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PAPERS: Michael J Radcliffe, George T Lewith, Richard G Turner, Philip Prescott, Martin K Church, and Stephen T Holgate Enzyme potentiated desensitisation in treatment of seasonal allergic rhinitis: double blind randomised controlled study BMJ 2003; 327: 251-254 [Abstract] [Full text]

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Why a mixture of allergens ?

Eduardo Costa Silva   (2 August 2003)

What conclusion can be drawn ?

J P Dias   (3 August 2003)

Desensitisation for Hayfever

Stephen R Durham   (4 August 2003)

AS expected...

Hugo P. VAN BEVER   (4 August 2003)

Misleading heading

Joao A Fonseca   (5 August 2003)

Useless vs Helpful allergy therapy

michael l loren   (8 August 2003)

Enzyme potentiated desensitisation: Failure of intervention or inappropriate outcome measures?

Michal R Pijak, Frantisek Gazdik   (11 August 2003)

Enzyme potentiated desensitisation: Failure of intervention or inappropriate outcome measures?

Michal R Pijak, Frantisek Gazdik   (12 August 2003)

Erratum

George T Lewith   (15 August 2003)

Immunotherapy is effective

Anthony J Frew   (5 September 2003)

Why a mixture of allergens ? 2 August 2003
Eduardo Costa Silva, Head of Allergy and Immunology Section of University Hospital Pedro Ernesto - UERJ Hospital Universitário Pedro Ernesto - Av. 28 de setembro, 87 - Rio de Janeiro - Brasil Send response to journal: Re: Why a mixture of allergens ?	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
What conclusion can be drawn ? 3 August 2003
J P Dias, GP RH12 3LL Send response to journal: Re: What conclusion can be drawn ?	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
Desensitisation for Hayfever 4 August 2003
Stephen R Durham, Professor of allergy and respiratory medicine Royal Brompton and Harefield Hospitals NHS Trust Sydney Street London SW3 6NP Send response to journal: Re: Desensitisation for Hayfever	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.
AS expected... 4 August 2003
Hugo P. VAN BEVER, Professor in Pediatrics SINGAPORE Send response to journal: Re: AS expected...	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
Misleading heading 5 August 2003
Joao A Fonseca, Allergy&Clinical Immunology specialist Hospital S Joao, Opotto, Portugal Send response to journal: Re: Misleading heading	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
Useless vs Helpful allergy therapy 8 August 2003
michael l loren, assistant prof, pediatrics, U of Kansas Independence, MO 64057 Send response to journal: Re: Useless vs Helpful allergy therapy	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
Enzyme potentiated desensitisation: Failure of intervention or inappropriate outcome measures? 11 August 2003
Michal R Pijak, Consultant in rheumatology and clinical immunology Institute of Preventive and Clinical Medicine, Limbova 14, 83301 Bratislava, Slovakia, Frantisek Gazdik Send response to journal: Re: Enzyme potentiated desensitisation: Failure of intervention or inappropriate outcome measures?	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
Enzyme potentiated desensitisation: Failure of intervention or inappropriate outcome measures? 12 August 2003
Michal R Pijak, Consultant in rheumatology and clinical immunology Institute of Preventive and Clinical Medicine, Limbova 14, 83301, Bratislava, Slovakia, Frantisek Gazdik Send response to journal: Re: Enzyme potentiated desensitisation: Failure of intervention or inappropriate outcome measures?	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
Erratum 15 August 2003
George T Lewith, Senior Research Fellow Complementary Medicine Research Unit, Royal South Hants Hospital, Southampton, SO14 0YG Send response to journal: Re: Erratum	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
Immunotherapy is effective 5 September 2003
Anthony J Frew, Professor University of Southampton Send response to journal: Re: 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