House dust mite control measures in the management of asthma: meta-analysis
BMJ 1998; 317 doi: https://doi.org/10.1136/bmj.317.7166.1105 (Published 24 October 1998) Cite this as: BMJ 1998;317:1105All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
EDITOR-Gotzsche et al1 conclude that avoidance of indoor allergens by
physical and chemical measures is not effective as treatment for atopic
asthma.
We investigated the effect of allergen avoidance strategies
(encasing, acaricides) in patients with atopic dermatitis and also
obtained some negative results: A placebo-controlled allergen elimination
study was performed in 20 adult patients with moderate to severe atopic
dermatitis; the study period was 1 year. All patients were sensitised to
house dust mite (RAST-class ³ 3) and were exposed to a significant amount
of the mite allergen Der p 1 on their mattress (³ 2 µg/g). Disease
severity was evaluated every 2 months using an established score (SCORAD)
and the serum concentration of eosinophil cationic protein (ECP), a
disease activity marker, was monitored by a commercial assay. In addition,
the use of topical steroids was quantified and the patients noticed their
subjective impression of pruritus and sleeplessness on a visual scale
weekly.
Der p 1 levels dropped in the verum group to almost undetectable
concentrations. However, although in both groups (placebo and verum)
objective parameters (SCORAD and ECP) improved temporarily, no statistical
difference between placebo and verum group was observed. But there was a
marked difference between both groups with respect to the subjective
parameters: After 4 months of allergen exclusion, the verum group
constantly reported to suffer significantly less from nocturnal pruritus
and sleeplessness than the placebo group.
We conclude that allergen
avoidance leads to a better quality of life since sleep is improved. But
reducing indoor allergen exposure is not sufficient to improve the overall
disease activity. The reason for this may be an ongoing exposure to other
allergens including outdoor allergens and irritants. Our results disagree
with those of another placebo-controlled trial on dust mite avoidance
measures in atopic dermatitis published recently2: Performing a 6 months-
trial, these authors had observed a significant improvement of the
clinical score in the verum group. The difference may be explained by a
partly different study population (inclusion of children in the latter
study). Allergen avoidance may be more effective in children than in
adults and this should be investigated in controlled trials. Taken
together, our results are in accordance with D. Strachan3 and we conclude:
House dust mite allergen avoidance in atopic dermatitis: ''Benefits
unproved but not yet excluded".
C. Gutgesell
S. Heise
S. Seubert
A. Seubert
Ch. Neumann
Department of Dermatology,
University of Göttingen,
Germany
1 Gotzsche PC, Hammarquist C, Burr M. House dust mite control
measures in the management of asthma: meta-analysis. BMJ 1998 Oct
24;317(7166):1105-10.
2 Tan BB, Weald D, Strickland I, Friedmann PS. Double-blind controlled
trial of effect of housedust-mite allergen avoidance on atopic dermatitis.
Lancet 1996 Jan 6;347(8993):15-8
3 Strachan DP. House dust mite allergen avoidance in asthma. Benefits
unproved but not yet
excluded. BMJ 1998 Oct 24;317(7166):1096-7.
Competing interests: No competing interests
EDITOR-The meta-analysis of Grtzsche1 concluded that house dust mite
control measures are not clinically effective in house dust mite allergic
asthmatics. Strachan2 indicated that this was probably a consequence of
the fact that several control measures used in the included studies, did
not result in a (relevant) reduction of house dust mite allergens.
Improvements in clinical condition are consequently not to be expected.
Some studies in the meta-analysis did find clinical effects while others
did not1. This might, however, not be a result of whether or not effective
allergen reduction occurred, but more a result of measuring different
groups of asthmatic subjects, who are in a different stage of their
asthmatic disease. We have reason to believe that early treatment of very
mild asthma might have more impact than treatment of moderate to severe
asthma.
In our department we performed two studies. First we investigated the
(clinical) effects of a combined allergen avoidance strategy (house dust
mite (HDM) impermeable covers for mattresses and bedding and Acarosan® for
living room and bedroom floors) in a group of subjects, allergic to HDM,
without a diagnosis of asthma yet but with some early signs of asthma3.
Secondly, we investigated this same combined strategy in a group of
patients, with a confirmed diagnosis of moderate asthma. In the first
study we found that peak flow parameters and asthma symptom scores were
stabilised during the follow-up period (figure 1a), suggesting that a
delay in the onset of asthma may occur in some allergic subjects. In the
second study, no clinical effects could be observed in diagnosed allergic
subjects with moderate asthma (figure 1b). This negative result was not a
consequence of a failure in allergen avoidance. Allergen concentrations
were reduced, especially on mattresses (ten-fold, p=0.0001)4.
The question is why no positive clinical effects were found in the group
of allergic subjects with already established asthma, but were found in an
allergic group that had not developed asthma yet? We hypothesise that
allergen avoidance as early preventive measure has more impact than as
treatment of moderate asthma. When asthma is already established, it may
be that very small amounts of allergens are sufficient to trigger a
deterioration in asthma. Furthermore, allergen reduction need some time to
reverse the already developed process of inflammation and consequently it
needs some time to establish effects. In allergic patients without asthma
yet, a reduction in allergen load might prevent further development of
asthma, as it is probably possible to prevent or to slow down the process
of inflammation in this early stage of the disease. The general
observation that avoidance measures are more effective in children than in
adults, does support this vision5. This implies that allergen avoidance
measures have to be applied in an early stage of the disease (secondary or
even primary prevention6) in order to be clinically effective.
Summarised, we believe that the conclusion of Grtzsche et al. is covering
only one aspect. It seems that HDM control measures might be effective in
patients in an early stage of their asthmatic disease, and might therefore
recommended as an early intervention. More research has to be performed to
investigate this hypothesis.
Sonja G.M. Cloosterman, MSc1
Constant P. van Schayck, MSc, PhD1/2
1 Dept. of General Practice and Social Medicine, University of Nijmegen
2 Dept. of General Practice, University of Maastricht
The Netherlands
Corresponding address:
Mrs. S.G.M. Cloosterman, MSc
Dept. of General Practice and Social Medicine, 229
University of Nijmegen
P.O.box: 9101
6500 HB Nijmegen
Tel.: +31 24-3616968/3613315
Fax.: +31 24-3617084
email: S.Cloosterman@hsv.kun.nl
References
1. Gotzsche PC, Hammarquist C, Burr M. House dust mite control measures in
the management of asthma: meta-analysis. Br Med J 1998;317:1105-10.
2. Strachan DP. House dust mite allergen avoidance in asthma:
Benefits unproved but not yet excluded. Br Med J 1998;317:1096-7.
3. Cloosterman SGM, Hofland ID, Lukassen HGM, Wieringa MH, Folgering
HTM, van der Heide S, Brunekreef B, Schayck CPv. House dust mite avoidance
measures improve peak flow and symptoms in patients with allergy but
without asthma: A possible delay in the manifestation of clinical asthma?
J Allergy Clin Immunol 1997;100:313-9.
4. Cloosterman S, Hofland I, van der Heide S, Brunekreef B, Eslhout
Fv, Folgering H, Schayck Cv. Effects of house dust mite impermeable covers
and an acaricide on Der p 1 Levels. Eur Respir J 1998;12:69S(Abstract)
5. Ehnert B, Lau-Schadendorf S, Weber A, Buettner P, Schou C, Wahn U.
Reducing domestic exposure to dust mite allergen reduces bronchial
hyperreactivity in sensitive children with asthma. J Allergy Clin Immunol
1992;90:135-8.
6. Schönberger HJAM, Schayck CPv. Prevention of asthma in genetically
predisposed children in primary care-from clinical efficacy to a feasible
programme. Clin Exp Allergy 1998;28:1325-31
Competing interests: No competing interests
4th November, 1998.
The Editor
BMJ
BMA House
Tavistock Square
LONDON
WC1H 9JR.
Sir
Gotzsche PC, Hammarquist C, Burr M. House dust mite control measures
in the management of asthma: meta-analysis. BMJ 1998; 317: 1105-1110.
The enormous heterogeneity of peak expiratory flow rates makes them
very poor measures of asthma severity when studying populations. Gregg
and Nunn’s results from mini-Wright peak flow meters demonstrate a wide
variation between individuals - age and height explain only 30% of the
variation in peak flow rates(1,2). Peak expiratory flow rate nevertheless
remains a useful measure for self-monitoring of asthma.
It is therefore not surprising that in using peak expiratory flow
rate as one of their principle measures of asthma severity Gotzche,
Hammarquist and Burr found measures to eradicate house dust mite had no
statistically significant effect(3). In addition to the important
distinction made by Strachan between efficacy and clinical effectiveness
in efforts to reduce house dust mite(4) the measure of clinical
effectiveness should be valid. I suggest that failure to distinguish
between two population distributions of peak expiratory flow rate does not
provide a valid measure of asthma.
David S Morrison
Specialist Registrar in Public Health Medicine
Greater Glasgow Health Board
Dalian House
PO Box 15327
350 St Vincent Street
GLASGOW
G3 8YU.
Telephone 0141 201 4900.
1 Nunn AJ, Gregg I. New regression equations for predicting peak
expiratory flow in adults. BMJ 1989;298:1068-70.
2 Gregg I, Nunn AJ. Peak expiratory flow in symptomless elderly smokers
and ex-smokers. BMJ 1989;298:1071-1072.
3 Gotzsche PC, Hammarquist C, Burr M. House dust mite control measures
in the management of asthma: meta-analysis. BMJ 1998;317:1105-1110.
4 Strachan DP. House dust mite allergen avoidance in asthma. BMJ
1998;317:1096-1097.
Competing interests: No competing interests
Please note:
As Dr Platt-Mills's secretary, Dr Malone typed this rapid response. She does not consider herself to be an author.
Dr. Gotzsche and his colleagues reported a "meta analysis" of the
published controlled trials of dust mite avoidance in the treatment of
asthma (1). It is well known that several of the approaches used in the
past for decreasing mites in houses were not effective; e.g. vacuuming
carpets or mattresses, acaricidal foams, and HEPA room air cleaners (1,2).
In their paper, the authors concede that in twelve out of the 23 studies,
the avoidance measures used did not decrease mite allergen. In addition,
5 studies failed to measure whether dust mite exposure changed. It is
bewildering that the authors would apply, or the journal publish, an
analysis including all these studies as if they were comparable to
controlled trials in which a significant decrease in mite allergen was
achieved. This would be equivalent to publishing an analysis of the
effectiveness of inhaled steroids based on studies in which the authors
concluded that the actuation failed to deliver the drug, or compliance was
not assessed. Indeed, many of the older mite "avoidance" studies included
in the "meta-analysis" have so little insight into the factors that
influence mite allergen in a house, that it is amusing to reread them
today (3,4).
The authors state that the results were the same for those studies
where successful reduction in exposure to mite allergen was achieved.
However, this conclusion is strikingly different from that of three groups
who have recently analyzed the same studies (2,5,6). Each of these
reports concluded that the evidence strongly favored the use of physical
avoidance measures for treating mite allergic children with asthma. There
are five published controlled trials of allergen avoidance that have
achieved a prolonged decrease in allergen (i.e. 6 months or more)
(7,8,9,10,11). Given the conclusions of Dr. Gotzsche and his colleagues,
your readers might be surprised to find that in four of those studies, the
authors reported highly significant improvement in the active avoidance
group (7,8,9,11). In their attempt to achieve a "meta-analysis", the
authors restricted their calculations to two outcomes (symptoms and AM
peak flow), ignoring the fact that these were not the primary outcomes of
the successful studies. Thus, the controlled trial by Ehnert and her
colleagues in Berlin (8), which produced the most convincing decrease in
mite allergen and highly significant decrease in BHR, was not included in
either of the comparisons in your recent paper (see Figs 2 and 3 in Ref.
1).
There is consistent evidence that allergic patients who are removed
from a high mite environment improve clinically, and in terms of bronchial
reactivity (2). The question has always been whether it is possible to
achieve the same effect under normal household conditions. Gotzche and
colleagues reached a negative conclusion by including studies that had no
effect, or unknown effects, on mite allergen and imposing an analysis that
was simplistic and unrelated to the successful results. The correct
conclusions are: first that reduction of mite allergens in a humid
climate is not easy and requires understanding the factors that influence
mite growth; and second, that four out of five controlled trials that have
achieved prolonged decrease in mite allergen have achieved impressive
clinical results.
Yours sincerely,
Thomas A.E. Platts-Mills, M.D., Ph.D. Martin D.
Chapman, Ph.D.
Head, Div of Asthma, Allergy & Immun Professor of
Med. & Micro.
Dir, UVA Asthma & Allergic Dis Ctr
Lisa M. Wheatley, M.D.
Assistant Professor of Medicine
TPM/nmReferences
1. Gotzshe PC, Hammarquist C, Bur M. House dust mite control
measures in the management of asthma: meta-analysis. BMJ 1998;317:1105-
1110.
2. Report of 3rd International Workshop, Cuenca Spain. Indoor
allergens and asthma. J Allergy Clin Immunol 1997;100;S1-S24.
3. Burr MI, Dean BV, Merrett TG, Neale E, St Leger AS, Verrier-Jones
ER. Effects of anti-mite measures on children with mite-sensitive asthma:
a controlled trial. Thorax 1980;35:506-12.
4. Antonicelli I, Bilo MB, Pucci S, Schou C, Bonifazi F. Efficacy of
an air-cleaning device equipped with a high efficiency particulate air
filter in house dust mite respiratory allergy. Allergy 1991;46:594-600.
5. Guidelines for the diagnosis and management of asthma. Expert
Panel Report II. Bethesda, MD: National Institutes of Health, 1997 (NIH
publication no. 97-4051).
6. Colloff MJ, Ayres J, Carswell F, Howarth PH, Merrett TG, Mitchell
EB, Walshaw MJ, Warner JO, Warner JA, Woodcock AA. The control of
allergens of dust mites and domestic pets: a position paper. Clin Exp
Allergy 1992;22:1-28.
7. Murray AB, Ferguson AC. Dust-free bedrooms in the treatment of
asthmatic children with house dust or house dust mite allergy: a
controlled trial. Pediatrics 1983;71:418-422.
8. Ehnert B, Lau-Schadendorf S, Weber A, Buettner P, Schou C, Wahn U.
Reducing domestic exposure to dust mite allergen reduces bronchial
hyperreactivity in sensitive children with asthma. J Allergy Clin Immunol
1992;90;135-8.
9. Walshaw MJ, Evans CC. Allergen avoidance in house dust mite
sensitive adult asthma. QJ Med 1986;58:199-215.
10. Carswell F, Birmingham K, Oliver J, Crewes A, Weeks J. The
respiratory effects of reduction of mite allergen in the bedroom of
asthmatic children: a double blind controlled trial. Clin Exp Allergy
1996;26:386-96.
11. Halken S, Niklassen U, Hansen LG, Nielsen F, Host A, Osterballe O,
Veggerby MC, Poulsen LK. Encasing of mattress in children with asthma and
house dust mite allergy. J Allergy Clin Immunol 1997;99:S320.
Competing interests: No competing interests
Each method needs to be analysed separately in order to be able to
draw the right conclusions. In this analyses 11 different prevention
methods have been analysed as a whole and as if they are more or less
alike. The validity is therefore poor.
The maximum allergen load has been found deep inside the mattresses.
Several published studies show that particle impermeable covers reduce the
allergen exposure with more than 90 percent. Airborne mite allergens are
only detected after vigourous disturbance. The role of chemicals,
cleaning, vacuum cleaning, air cleaners and ionisers are unclear.
There is a dose-response relationship between exposure and
sensitization. However, some patients react to very low and others require
higher doses. Besides that and the fact that some methods are found to be
ineffective in reducing the allergen exposure, the allergen load vary
extremely in the studies, some studies run only a couple of
weeks,compliance, design and measurements differ etc.
Seven completely different physical methods have been analysed.
Allergen reduction were successful in nine studies. Eight used bedding
covers.
Twelve were unsuccessful.Six of them used aircleaning. Gillies
1987(13)(covers) is said to have no reduction though there was a
significant fall both in the test(mite count fell from 40.00 to 0.85 after
12 weeks) and the control(from 21.75 to 10.33 after 6 weeks observation
and to 2.17 after another 6 weeks with covers).
Marks 1994(14)(covers)is also said to have no reduction, though it
was and a published re-analyse 1995 showed a significant correlation
between allergen concentration and changes in AHR and symptom score.
In Burr 1980(8)(new bedding,covers)the bedding was entirely free from
mites at start - no reduction could be expected. Burr 1980(7) used washing
and vacuum cleaning that later on has been shown not to be effective
enough (Tovey 1997).
Many patients are treated with steroids, effectively reducing the
inflammation and improving the symptoms. Improvement in the symptoms would
therefore not be expected from added preventive measures in a couple of
weeks. In most studies medication is not monitored. In the study by Huss
(25)(covers) the symptoms were improved and medication reduced. In the
study by Walshaw and Evans 1986 (19)(covers) medication was reduced with
40 percent. In Carswell 1996(23)(covers) inhaled brochodilators and
steroids was less in the active group than in the control group, 17% and
54% and 13% and 35% respectively. In a double-blind placebo controlled
study by Halken et al(covers, JACI 1997 abs) steroids was reduced with 46
percent in the test group.
Competing interests: No competing interests
The recent paper by Gotzsche, Hammarquist and Burr[1] highlights a
recurring problem with systematic review and meta-analysis, namely
ignoring or paying lip service to the importance of power. The continued
publication of articles with inadequate power in social and health
sciences has been noted on many occasions[2,3,4], without any apparent
effect[3]. These articles are, however, frequently combined into meta-
analyses with scant regard to their power. The power of a study is the
probability that it will lead to statistically significant results[2]. In
a recent systematic review of the literature examining the prevention of
pregnancy, for example, 9 of the 15 articles included had "low statistical
power". Given that they had low statistical power, should they have been
included?
In the present study[1], the major results are that 41 out of 113
patients exposed to treatment interventions improved,
compared with 38 out of 117 in the control groups. If we imagine this had
been run as a single experimetn with this number of subjects and we
carried out a chi square test on the results, they would have indeed been
nonsignificant (x2=1.27 p=.161, phi 0.076). Suppose that we had
originally believed that the effect size of treatment would be small, that
is about 0.1[2], then to have an adequate sample with power of 0.8 to
detect a significant difference, we would need 785 subjects for the 0.05
level and 1168 for the 0.01 level.
To put it another way the power of this study to detect a significant
difference of a small effect size is inadequate. It is also inadequate to
detect a medium effect size. Given that this is the case, would it be
published if it were a single study, and should it be published because it
is a meta-analysis?
References
1. Gotzsche PC, Hammarquist C, Burr M. House dust mite control measures in
the management of asthma: meta-analysis. BMJ 1998; 317:1105-1110.
2. Cohen J. A power primer. Psych Bull 1992; 112: 155-159.
3. Sedlmeier P, Gigerenzer G. Do studies of statistical power have any
effect on the power of studies? Psych Bull 1989; 105: 309-316.
4. Polit DF, Sherman RE. Statistical power in nursing research. Nurs Res
1990; 39:365-368.
5. NHS Centre for reviews and Dissemination. Effective Health Care 1997;
3(1); 1-11.
Competing interests: No competing interests
Missing Data
Careful readers of this review might have noticed an
inconsistency between the list of studies selected for inclusion, and
those actually used for the meta-analysis.
The review purports to include 23 studies (counting one
three-arm trial as two studies). However, examination of Figures 1 through
3 reveals that outcomes for the following 6 studies were not included in
the meta-analysis:
Ehnert et al (1992)
Van der Heide et al (1997)
Sette et al (1994)
Gillies et al (1987)
Verrall et al (1988)
Ehnert et al (1992)
The explanation, from one of the authors (Peter C. Gøtzsche,
private communication), is that "some trials did not provide data that
could be used for meta-analysis."
Competing interests:
None declared
Competing interests: No competing interests