Sherriff and colleagues report an apparent association between
mothers’ self-reported frequency of use of assorted household ‘chemicals’
during pregnancy and ‘persistent wheeze’ in their offspring. Since their
paper suggests this may help explain recent rises in asthma, the
robustness of the data and other explanations for the observed statistical
association need careful consideration.
Sherriff and colleagues report an apparent association between
mothers’ self-reported frequency of use of assorted household ‘chemicals’
during pregnancy and ‘persistent wheeze’ in their offspring. Since their
paper suggests this may help explain recent rises in asthma, the
robustness of the data and other explanations for the observed statistical
association need careful consideration.
We see several concerns, including both exposure and outcome
measures, lack of a plausible biological mechanism for the suggested in
utero effect, and the possibility of both recall and selection bias.
The definition of persistent wheeze is weak, and far removed from
criteria currently considered to define asthma . Offspring are
categorised as having ‘persistent wheeze’ if mothers’ responses indicate
one instance of wheezing in three consecutive 12 month periods.
It is curious that the association appears using frequency of use
scores which treat 11 disparate product types as equal, irrespective of
composition, and remains when each in turn was removed from the analysis.
Some product types have nothing at all in common: we can see no
significant ingredient that is common even to the majority, nor any likely
shared toxic mode of action. Contrary to the authors’ suggestion
formaldehyde is little used in the products surveyed.
Self-reported frequency of use is a very poor measure of exposure:
variations in quantity of product used, duration of use and routes of
exposure (inhalation, dermal, ingestion etc) can yield scores which run
contrary to actual exposure.
We see little justification for aggregating disparate product
exposures as ‘Total Chemical Burden’ by analogy with particulate air
pollution: the action of particulates is plausibly associated more with
size, geometry and/or absorptive capacity than with chemical composition.
This concept cannot simply be extrapolated to vapours or non-particulates,
and the term itself unfortunately suggests some absorbed, retained load:
‘sum of reported product use frequencies’ would have been more
appropriate.
We are not aware of any substantiated toxicological effect that is
shared by all chemicals irrespective of composition, especially given that
the notion of a ‘chemical’ is essentially subjective. All matter,
natural or synthetic, is composed of atoms and molecules. How do the
products considered differ from the many household chemicals not
considered, and chemicals that make up the natural environment to which
people are continuously exposed?
It seems unlikely that the association is driven by one product type
since it remained when each in turn was removed from the analysis.
Further, previous analyses of these questionnaires for two specific types
(aerosols and air fresheners) found no association with wheeze . Per
capita consumption of cleaning products in different European countries
also shows no correlation with the patterns of asthma .
Other than chance, how else might the observed association have
arisen? Apart from confounding by other chemicals in the built or
natural environment, certain mothers may have over-reported both chemical
use and wheezing symptoms. While ‘chemicals’ are heterogeneous in terms
of composition and toxicology, the term perhaps has some homogeneous
psychological significance for certain people. We understand the question
about frequency of use was headed “Chemicals …… in your environment”.
The authors acknowledge some selection bias: “those excluded from the
analysis due to lack of chemical use data were more likely to have wheezed
at all ages than those included, and those excluded from the analysis due
to missing symptom data had, on average, higher TCB scores than those in
the analysis”. This is potentially significant since the numbers
excluded from the study for missing data (50%) are large.
Scrutinising household products for any possible role in the rise in
asthma is important but, to be meaningful, exposures must be properly
defined.
--------------------------------
References
1.Sherriff A, Farrow A, Golding A, the ALSPAC Study Team, Henderson
J. Frequent use of chemical household products is associated with
persistent wheezing in pre-school age children. Thorax 2005; 60: 45-49
2.Asher MI and Weiland SK on behalf of the ISAAC Steering Committee
(1998) The International Study of Asthma and Allergies in Childhood
(ISAAC). Clin Exp Allergy 28, Suppl 5, 52-66.
3. Farrow A, Taylor H, Northstone K, Golding J. Symptoms of Mothers
and Infants Related to Total Volatile Organic Compounds in Household
Products. Arch Environ Health. 2003 Oct;58(10):633-41.
4. Pickup J. Trends in home and consumer hygiene. In 'Are we too
clean? - a question of immunity balance'. RIPH Symposium Report. Published
as a supplement to Health & Hygiene. London: Royal Institute of Public
Health 2003: 6-7.
I read with great interest the paper by de Jong et al. [1]. The authors conclude from a carefully conducted study that scores derived from CT scans are more sensitive in detecting progression of cystic fibrosis in children and adults than pulmonary function tests. I have no difficulty in accepting any such outcome. However, it seems that undue reliance was placed on predicted pulmonary indices, and...
I read with great interest the paper by de Jong et al. [1]. The authors conclude from a carefully conducted study that scores derived from CT scans are more sensitive in detecting progression of cystic fibrosis in children and adults than pulmonary function tests. I have no difficulty in accepting any such outcome. However, it seems that undue reliance was placed on predicted pulmonary indices, and that the value of a control group was not fully appreciated. The interpretation of longitudinal data on lung function is bedeviled by the fact that lung volumes and ventilatory flows increase due to growth up to age 30+ years, and decline thereafter [2]. Since in the type of study carried out by de Jong a matched control group is usually too costly to be feasible, it is often replaced with predicted values, as was done in this study. This approach has potential problems which I will illustrate in children and adolescents.
The authors selected prediction equations for their youngest subjects that have been shown to fit a cross-section of healthy European children and adolescents well [3]. In using them they implicitly assumed that healthy individuals will track along the cross-sectional predicted values. Improvement or decline in these indices in sick children then indicates either improvement or deterioration in their condition. However, cross-sectional prediction equations do not describe the longitudinal trajectory of individuals. The top panel in figure 1 shows the mean FEV1 and its 95% confidence interval, expressed as either Z-score or per cent predicted, in over 350 healthy non-smoking boys followed up at half year intervals for up to 7 years; their cross-sectional data contributed to the prediction equations [3] used by de Jong et al. In this study the variability of FEV1 within subjects tested on 5 consecutive days was 2.7% [4], relatively small compared to 11.6% between individuals [3]. Whilst the overall mean FEV1 is very nearly 100% predicted, there is a clear trend with a minimum at about age 13-14 yr. The lower panel illustrates the pattern in 6 boys. Five show a steady rise after age 13-14 yr, in three of them preceded by a decline of up to one unit Z-score (11% predicted); one boy seems to be tracking at about a constant level. Although the selected reference equation has gone a long way in accommodating the changing relationship between body and lung dimensions at these ages [3] and the above pattern would be more pronounced with older prediction equations, this equation nor any other one available does not describe individual growth curves. In de Jong's study Z-scores were recorded at three year intervals. Note how even in a healthy individual in this age range such scores might have easily gone up or down by as much as one unit, a fall in the youngest subjects being compensated by a rise in the older ones. Similar reasoning holds for girls and for adults.
These observations underline the fact that cross-sectional spirometric reference values, apart from being imperfect, do not describe the growth and decline of pulmonary function within individuals. It follows that it might be useful to analyse separately longitudinal changes in those under 13 year, and in older adolescents possibly up to 30 yr. Even then spirometric findings need to be compared to findings in a matched control group. Given the difficulties in interpreting longitudinal spirometric data, obviously the CT technique provides an apparently reliable and reproducible as well as practical alternative for assessing the progression of lung disease in cystic fibrosis, albeit a costly one.
References
1
De Jong PA, Lindblad A, Rubin L, et al. Progression of lung disease on computed tomography and pulmonary function tests in children and adults with cystic fibrosis. Thorax 2006; 61: 80-85.
2
Van Pelt W, Borsboom GJJM, Rijcken B, et al. Discrepancies between longitudinal and cross-sectional change in ventilatory function in 12 years of follow-up. Am J Respir Crit Care Med 1994; 149: 1218-1226.
3
Quanjer PH, Borsboom GJ, Brunekreef B, et al. Spirometric reference values for white European children and adolescents: Polgar revisited. Pediatr Pulmonol 1995; 19: 135-142.
4
Schrader PC, Quanjer PH, van Zomeren BC, et al. Selection of variables from maximum expiratory flow-volume curves. Bull Europ Physiopath Resp 1983; 19: 43-49.
The letter is most interesting as it extends and develops the earlier
ideas that polyphenols have important biological effects in occupational
exposure. It could be added that raw cotton dust contains an average of
1.6 mg tannic acid/g dry weight (1). Similar values as reported have been
obtained for oak and other hard wood species (2). The polyphenols can also
be used to identify the inhaled wood dust...
The letter is most interesting as it extends and develops the earlier
ideas that polyphenols have important biological effects in occupational
exposure. It could be added that raw cotton dust contains an average of
1.6 mg tannic acid/g dry weight (1). Similar values as reported have been
obtained for oak and other hard wood species (2). The polyphenols can also
be used to identify the inhaled wood dust (3).
We read with great interest the case report by Moore et al (1) on the
diaphragm weakness of two patients after anatomically distant surgery. We
are currently following a patient who had bilateral paralysis of the
diaphragm after a nephrectomy for renal cancer. The patient, a 60 year old
male, non-smoker, without any concomitant cardiac or lung disease,
underwent surgery in August 2004 and immediate...
We read with great interest the case report by Moore et al (1) on the
diaphragm weakness of two patients after anatomically distant surgery. We
are currently following a patient who had bilateral paralysis of the
diaphragm after a nephrectomy for renal cancer. The patient, a 60 year old
male, non-smoker, without any concomitant cardiac or lung disease,
underwent surgery in August 2004 and immediately after the operation he
complained of orthopnea. Chest x-rays showed the elevation of both hemi-
diaphragms, which was not present preoperatively, along with a restrictive
ventilatory defect detected by spirometry (TLC 61% pred, VC 72% pred, FEV1
67% pred, FEV1/VC 70%). The diagnosis of bilateral paralysis was confirmed
by EMG and respiratory muscle strength assessment in October 2004. Because
of a nocturnal oxygen desaturation, he started with nightly non-invasive
ventilation. Up to now he has also undergone periodic courses of
respiratory muscle training. In 2004 and 2005, he was periodically checked
and an improvement in VC was found, but not in PImax nor in TwPdi.
Moreover, the December 2005 check-up revealed that nocturnal oxygen
desaturation significantly improved and that the patient stopped the
ventilation support.
Diaphragm paralysis is associated with renal cancer and is considered
to be a paraneoplastic syndrome (2,3), however, in our patient the
temporal link between the surgical operation and paralysis is evident.
Moreover, during the operation and after the perioperative period our
patient did not undergo a central venous cannulation nor did he experience
any electrolyte disturbance. Postoperatively, the patient also underwent
magnetic resonance imaging, which excluded any injury to his spinal cord.
Therefore, the similarity between the case histories presented by Moore et
al (1) and our patient appears to be evident.
Additionally, we think that the patient’s follow-up is of interest.
So far, the patient’s VC has recovered 0.48 L, being 4.2 L and 86 % of
predicted value in clinostatism. Furthermore, VC now accounts for 2.3 L
and 47% of predicted in orthostatism and can assure a normal oxygen
saturation during the sleep. However, the patient’s diaphragm is still
paralysed, since the TwPdi value is extremely low (3 cm H2O) and the fall
in VC from clinostatism to orthostatism is significant (45%). The recovery
of the VC might be due only to the increase in strength of the accessory
inspiratory muscles, likely due to the respiratory muscle training
courses. This finding further supports the recommendation by Moore et al
(1) to measure the diaphragm strength apart from the global inspiratory
muscle strength in patients with raised hemi-diaphragms after surgery.
References
1. Moore AJ, Moxham J, Polkey MI. Diaphragm weakness as a cause of
breathlessness after anatomically distant surgery. Thorax 2005; 60:786-787
2. Thomas NE, Passamonte PM, Sunderrajan EV, et al. Bilateral
diaphragmatic paralysis as a possible paraneoplastic syndrome from renal
cell carcinoma. Am Rev Respir Dis 1984; 129:507-509
3. Rijnders B, Decramer M. Reversibility of paraneoplastic bilateral
diaphragmatic paralysis after nephrectomy for renal cell carcinoma. Ann
Oncol 2000; 11:221-225.
The review of Pulmonary Rehabilitation in the UK (Thorax, 2001: 56:
827-834) by Dr MDL Morgan begins by noting the lag between the quality of
pulmonary rehabilitation services in the USA compared to their virtual
absence in the UK. Dr Morgan goes on to mention that psychology is one of
the disciplines included in the multiple disciplines that comprise an
effective pulmonary rehabilitation program. In fact, most of the le...
The review of Pulmonary Rehabilitation in the UK (Thorax, 2001: 56:
827-834) by Dr MDL Morgan begins by noting the lag between the quality of
pulmonary rehabilitation services in the USA compared to their virtual
absence in the UK. Dr Morgan goes on to mention that psychology is one of
the disciplines included in the multiple disciplines that comprise an
effective pulmonary rehabilitation program. In fact, most of the leading
hospitals in the US that have pulmonary rehabilitation programs are indeed
truly "multidisciplinary" and the psychosocial and emotional functioning
of the clients constitutes an important ingredient of such programs.
However, the "most recent definition of pulmonary rehabilitation" cited by
Dr Morgan waters down the role of psychology and the program that he
recommends for the UK appears to be primarily exercise based and
physiotherapy-led. In fact,the process and components of pulmonary
rehabilitation described by Dr Morgan comprise almost entirely of
exercise. Dr Morgan acknolwedges only that the "coexistence of reduced
self-efficacy and the affective component is likely to have an effect on
performance," and even so, in the next sentence he, astonishingly,
essentially dismisses the need for a psychologist in such programs:
"psychological and behavioural intervention is already embedded in the
structure of rehabilitation programmes through the delivery of education,
small group discussions and relaxation therapy.... The role of
specific, individual or group psychotherapy is also unclear." According
to him, the only area where psychologists may contribute is in the
assessment of motivation!
Dr Morgan recommends the usage of mental health
questionnaires, presumably psychosocial and mental health variables are
only to be measured not targeted for treatment -- as the presumtion sems
to be that with improved lung function, all such parameters will
automatically improve as well. If this were so, then we would hope that
problems in treatment compliance, severe panic attacks with or without
agoraphobia, debilitating anxiety, depression, fear of death and dying
frequently seen in COPD patients will also automatically resolve without
the need for a professional psychologist on a pulmonary rehabilitation
program. When read closely, the program described in this article does
not resemble a multidisciplinary program at all and hence it should simply
be called a Physiotherapy or Exercise-Based program. Sadly, the kind of
program described will fail many of the COPD patients and Pulmonary
Rehabilitation in the UK will continue to be well behind the well-rounded,
well-funded multidisciplinary prgrams in the US.
We thank Drs Clifford and Deshpande for their comments on our paper
[1]. Both are concerned about the cost-effectiveness of Palivizumab.
Our paper, however, was not about the cost-effectiveness of Palivizumab
but to examine prospectively healthcare utilisation and respiratory
morbidity due to RSV infection in prematurely born infants. Importantly,
we demonstrated an...
We thank Drs Clifford and Deshpande for their comments on our paper
[1]. Both are concerned about the cost-effectiveness of Palivizumab.
Our paper, however, was not about the cost-effectiveness of Palivizumab
but to examine prospectively healthcare utilisation and respiratory
morbidity due to RSV infection in prematurely born infants. Importantly,
we demonstrated an effect not only on hospital admission, but also on GP
attendances and subsequent cough and wheeze.
In response to Dr Clifford’s specific comments:
• We take conflicts of interest statements very seriously.
• We cannot comment on the percentage of smokers in the non-consenters, as
it would be unethical to collect detailed data on parents who had refused
to take part in the study.
• It is a pity Dr Clifford did not contact us directly as we would have
been very pleased to have given him our raw data, if he wished to
undertake an appropriately designed cost effectiveness study, and
contacting us would have revealed that the two infants who received
Palivizumab and had an RSV LRTI were not admitted to hospital.
• We agree it is very important to find effective ways to stop antenatal
women and house-holders of premature babies smoking. As our data
demonstrate current methods are clearly ineffective.
In response to Dr Deshpande:
• We apologise the duration of oxygen therapy was given in a confusing
fashion, as postmenstrual age (wks), not as number of weeks since birth.
• The 40% rate of BPD at 36 weeks post menstrual age is very similar to
the 46% reported recently [2].
• We have recently reported [3] that diminished lung function is a risk
factor for RSV infection and subsequent respiratory morbidity, but in that
paper also report that RSV infection is an independent risk factor for
days of cough and wheeze.
In conclusion, we emphasize our study was not about the cost-
effectiveness of Palivizumab, but to assess health care utilisation and
respiratory morbidity following RSV infection. From the results of all
studies, hypotheses are generated and need to be tested – hence our
comments regarding consideration of giving Palivizumab to infants who have
siblings and whose mothers smoked during pregnancy. We hope our comments
will encourage researchers to undertake an appropriately designed study to
test this.
References
1 Broughton S, Roberts A, Fox G, Pollina E, Zuckerman M, Chaudhry S,
Greenough A. Prospective study of healthcare utilisation and respiratory
morbidity due to RSV infection in prematurely born infants. Thorax
2005;60:1039-1044.
2 Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA, Wrage
LA, Poole K. Validation of the National Institutes of Health concensus
definition of bronchopulmonary dysplasia. Pediatrics 2005;116:1353-60.
3 Broughton S, Bhat R, Roberts A, Zuckerman M, Rafferty G, Greenough A.
Diminished lung function, RSV infection and respiratory morbidity in
prematurely born infants. Arch Dis Child 200691:26-30.
We read with great interest the article by MacRedmond et al (1) on
Screening for lung cancer using low dose CT scan and the related editorial
by Gleeson which provides a comprehensive summary on the benefits and
potential pitfalls of such a screening.
However, we notice in both articles, another important issue of
potential radiation risks associated with a low dose CT screening for lung
cancer has not been addr...
We read with great interest the article by MacRedmond et al (1) on
Screening for lung cancer using low dose CT scan and the related editorial
by Gleeson which provides a comprehensive summary on the benefits and
potential pitfalls of such a screening.
However, we notice in both articles, another important issue of
potential radiation risks associated with a low dose CT screening for lung
cancer has not been addressed.
There have been reports previously which suggest radiation risks even
with a low dose CT scan as part of a regular screening (2) and also of a
possible synergestic interaction between smoking risk and radiation
exposure (4)(5)(6).
David Brennar in his article (2) estimates that, if 50% of all
current and former smokers in the U.S. population aged 50–75 years
received annual CT screening, the estimated number of lung cancers
associated with radiation from screening would be 1.8% (95% credibility
interval: 0.5%, 5.5%) more than the otherwise expected number. Considering
an upper limit of 5.5% increase in lung cancer risk attributable to annual
CT-related radiation exposure, he feels mortality benefit of considerably
more than 5% may be necessary to outweigh the potential radiation risks.
This estimation was derived from cancer incidence data for atomic bomb
survivors.
Several other reports (3)(4)(5)(7) exist which suggest link between
radiation exposure and lung cancer.
Hence, potential radiation risks associated with multiple CT scans
should be considered as one of the limiting factors for such a screening.
References:
(1). R MacRedmond et al. Screening for lung cancer using low dose CT
scanning: results of 2 year follow up. Thorax 2006; 61: 54-56
(2). David J. Brenner, Radiation Risks Potentially Associated with
Low-Dose CT Screening of Adult Smokers for Lung Cancer. Radiology
2004;231:440-445
(3). Gilbert ES, Stovall M, Gospodarowicz M, et al. Lung cancer after
treatment for Hodgkin’s disease: focus on radiation effects. Radiat Res
2003; 159:161-173.
(4). Tokarskaya ZB, Scott BR, Zhuntova GV, et al. Interaction of
radiation and smoking in lung cancer induction among workers at the Mayak
nuclear enterprise. Health Phys 2002; 83:833-846
(5). Neugut AI, Murray T, Santos J, et al. Increased risk of lung
cancer after breast cancer radiation therapy in cigarette smokers. Cancer
1994; 73:1615-1620.
(6). Pierce DA, Sharp GB, Mabuchi K. Joint effects of radiation and
smoking on lung cancer risk among atomic bomb survivors. Radiat Res 2003;
159:511-520.
(7). Pershagen G, Akerblom G, Axelson O, et al. Residential radon
exposure and lung cancer in Sweden. N Engl J Med 1994; 330:159-164
We read with interest the recent paper by Sin and colleagues (1)
which, we believe, raises more questions that it answers.
A major concern is the fact that ascertainment of mortality was
incomplete for a significant proportion of patients (973/5086),
corresponding to 19% of the total (not the reported 12%), who did withdraw
prematurely from the study. This loss to follow up was more likely...
We read with interest the recent paper by Sin and colleagues (1)
which, we believe, raises more questions that it answers.
A major concern is the fact that ascertainment of mortality was
incomplete for a significant proportion of patients (973/5086),
corresponding to 19% of the total (not the reported 12%), who did withdraw
prematurely from the study. This loss to follow up was more likely to
occur in the placebo group. The authors use the ISOLDE study (2) to claim
that patients who withdrew prematurely were more likely to die and that
therefore the hazard ratio is in fact an underestimate of the benefit of
inhaled corticosteroids (ICS). However, the ISOLDE data are themselves
contradictory on this point. The claim is based on an abstract from the
ISOLDE study that states that 29 deaths occurred before withdrawal and 74
subsequently (3). On the other hand, the original ISOLDE article reported
68 deaths before withdrawal, which would leave only 35 afterwards.(2) The
claim of a higher death rate after withdrawal may therefore be incorrect.
We believe that differential identification of deaths may have
occurred as suggested by Figure 1 in the paper and that this could easily
have biased the hazard ratio. The figure first implies a hazard ratio of
1, with no difference in mortality between the ICS and placebo group,
during the first 9 months of follow-up, the only time period where every
single patient is included and loss to follow-up is of no consequence.
This initial 9-month period thus involves all 5086 patients and around 50
deaths, a quarter of all deaths. The subsequent apparent benefit of ICS
is exclusively the result of spurts of excess mortality in the placebo
group that occurred at unusually specific time points, namely between the
9th and 12th months of follow-up, as well as just after the 24th month.
In contrast, the rate of mortality in the ICS group appears to be fairly
constant at roughly 1.6 deaths per 100 per year throughout the 3-year
follow-up. From the natural history of COPD, however, we would also
expect a constant rate of mortality in the placebo group, albeit at a
higher rate, if indeed ICS are beneficial. This observation of spurts of
excess mortality in the placebo group at specific time points is more
suggestive of a study design effect than of a real drug effect. Indeed,
if ICS were effective, their benefit would be more likely gradual
throughout the follow-up, rather than kicking in to prevent short spurts
in mortality precisely at 9 and 24 months after initiation. This
phenomenon suggests differential misclassification of deaths or
informative censoring between the placebo and ICS groups. The authors
could describe the 20 or so deaths, as well as the withdrawals, occurring
in the placebo group between the 9th and 12th months of follow-up, and
after the 24th month.
The reduction in all-cause mortality resulted from a reduction of
deaths due to cancer and to other causes, but not a reduction in cardiac
deaths, and is therefore not consistent with the mechanism of benefit of
inhaled corticosteroids in reducing overall mortality which is usually
postulated (4). Some of the apparent beneficial effect of ICS might be
the result of withdrawal of these medications (5) which will occur in the
placebo arm of the trials included in the ISEEC study. Such withdrawal
might result in relative adrenal insufficiency. It would therefore be
useful to stratify the analysis of the possible benefit of ICS in reducing
mortality by prior use of corticosteroids, both inhaled and systemic. Such
a stratified analysis should also be considered in the much anticipated
TORCH study.
Pierre Ernst and Samy Suissa,
McGill Pharmacoepidemiology Research Unit,
McGill University.
Reference List
1. Sin DD, Wu L, Anderson JA et al. Inhaled corticosteroids and
mortality in chronic obstructive pulmonary disease. Thorax 2005;
60(12):992-997.
2. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen
TK. Randomised, double blind, placebo controlled study of fluticasone
propionate in patients with moderate to severe chronic obstructive
pulmonary disease: the ISOLDE trial. Br Med J 2000; 320(7245):1297-1303.
3. Waterhouse JC, Fishwick D, Burge PS. What caused death in the
ISOLDE study ? European Respiratory Journal 14[Supp. 30], 387S. 1999.
4. Sin DD, Lacy P, York E, Man SF. Effects of fluticasone on
systemic markers of inflammation in chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2004; 170(7):760-765.
5. Wouters EF, Postma DS, Fokkens B et al. Withdrawal of fluticasone
propionate from combined salmeterol/fluticasone treatment in patients with
COPD causes immediate and sustained disease deterioration: a randomised
controlled trial. Thorax 2005; 60(6):480-487.
Inhaled corticosteroids have for some time been seeking a broader
indication in COPD. The recent meta-analysis by Sin et al.[1] suggesting
protection against all-cause mortality is therefore of some interest.
Although not universally confirmed[2,3], this tantalising concept is being
prospectively evaluated in a 3 year study of high dose inhaled
corticosteroids (Flixotide 500mcg bid, alone or in combina...
Inhaled corticosteroids have for some time been seeking a broader
indication in COPD. The recent meta-analysis by Sin et al.[1] suggesting
protection against all-cause mortality is therefore of some interest.
Although not universally confirmed[2,3], this tantalising concept is being
prospectively evaluated in a 3 year study of high dose inhaled
corticosteroids (Flixotide 500mcg bid, alone or in combination with long
acting beta-agonist) in COPD patients with FEV1 < 60%.[4]
But how might this protection be afforded? Local effects may
teleologically provide organ specific protection, potentially reflected by
reduced frequency or severity of pulmonary exacerbations. However, COPD is
recognised as a systemic inflammatory condition associated with raised
systemic inflammatory markers such as CRP, and this marker is increasingly
recognised as an independent risk factor for cardiac mortality.[5]
Important questions revolving around the determinants of all cause
mortality both generally and in COPD remain unresolved. How for instance
should we interpret a positive trial outcome without comparative data
regarding the relative impacts of the modification of such risk factors as
comorbidity, smoking, diet, exercise and weight reduction? Secondly, if
the benefits provided by corticosteroids could be largely attributed to
systemic antiinflammatory activity then systemic corticosteroid dosing (i.e.
oral prednisolone) may be more efficient and potentially cheaper. Finally,
these questions will be further complicated by uncertainties regarding
dosing, the need for concomitant long acting beta-agonists and adverse
effect thresholds.
Currently recommended indications for inhaled corticosteroids in COPD
include the prevention of exacerbations in those with FEV1 < 50% and
“the prevention of decline in health status”[6,7]. Clarification and the
beneficial extension of these indications will be welcomely received.
Reference
1. Sin DD, Wu L, Anderson JA et al. Inhaled corticosteroids and
mortality in chronic obstructive pulmonary disease. Thorax. 2005; 60: 992-
7.
2. Alsaeedi A, Sin DD, McAlister FA. The effects of inhaled
corticosteroids in chronic obstructive pulmonary disease: a systematic
review of randomized placebo-controlled trials. Am.J.Med. 2002; 113: 59-
65.
3. Fan VS, Bryson CL, Curtis JR et al. Inhaled corticosteroids in
chronic obstructive pulmonary disease and risk of death and
hospitalization: time-dependent analysis. Am.J.Respir Crit Care Med. 2003;
168: 1488-94.
4. Vestbo J. The TORCH (towards a revolution in COPD health)
survival study protocol. Eur.Respir J. 2004; 24: 206-10.
5. Folsom AR, Aleksic N, Catellier D, Juneja HS, Wu KK. C-reactive
protein and incident coronary heart disease in the Atherosclerosis Risk In
Communities (ARIC) study. Am.Heart J. 2002; 144: 233-8.
6. Celli BR, MacNee W. Standards for the diagnosis and treatment of
patients with COPD: a summary of the ATS/ERS position paper. Eur.Respir J.
2004; 23: 932-46.
I read with interest the article by Broughton et al, and wish to
offer following
comments.
1. The duration of oxygen therapy (in both Table 1 and the text)
ranges from
30 to 107 weeks, thus qualifying every baby in the cohort as having BPD.
Even if this was in days, it would make every baby oxygen dependent 28
days
after birth, c...
I read with interest the article by Broughton et al, and wish to
offer following
comments.
1. The duration of oxygen therapy (in both Table 1 and the text)
ranges from
30 to 107 weeks, thus qualifying every baby in the cohort as having BPD.
Even if this was in days, it would make every baby oxygen dependent 28
days
after birth, compared to 19% in other studies(1).
2. The rate of BPD in this cohort was 40% - much higher than has been
reported for babies of similar gestation in recent years(1,2). In view of
this
high rate of BPD and prolonged oxygen dependency, the studied cohort
might have consisted of rather sick infants.
3. Since discharge home on oxygen is mentioned as one of the
explanatory
variables, it would be helpful to know its frequency and significance in
relation to the risk of hospital admission and RSV infection.
4. It is not clear if the healthcare utilisation includes all events
after discharge
from the neonatal unit, or only those after a RSV infection. The authors
have
elsewhere suggested that babies with lung function deficits at discharge
from
the neonatal unit are more likely to sustain symptomatic RSV
infections(3). If
the healthcare utilisation includes all post-discharge events, then is it
possible that the excessive healthcare utilisation of RSV-infected infants
a
manifestation of their underlying lung deficit rather than effect of RSV?
5. The authors suggest consideration of palivizumab for the two risk
factors
of RSV LRTI – maternal smoking during pregnancy and presence of school
aged siblings. However, palivizumab has been shown to be effective in
‘reducing hospitalisations from RSV’ rather than ‘preventing RSV
infection’
itself(4), and the validity of this extrapolation remains to be tested.
Indeed,
the indicator for healthcare utilisation (GP attendances) just reached
significance among non-admitted RSV-infected infants as compared to no
LRTI infants, the use of reliever medications being comparable in all
three
groups. I am not sure widening the indications for palivizumab to the
suggested groups will prove to be cost-effective.
Conflict of interest: I have previously questioned the cost-
effectiveness of palivizumab in relation to its recommended indications.
References
1. Manktelow BN, Draper ES, Annamalai S, Field D. Factors affecting
the incidence of chronic lung disease of prematurity in 1987, 1992, and 1997.
Arch Dis Child Fetal Neonatal Ed 2001;85(1):F33-5.
2. Smith VC, Zupancic JA, McCormick MC, Croen LA, Greene J, Escobar
GJ,
et al. Trends in severe bronchopulmonary dysplasia rates between 1994 and
2002. J Pediatr 2005;146(4):469-73.
3. Broughton S, Bhat R, Roberts A, Zuckerman M, Rafferty G, Greenough
A.
Diminished lung function, RSV infection, and respiratory morbidity in
prematurely born infants. Arch Dis Child 2006;91(1):26-30.
4. Palivizumab, a humanized respiratory syncytial virus monoclonal
antibody, reduces hospitalization from respiratory syncytial virus
infection in
high-risk infants. The IMpact-RSV Study Group. Pediatrics 1998;102(3 Pt
1):
531-7.
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