Enzyme potentiated desensitisation in treatment of seasonal allergic rhinitis: double blind randomised controlled study
BMJ 2003; 327 doi: https://doi.org/10.1136/bmj.327.7409.251 (Published 31 July 2003) Cite this as: BMJ 2003;327:251All rapid responses
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In our acknowledgement for the above paper we mentioned that we had
support from Great Universal Stores. We would like to correct any
misunderstanding. We received support from the GUS Charitable Trust which
derives its income from GUS plc. We are sorry for any confusion this
error may have caused.
Competing interests:
Funds for research
Competing interests: No competing interests
Editor - Radcliffe et al state that their study was "sufficiently
powered to detect a clinically important difference in response to
treatment, whether measured by proportion of symptom-free days or by
quality of life scores." (1) Such statement is misleading since the
calculation of the sample size was based on a crude and purely
retrospective assessment of the sensitivity of the study.
By using a composite questionnaire, different symptoms would require
a varying number of subjects since a variable with a higher mean value
may also have a larger variance of error and therefore may require a
larger number of subjects. (2) A high baseline severity of rhinitis
might also contribute to the lack of differences in the proportion of
symptom-free days and the use of rescue drugs.
Recently, it has been shown that when evaluating dyspnea in patients
with acute asthma, a difference in the visual analogue scale of less than
22% is unlikely to be clinically important. (3) However, the utilization
of subjective rating scales, for several decades, has been ignoring the
fact that an untrained person is capable of distinguishing only four or
five grades of intensity of experimental pain. By analogy, patients in
Radcliffe et al´s study might have difficulty in self-assessing of nasal
symptoms by using a scale with seven grades.
Lastly, several drawbacks of the conjunctival provocation test are
also worth to be pointed out. This test appears to be useful only in
patients who are reactive to a single allergen, but not in patients
reactive to multiple agents (4). Furthermore, there is a decrease in the
activity of the atopic disease as measured by CPT between the two seasons
(5) On the other hand, the CPT could remain positive even if the patient
has no conjunctival symptoms.
Michal R Pijak, Consultant in rheumatology and clinical immunology.
Department of Clinical Immunology, Institute of Preventive and Clinical
Medicine,
Limbova 14, 833 01 Bratislava, Slovakia, pijak@upkm.sk
Frantisek Gazdik, Research fellow.
Department of Clinical Immunology, Institute of Preventive and Clinical
Medicine,
Limbova 14, 833 01 Bratislava, Slovakia, gazdik@upkm.sk
References
1. Radcliffe MJ, Lewith GT, Turner RG, Prescott P, Church MK, Holgate
ST. Enzyme potentiated desensitisation in treatment of seasonal allergic
rhinitis: double blind randomised controlled study. BMJ. 2003;327:251-4.
2. Dong M, Petersen MR, Mendell MJ. Using pilot data to estimate
sample size and compare question forms for a crossover study. J Occup
Health 1998;40:307-12.
3. Karras DJ, Sammon ME, Terregino CA, Lopez BL, Griswold SK, Arnold
GK. Clinically meaningful changes in quantitative measures of asthma
severity. Acad Emerg Med. 2000;7:327-34.
4. Garcia-Ortega P, Costa B, Richart C. Evaluation of the
conjunctival provocation test in allergy diagnosis. Clin Exp Allergy
1989;19:529-32.
5. Moller C, Elsayed S. Seasonal variation of the conjunctival
provocation test, total and specific IgE in children with birch pollen
allergy. Int Arch Allergy Appl Immunol 1990;92:306-8.
Competing interests:
None declared
Competing interests: No competing interests
Editor - Radcliffe et al state that their study was "sufficiently
powered to detect a clinically important difference in response to
treatment, whether measured by proportion of symptom-free days or by
quality of life scores." (1) Such statement is misleading because
calculation of sample size was based on crude and purely retrospective
assessment of the sensitivity of the study.
By using composite questionare, different symptoms would require a
different number of subjects because a variable with a higher mean value
may also have a higher error variance and therefore may require a larger
number of subjects.(2) High baseline severity of rhinitis could also
contribute to the lack of differences in the proportion of symptom-free
days and the use of rescue drugs.
Recently it has been shown that when evaluating dyspnea in patients
with acute asthma, a difference in visual analogue scale less than 22% is
unlikely to be clinically important.(3). However, the use of subjective
rating scales for several decades ignored, that an untrained person is
able to distinguish only four or five grades of intensity of experimental
pain. By analogy, patients in Radcliffe et al´s study could have a
difficulty in self-assessment of nasal symptoms by using the scale with
seven grades.
Finally, a few drawbacks of the conjunctival provocation test
deserve attention. This test appears to be useful only in patients
reactive to a single allergen, but not in patients reactive to multiple
agents (4). Furthermore there is a decrease in the activity of the atopic
disease as measured by CPT between the two seasons (5) On the other hand
the CPT may remain positive even if the patient have no conjunctival
symptoms.
Michal R Pijak, Consultant in rheumatology and clinical immunology.
Department of Clinical Immunology, Institute of Preventive and Clinical
Medicine,
Limbova 14, 833 01 Bratislava, Slovakia, pijak@upkm.sk
Frantisek Gazdik, Research fellow.
Department of Clinical Immunology, Institute of Preventive and Clinical
Medicine,
Limbova 14, 833 01 Bratislava, Slovakia, gazdik@upkm.sk
References
1. Radcliffe MJ, Lewith GT, Turner RG, Prescott P, Church MK, Holgate
ST. Enzyme potentiated desensitisation in treatment of seasonal allergic
rhinitis: double blind randomised controlled study. BMJ 2003;327:251-4.
2. Dong M, Petersen MR, Mendell MJ. Using pilot data to estimate
sample size and compare question forms for a crossover study. J Occup
Health 1998;40:307-12.
3. Karras DJ, Sammon ME, Terregino CA, Lopez BL, Griswold SK, Arnold
GK. Clinically meaningful changes in quantitative measures of asthma
severity. Acad Emerg Med 2000;7:327-34.
4. Garcia-Ortega P, Costa B, Richart C. Evaluation of the
conjunctival provocation test in allergy diagnosis. Clin Exp Allergy
1989;19:529-32.
5. Moller C, Elsayed S. Seasonal variation of the conjunctival
provocation test, total and specific IgE in children with birch pollen
allergy. Int Arch Allergy Appl Immunol 1990;92:306-8.
Competing interests:
None declared
Competing interests: No competing interests
Enzyme potentiation has always been controversial and unproven and
BMJ showed again that it doesn't work.
However readers of the BMJ, the old method of allergy shots, that has
been around for over 50 years, is still quite helpful and safe and
endorced by the World Health Organization as a useful therapy. Consider
allergy desensitization in those patients who are frustrated with symptoms
that are poorly responsive to medications.
Competing interests:
None declared
Competing interests: No competing interests
Editor,
I was quite surprised with the misleading heading "Can we
modify allergy in hay fever?". This links to a randomized trial regarding
an unconventional therapy, seldom used in allergy practices in Western
Europe. The alternative treatment depicted in the article may be included
in the ill defined group of immunotherapy but if one really wants to
"modify allergy" we do have evidence that well performed allergy vaccines
are effective, safe and with long-term benefits (World Health Organization
Position Paper).
The article is significant in the sense it proves this "enzyme potentiated
desensitisation" is not effective and should not be used. It is important
that all "alternative" therapies came under the scrutiny of science with
appropriate research methods, but Editors should be careful not to mislead
readers not familiar with a specific research topic.
Would the editors of this prestigious journal issue a similar statement:
"Can we modify infection?" if a study regarding bacterial infection
treated with antifungal therapy showed no treatment effect?
UK has an high prevalence of allergic diseases, a shortage of allergy
specialists (1) and an unfortunate past regarding allergy vaccines. I hope
these are sufficient motives for the editorial board to release a clarifying
note about that heading.
1-Lack of allergy specialists drives patients to alternative
treatments. Owen Dyer. BMJ 2003; 326: 1415.
Competing interests:
None declared
Competing interests: No competing interests
It is amazing that types of so-called immunotherapy are still used
(i.e. studied) of which underlying mechanisms are totally unknown (if
there are any…) and of which, based on present knowledge of mechanisms of
allergic diseases, no logic hypothesis can be put forward (except
“immunomodulation”). This present study shows that it is very clear that
administration of mixtures of allergens in low dose, by two preseasonal
injections, is ineffective, a finding already shown by other investigators
(cfr. the Adkinson study in NEJM 1997, 336, 324-32). I really did not see
the point in using mixtures of allergens, including cat, mould spores, and
dust and storage mites, in patients suffering from allergic seasonal
rhinitis, who are allergic to timothy grass. Furthermore, no concentration
of allergen of the extracts is mentioned in the text (homeopathic
dosage?). Therefore, I believe that it would be advisable to focus
research, trying to answer questions that still remain on immunotherapy of
which the effectiveness already was demonstrated in well-designed studies
(i.e. studies using one purified allergen in sufficient concentration by
repeated injections during 3 – 5 years).
Competing interests:
None declared
Competing interests: No competing interests
Editor,
Desensitisation for hayfever, using conventional high-dose extracts,
does work (1) and does modify allergy, as reflected by longterm disease
remission for at least 3 years following treatment (2) and data suggesting
reduced progression of hayfever to asthma in children (3). On the other hand, the negative results of the study by Radcliffe et al concerning
enzyme-potentiated desensitisation using low-dose extracts are convincing
(4) and seriously question the use of this alternative therapy.
It is unfortunate that your journal cover banner heading did not
distinguish the two forms of therapy, with the likely result that general
practitioners will be discouraged from referring the small but significant
proportion of patients with severe hayfever, unresponsive to nasal
corticosteroids and antihistamines, to NHS allergy clinics for
consideration of high-dose desensitisation.
Equally upsetting, was the depiction of a 'stargazer', I presume a
type of lily, as a cause of hayfever. Hayfever is caused by wind-pollinated plants which include grasses, trees and weeds. Lilies are
insect-pollinated. They look nice and smell nice, and they attract
insects, but they don't cause hayfever.
1. Varney V, Gaga M, Frew AJ, Aber VA, Kay AB, Durham SR. Usefulness
of immunotherapy in patients with severe summer hayfever uncontrolled by
anti-allergic drugs. Br Med J 1991;302:265-269.
2. Durham SR, Walker SM, Varga EM, Jacobson MR, O’Brien F, Noble W,
Till SJ, Hamid Q, Nouri-Aria K. Long term clinical efficacy of grass
pollen immunotherapy. New Engl J Med 1999;341:468-75.
3. Moller C, Dreborg S, Ferdousi HA, Halken S Host A, Koivikko A,
Koller D, Niggemann B, Norberg LA, Urbanek R, Valovirta E, Wahn U,
Jacobsen L. Pollen immunotherapy reduces the development of asthma in
chidren with allergic rhinoconjunctivitis (The PAT study). J allergy Clin
Immunol 2002; 109:251-6.
4. Radcliffe MJ, Lewith GT, Turner RG, Prescott P, Church MK, Holgate
ST. Enzyme potentiated desensitisation in treatment of seasonal allergic
rhinitis: double blind randomised controlled study. BMJ 2003; 327:251-4.
Competing interests:
I have recieved research funding, and consultancy and lecture fees from ALK Abello, Horsholm, Denmark, a manufacturer of high-dose vaccines for hayfever.
Competing interests: No competing interests
Editor – the most interesting and valid conclusion to be reached from
the paper by Radcliffe et al (BMJ 2nd Aug 2003) was how little relevance
the findings of a randomised controlled trial can have in the harsh
environment of the real world. To many, the words ‘randomised’ and
‘controlled’ are held as holy grails; a euphemism for ‘good research’, and
here is an excellent example that this need not be the case.
The highly selected study population are from the rarified group of
patients whose symptoms are already uncontrolled by antihistamines and
intra-nasal steroids.
So what is the reader meant to conclude when he/she finds that
desensitization is no better ? All this paper tells me is that there is a
group of people for whom nothing seems alleviate severe symptoms of hay
fever. So what can we expect next ? Perhaps a trial of acupuncture in
pain unresponsive to morphine ?
Given that the authors themselves cite prolonged clinical remission
as a potential benefit of this treatment it is very disappointing that
they did not even attempt to show or refute this.
The lack of generalisability from the conclusions of the data from
‘randomised’ trials because of excessively narrow patient selection should
be of concern to us all.
Also of concern should be the sensational Tabloid style cover to this
BMJ (“Injections to desensitize people don’t work”). Headlines like this
should have no place in a supposedly reputable journal, particularly on
the basis of a single study as poorly conducted as this, particularly when
later you report that the WHO and six previous studies found beta-
glucoronidase enzyme to be effective.
Dr Jean-Pierre Dias, General Practitioner, Horsham, West Sussex,
No competing Interests
Competing interests:
None declared
Competing interests: No competing interests
The OMS Position Paper on Immunotherapy and other publications have
made clear that immunotherapy must be specific to the allergen
involved in the clinical disease.
Why do a large and well designed study using a non-specific vaccine to
patients with a specific sensitization to a pollen allergen?
Could the results be different with a specific vaccine?
Competing interests:
None declared
Competing interests: No competing interests
Immunotherapy is effective
While welcoming the publication of the study by Radcliffe et al on
Enzyme potentiated desensitisation (BMJ 2 August 2003), I was unhappy
about the headline that you put on the front cover. EPD is an
unconventional form of desensitisation which nobody in mainstream allergy
has ever thought was efficacious. In contrast, conventional high dose
injection immunotherapy has been shown to be effective in a wide range of
clinical trials over the years, including publications in the BMJ and New
England Journal of Medicine (Refs 2,3). The implication of your headline
is that injections to desensitise people do not work in hayfever when in
fact they clearly do. The central issue with conventional desensitisation
is whether it is cost effective and safe. Unfortunately there is a lot of
ignorance about allergy and desensitisation in the community and your
headline will only help to compound this.
I do hope that if you are sent papers demonstrating the effectiveness
of desensitisation in hayfever that you will be willing to publish these
and set the records straight.
Ref 1. Radcliffe MJ et al. BMJ 2003;327:251-254
Ref 2. Varney VA et al. BMJ 1991;302:265-269
Ref 3. Durham SR et al. NEJM 1999;341:468-475
Competing interests:
AJF has participated in scientific studies of the mechanism of immunotherapy and in several clinical trials of injection and sublingual immunotherapy
Competing interests: No competing interests