
that we used oesophageal pH measurements in most patients (32 out of 50)...
We thank Professor Morice and his colleagues for their interest and
for the issues raised vis-a-vis our manuscript.
The main issue raised concerns the possibility that we may have
missed gastrooesophageal disorders such as reflux and dysmotility in our
cohort of chronic cough patients. In our assessment protocol, we state
that we used oesophageal pH measurements in most patients (32 out of 50),
together with a trial of proton pump inhibitor. We are pleased to read
from Professor Morice that proton pump inhibitors “only improve symptoms
in a proportion of patients with reflux cough”, when they reported
previously a very excellent 82% therapeutic response in this group treated
with 'proton pump inhibitors, alginates and conventional advice regarding
diet and posture' [1]. We agree entirely that proton pump inhibitors are
not very efficacious in reflux cough. We have not performed oesophageal
manometry and are aware of Professor Morice’s interesting observations.
They also report that patients with abnormal oesophageal manometry respond
to proton pump inhibition, and therefore we would have picked up such
patients with a proton pump inhibitor trial of therapy. However, the
direct link between oesophageal dysmotility and chronic cough still
remains to be established.
We do not believe we have missed reflux as an associated cause of the
cough and therefore do not agree with the explanation that the reduced
exhaled breath condensate pH is a reflection of larngophargeal reflux
throughout the diagnostic categories. Rather, this is likely to be related
to the chronic inflammatory and remodelling process that is present in the
submucosa of chronic cough patients, associated with asthma or non-
asthmatic causes [2, 3, 4]. We must emphasise that we are assuming that
exhaled breath condensate is a reflection of the epithelial surface
liquid, which needs to be confirmed.
References
(1) Kastelik JA, Redington AE, Aziz I, Buckton GK, Smith CM,
Dakkak M
et al. Abnormal oesophageal motility in patients with chronic cough.
Thorax 2003;58:699-702.
(2) Niimi A, Matsumoto H, Minakuchi M, Kitaichi M, Amitani R.
Airway
remodelling in cough-variant asthma. Lancet 2000;356:564-5.
(3) Boulet LP, Milot J, Boutet M, St Georges F, Laviolette M.
Airway
inflammation in non-asthmatic subjects with chronic cough. Am J Respir Crit
Care Med 1994;149:482-9.
(4) Niimi, A., Cosio, B., Oates, T., Nicholson, A., and Chung,
K. F.
Airway inflammation and remodelling in non-asthmatic patients with chronic
cough: comparison with asthmatics. Amer J Resp Crit Care Med 2003; 167:
A353 (Abstract).
The authors wish to thank Fimognari and colleagues for highlighting
the difficult issue of defining chronic obstructive pulmonary disease
(COPD). In most circumstances, a spirometric cutoff is used to define
COPD, but there is no uniform consensus on what that should be and
different expert panels have promulgated different spirometric cutoff
values [1-4]. COPD is a disease characterized by lung inflam...
The authors wish to thank Fimognari and colleagues for highlighting
the difficult issue of defining chronic obstructive pulmonary disease
(COPD). In most circumstances, a spirometric cutoff is used to define
COPD, but there is no uniform consensus on what that should be and
different expert panels have promulgated different spirometric cutoff
values [1-4]. COPD is a disease characterized by lung inflammation and
patient symptoms (most notably dyspnea). Studies have shown that the
relationship between airway inflammation and patient symptoms with forced
expiratory volume in one second (FEV1) is a continuum, and not threshold-
dependent [5,6]. Thus, any attempts to impose FEV1 (or FEV1 to forced
vital capacity, FVC, ratio) limits in defining COPD are bound to be
arbitrary and contentious. Rather than relying on arbitrary cutoffs, for
large population-based studies, it is reasonable (and useful) to compare
the outcome of interest (in this case systemic inflammation) between
extremes of FEV1 (e.g. worst FEV1 quartile to best quartile group). This
method avoids imposing any arbitrary constraints in the definition of COPD
and allows maximal utilization of the data points. However, a potential
limitation of this approach is the possibility of diagnostic
misclassification between restrictive and obstructive lung diseases. To
specifically address this concern, we excluded population-based studies
wherein a FEV1 to FVC ratio was not used to define COPD (Mendall, Dahl,
and Engstrom’s studies [7-9]) and re-analyzed the C-reactive protein (CRP)
and fibrinogen data. Even after the exclusion of these studies, the
standardized mean difference in the CRP level between COPD and control
subjects was 0.68 units (95% confidence interval, CI, 0.38 to 0.98) or
4.85 mg/L (95% CI, 1.92 to 7.78). For the fibrinogen data, the
standardized mean difference between COPD and control subjects was 0.48
units (95% CI, 0.43 to 0.54) or 0.42 g/L (95% CI, 0.00 to 0.84). These
results indicate that the possible contamination of individuals with
restrictive defect in the groups with low FEV1 or FVC did not influence
the overall findings. Finally, we did not include data from one of our
previous reports [10] because the study sample was taken from the same
source population as Mannino and colleague’s study [11], which was
included in the meta-analysis.
Don D. Sin
Wen Qi Gan
S. F. Paul Man
Department of Medicine, University of British Columbia, Vancouver, Canada
Ambikaipakan Senthilselvan.
Department of Public Health Sciences, University of Alberta, Edmonton,
Canada
References
(1) Fabbri LM, Hurd SS; GOLD Scientific Committee. Global Strategy for the
Diagnosis, Management and Prevention of COPD: 2003 update. Eur Respir J.
2003; 22:1-2.
(2) The COPD Guidelines Group of the Standards of Care Committee of
the British Thoracic Society. British Thoracic Society guidelines for the
management of chronic obstructive pulmonary disease. Thorax. 1997;52(suppl
5):S1-S28.
(3) Siafakas NM, Vermeire P, Pride NB, et al. Optimal assessment and
management of chronic obstructive pulmonary disease (COPD). The European
Respiratory Society Task Force. Eur Respir J. 1995;8:1398-420.
(4) American Thoracic Society. Standards for the diagnosis and care
of patients with chronic obstructive pulmonary disease. Am J Respir Crit
Care Med. 1995; 152:S77-S120.
(5) Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway
obstruction in chronic obstructive pulmonary disease. N Engl J Med.
2004;350:2645-53.
(6) Sin DD, Jones RL, Mannino DM, Paul Man SF. Forced expiratory
volume in 1 second and physical activity in the general population. Am J
Med. 2004;117:270-3.
(7) Mendall MA, Strachan DP, Butland BK, et al. C-reactive protein:
relation to total mortality, cardiovascular mortality and cardiovascular
risk factors in men. Eur Heart J 2000;21:1584-90.
(8) Dahl M, Tybjaerg-Hansen A, Vestbo J, et al. Elevated plasma
fibrinogen associated with reduced pulmonary function and increased risk
of chronic obstructive pulmonary disease. Am J Respir Crit Care Med
2001;164:1008-11.
(9) Engstrom G, Lind P, Hedblad B, et al. Lung function and
cardiovascular risk: relationship with inflammation-sensitive plasma
proteins. Circulation 2002;106:2555-60.
(10) Sin DD, Man SF. Why are patients with chronic obstructive
pulmonary disease at increased risk of cardiovascular diseases? The
potential role of systemic inflammation in chronic obstructive pulmonary
disease. Circulation 2003;107:1514-9.
(11) Mannino DM, Ford ES, Redd SC. Obstructive and restrictive lung
disease and markers of inflammation: Data from the third national health
and nutrition examination. Am J Med 2003;114:758-62.
Thank you for a well-reasoned explanation on the effect of yoga on
asthma.
The study quoted [1] which justifies the Buteyko technique was flawed
by:
* unequal groups in that the Buteyko group initially required 1½ times the
steroids of the control group
* the Buteyko group receiving seven times the follow-up phone calls as the
control group, plus extra breathin...
Thank you for a well-reasoned explanation on the effect of yoga on
asthma.
The study quoted [1] which justifies the Buteyko technique was flawed
by:
* unequal groups in that the Buteyko group initially required 1½ times the
steroids of the control group
* the Buteyko group receiving seven times the follow-up phone calls as the
control group, plus extra breathing classes.
Also, no significant difference was found in quality of life scores at the
end of the trial.
However, there is anecdotal evidence of excellent results in some
patients, representing the overlap of hyperventilation syndrome and asthma.[2] If patients with asthma are given the simple Nijmegen questionnaire [3] to identify coexisting hyperventilation syndrome, a chartered
physiotherapist can usually treat them successfully.[4]
References
(1) Bowler SD, Green A, Mitchell CA (1998) Buteyko breathing
techniques in asthma: a randomised controlled trial. Med.J.Aust, 169, 575-8.
(2) Demeter SL (1986) Hyperventilation syndrome and asthma. Am J Med 1986;81:989-94.
(3) Hough A. Physiotherapy in Respiratory Care, 3rd edition. (www.nelsonthornes.com), 2001.
Dear Editor
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Dear Editor
Thank you for a well-reasoned explanation on the effect of yoga on asthma.
The study quoted [1] which justifies the Buteyko technique was flawed by:
* unequal groups in that the Buteyko group initially required 1½ times the steroids of the control group
* the Buteyko group receiving seven times the follow-up phone calls as the control group, plus extra breathin...
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