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A trial of house dust mite extract in bronchial asthma
Br. J. Dis. Chest (1979) 73, 260
A TRIAL
MITE
ALLERGY
OF HOUSE DUST MITE EXTRACT IN BRONCHIAL ASTHMA SUBCOMMITTEE OF THE RESEARCH COMMITTEE BRITISH THORACIC ASSOCIATION*
OF THE
Summary Patients with asthma considered to be due to house dust mite allergy were allocated at random to treatment with (a) increasing weekly injections of house dust mite extract for 18 weeks followed by monthly injections to complete 18 months of treatment; (6) similar injections for 18 weeks followed by placebo injections up to 18 months or (c) placebo injections for 18 months. Fifty-six patients completed at least six months of observation. In patients not on corticosteroids the treated group did a little better than the controls, as judged by night asthma scores, discontinuation of bronchodilators and overall blind assessment of the records by a panel of independent physicians. No benefit was apparent by extending treatment from 18 weeks to 18 months. In contrast, patients on corticosteroids given placebo injections did a little better than the treated group. The extract used was stronger than the commercially available preparation and the injections had to be stopped in one-sixth of the patients because of side-effects. The improvement in patients not on corticosteroids in this trial was of doubtful clinical importance.
Some physicians believe that attempts at hyposensitization to house dust extract are worth while in asthmatics who become more wheezy when exposed to house dust. The British Tuberculosis Association trial in 1968, however, found no difference between a commercially available preparation and placebo injections. By the time the results were published it had become recognized that the major allergen in house dust was the house dust mite, Dermatophagoidespteronyssinus. Aqueous extracts of the mite later became available for treatment and in 1972 the Research Committee of the British Thoracic Association resolved to carry out a further multicentre double blind controlled study in patients with asthma. Materials
and Methods
Patients Physicians with an interest in asthma in the British Isles were asked to submit patients with asthma which they considered to be caused by house dust mite allergy. The patients had to have (a) a positive skin prick test with a 1.2% (w/v) solution of D. pteronyssinus extract, together with (b) a * Members of the Mite Allergy Subcommittee were: D. Davies (Chairman), G. Berry tician), E. Hills, S. La1 (Coordinator), M. McAllen, J. Morrison Smith and J. Pepys.
(Statis-
House Dust Mite Extract in Asthma
261
worsening of asthma after exposure to dust from house cleaning or bed making and/or a positive nasal provocation test with one of three strengths (0.005, 0.04 or 0.3%) of D. pteronyssinus extract. Eligible patients were aged 16 to 50 years, born in the British Isles of any racial group and with dyspnoea and wheezing at least once a week in the previous year and severe enough at times to interfere with normal activities. Excluded were patients (a) likely to have seasonal exacerbations of asthma, (b) with symptoms due to animal danders when continued exposure was likely, (c) with other recognizable unavoidable triggers, except exercise, (d) previously given a course of dust or mite extract injections, and (e) who were pregnant. The consent of the patient was obtained. In the initial weeks they were taught to keep a daily record card. This recorded the severity of day and night asthma, nasal symptoms and the use of bronchodilators, sodium cromoglycate and corticosteroid tablets and aerosols. Skin prick tests with nine other common allergens were done and the forced expiratory volume in one second (FEV1) before and after the inhalation of a bronchodilator was recorded. All subjects were given advice about house dust suppression, the details being left to individual physicians. Treatment An aqueous extract of D. pteronyssinus which had been grown on animal tissue of non-dermal origin (Bencard) was put up in strengths of 0.005, 0.04 and 0.3%. The control solution contained the vehicle only (glycerated extraction medium). Group A patients were given weekly injections of 0.1, 0.2, 0.3, 0.5, 0.7 and 1 ml, starting with the lowest concentration and increasing to higher ones. The schedule was modified to deal with local or generalized reactions. When the top dose had been reached (usually after 18 weeks) or, in a few cases, the maximum tolerated dose, this was continued at monthly intervals until 18 months’ treatment had been completed. Group B were given similar injections for 18 weeks but, when the maximum or maximumtolerated dose was reached, placebo injections were given at monthly intervals to complete 18 months. Group C were given placebo injections for 18 months. Patients were allocated randomly to one of the three treatments separately within centres and according to whether or not they were receiving corticosteroids (orally or by inhalation). When the patients had kept satisfactory records for four weeks, injections were started. They were seen by their physician at monthly intervals for two years. He issued new diary cards and recorded changes in severity of asthma and medicaments, absence from work and the FEV1. Every six months he also repeated skin and nasal tests with D. pteronyssinus extract, assessed changes in asthma severity and checked whether dust suppression measures were still being carried out. Total IgE and IgE and IgG specific to D. pteronyssinus were measured before the start of treatment and every six months for a total of two years. IgE specific to mite extract was measured by the radioallergosorbent test (RAST) (Ceska et al. 1972) and specific IgG by radio-immunoelectrophoresis, amodification of the method of Scheidegger (1955). All measurements were done in one batch at the end. Assessment
of progress
The serial records were used to assess the changes in every patient in two ways: 1. The mean values of the day and night asthma scores, use of bronchodilators, sodium cromoglycate and corticosteroids and FEVi expressed as a percentage of the predicted value were all calculated for the pre-treatment period (entry values and month 1). The same parameters were calculated again for months 2 and 3 and thereafter for each three month period up to 24 months. The changes in each variable from the pre-treatment value were calculated and the effects of treatment were assessed by analysis of variance on each variable separately and for each of the eight time periods from months 2-3 to months 21-24. 2. The six physicians on the subcommittee considered all the variables together in making a combined assessment of each patient’s progress. For every patient they used the mean values of each variable grouped into the time periods used in the first method of assessment and also the
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six-monthly assessments by the patient’s own doctor. Two print-outs were prepared for every patient, one to cover the first six months, i.e. up to the end of the weekly injection schedule, and the other to cover all 24 months of the trial. The trial regimen was not included in the print-outs which were distributed in random order to all six physicians on the subcommittee. Each physician independently made an assessment of every patient’s progress using five categories: much better, better, no change, worse and much worse. In making the assessments the physicians used their judgement to eliminate the effects of change in bronchodilator, sodium cromoglycate or corticosteroid treatment. For example, if a patient’s asthma score and FEVl had not altered but he had reduced his dose of corticosteroid then this would be judged as an improvement. The assessments of the six physicians were combined by assigning scores 2, 1, 0, - 1 and - 2 to the five categories and averaging the scores for every patient. The average scores were analysed by analysis of variance.
RESULTS
A total of 70 patients were submitted from 17 centres. completing six months in the trial, another five before 24 months. Seven of the patients withdrawn early did because they either changed their minds or proved Table I. Number
of patients
Fourteen patients withdrew before 12 months and another five before not start their injections (Table I), uncooperative. The other seven in trial
Treatment No.
of patients
Entering trial Withdrawals in Did not start Reactions to Other reasons Completing six Completing 12 Completing 24
first year injections injections months months months
A
B
c
Total
24
24
22
70
5 5 0 15 14 14
0 2 3 22 19 15
2 1 1 19 18 17
7 8 4 56 51 46
withdrawals in the first six months resulted from reactions to the injections; one had received placebo injections. In one case a severe reaction occurred after the dose had been increased three times despite local reactions, contrary to the protocol. One patient required hospital treatment after a reaction to an injection. Between six and twelve months five patients withdrew. One had a severe anaphylactic reaction in month 8, one suffered a bereavement, another became pregnant and the other two gave no reason. Only the 56 patients who remained in the trial for at least six months were included in the analysis. Those who withdrew later were retained in the analysis until the time of withdrawal. However, in the combined assessment at 24 months all the records were considered for patients remaining in the trial for 12 months or longer. Completion of injection courses If there were no local or generalized reactions a dose of 1 ml of the 0.3% extract should have been achieved in 18 weeks. In Groups A and B one patient in each took longer than 20 weeks and three in each never achieved the full dose. In the control group (C) two
263
House Dust Mite Extract in Asthma took longer than 20 weeks but all achieved the full dose. Information seven patients (three A, one B and three C).
was incomplete for
Initial characteristics of patients The features of the 56 patients who continued in the trial for at least six months are shown in Table II. There were some quite large differences between the treatment groups arising from the small numbers in the trial. For example, the percentage of males ranged from 37% to 73%. Since some of the factors may be of prognostic importance they were included as co-variates in the analysis in order to assesswhether the response was dependent on them and to make allowance for them in treatment comparisons. Table II.
Characteristics
at entry
to trial
of the
56 patients
who
completed
six months
Treatment Characteristic A Number Male Aged 30 or over Duration of asthma, 10 years or more* Provoking factors other than house dust Smokers Off work due to asthma in last six months Attacks of asthma every day in last six months FEVr less than 75% predicted Prick test positive for house dust/D. pteronyssinus only? for one other for two or more others Mean Day Night
asthma
scores1
before
treatment
15 11 10 11 4 3 7 6 9
(73%) (67%) (73%) (27%) (20%) (47%) (40%) (60%)
2 (13%) 4 (27%) 9 (60%)
B
22 12 (55%) 12 (55%) 14 (74%) 12 (55%) 5 (23%) 11 (50%) 10 (45%) 8 (36%) 6 (27%) 1 (5%) 15 (68%)
C
19 7 (37%) 1.5 (79%) 8 (50%) 11 (58%) 1 (5%) 15 (79%) 12 (63%) 12 (63%)
5 (26%) 5 (26%) 9 (47%)
(range) 0.8
(0.1-1.8)
0.7 (O-1.7)
0.6 (O-l .6) 0.3 (O-l .3)
0.9 (O-2.1) 0.4 (O-l .4)
* Not available on all patients. t Weal diameter at least 3 mm more than with control solution. 1 Asthma scores were noted daily on the record card. The day score was : 0 = free of wheezing and shortness of breath; 1 =short of breath on hurrying; 2=short of breath at normal pace; 3 = unable to work. The night score was : 0 = not woken by asthma; 1 = woken once or twice; 2 = awake a lot.
Asthma scores The change in day and night asthma scores are shown in Fig. 1. For patients on corticosteroids the control group did better than those on active treatment during the first few months. The difference was significant (PC 0.05) for the day score in months 4-9 and for the night score in months 4-6. Later the differences between treated and controls were smaller and not significant. For those not on corticosteroids there were no differences between treatments except that those in Group A had a better improvement in night score than those in Groups B and C. However, this difference between groups A and B was observed in the first six
British Thoracic Association
264 STEROID
GROUP
NON-STEROID
GROUP
11’.
-A --mL---
8
Treatment
.3 0
6
12
18
24
I 0
I
1
I
1
6
12
18
24
1
Months
Night asthma score
0 6
0
12
18
24
d
Ii
1;
I 18
2:
Fig. 1. Changes
in day and night asthma scores over trial period for 56 patients. Day scores: 0 = free of wheezing and shortness of breath; 1 = short of breath on hurrying; 2 = short of breath at normal pace; 3 =unable to work due to asthma. Night scores: 0 =not woken by asthma; 1 = woken once or twice; 2 = awake a lot
months when treatment chance,
patients
on
A and B were the same. This may have occurred because, by A had higher initial night scores.
treatment
Changes in medication Sodium cromoglycate was taken at some stage during the trial by 25 of the 32 patients not on corticosteroids and by 9 of the 24 on corticosteroids. Four patients (one A, one B,
House Dust Mite Extract in Asthma
265
:wo C) who did not take cromoglycate during the first three months were taking it at the :nd of the trial. Conversely, 11 patients (four A, three B, four C) who took it during the irst three months were not taking it at the end. In the non-corticosteroid group five patients (two A, one B, two C) took steroids at some stage during the trial. In the corticosteroid group (oral or inhaled) only two patients were not taking steroids at the end and both were in the control group. The mean number of cromoglycate capsules used initially and their subsequent changes and the mean corticosteroid dosage during the trial did not differ significantly between groups. Use of bronchodilators Bronchodilators were taken at some time by 49 of the 56 patients. Two patients (both B) who did not take bronchodilators during the first three months were taking them at the end. Seven patients (three A, four B) who took bronchodilators during the first three months were not taking them at the end. The difference in the proportions on active treatment and on placebo discontinuing bronchodilators (7/27 compared with O/17) was significant (P=O.O3, exact test). However, two of these patients went on to inhaled
mch better 0
n
Better
0
mm
ma 0
n nnnn
0
T-0
0
n 0 00
No change
00
mm
nnnn
00 0
00 u000
o:oo
mm
0
--
0
0 0
q n
n
0
Worst
n 0
Much worse
A STEROID
Fig. 22
2. Progress
in trial
assessed
C
B
A
GROUP at six months
c
B
NON-STEROID by
the
physicians
GROUP
on the
subcommittee
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266
corticosteroids during the trial and two others never averaged more than one bronchodilator tablet a day at peak usage. If these are excluded the difference between the active and placebo groups becomes insignificant.
The mean values (% predicted) for patients were calculated and there was no statistical difference between the groups. Combined assessment by physicians on the subcommittee In the second method of analysis an assessment was made taking into account all factors. The results, averaged over the six physicians, are shown in Figs 2 and 3. Agreement between the physicians was good. Every one made 107 assessments and on average over the 1.5 physician pairs there was exact agreement in 63 cases and agreement within one category in 103 cases. Such agreement would have been expected by chance in only 3.5 and 84 cases respectively. Comparing the patient’s own doctor’s assessment with that of the six physicians, there was exact agreement in only 32 cases and agreement within one category in 80 cases. Agreement could be expected by chance in 24 and 69 cases respectively. Much better
0
n 0 Better
00
0 No change
4
00
-
-
00
0
:.. w n
Worse
00
0 0
0
Much worse
B
A STEROID
Fig.
3. Progress
in trial
assessed
at end
c GROUP (24
months)
R
A
NON-STEROID by the
physicians
C GROUP on the
subcommittee
House Dust Mite Extract in Asthma
267
At six months, patients not on corticosteroids had done better than those on corticosteroids (PC 0.001). Differences between treatments were much less. In patients not on :orticosteroids the treated did better than the controls and in those on corticosteroids he controls did better. These differences were not statistically significant (0.1~ P> 0.05). At 24 months the differences between the groups followed a similar pattern but were smaller. The difference between patients on corticosteroids and those not on corticosteroids, and between treated and controls in the non-steroid group were both not significant (0.2> P> 0.1). Those on maintenance therapy for 18 months (Group A ~1 Zroup B) did not show any additional benefit. None of the individual characteristics (Table II) was significantly associated with the 3rogress at either six months or 24 months. At six months patients who had been off ,york due to asthma in the six months before entering the trial did better than those who nad not, but the difference was not significant (P> 0.1). The differences between the treatment groups were assessed after making allowances for each individual characteristic separately and also for groups of characteristics simultaneously. The conclusions given earlier were unchanged except that for patients on corticosteroids the advantage from placebo injections at six months was (0.2 > P> 0.1). Thus, the small beneficial effect of active injections for patients not on corticosteroids was not a consequence of the differences between the groups in types of patients, but the non-beneficial effect for patients on corticosteroids could have been due to such differences. Changes in skin and nose tests The weal diameters following the skin test with D. pteronyssinus were similar for all the treatment groups at entry (average 8 mm, range 3-17 mm), and there were no significant changes. Nasal challenge tests were not carried out on all patients and for others the results were difficult to interpret. However, within these limitations there was no noticeable effect of treatment. Serological tests Serological tests were carried out on entry to the trial and thereafter at six-monthly intervals. The results are summarized in Table III which shows the number of patients Table
111.
IgG
antibody
Treatment At A B C * Specific IgE 2500 per minute it was considered least 500.
entry 6115 3/21 7118
Serological
results Specijk
Increase by six months 7114 4116 3117
was considered compared with to have increased
At
entry 12jlS 15121 11/18
IgE
antibody* Increase by six months 3114 5116 2117
positive if the count exceeded the background count of 1500; if the count had increased by at
268
British Thoracic Association
with IgG antibody to the mite extract or specific IgE antibody, and also the number of patients whose antibody levels had increased after six months. The proportion of patients on active injections who increased their antibody levels was twice that of control patients for both IgG and specific IgE. However, the numbers were small and the difference could have easily been due to chance. There was no association between patient’s progress and the presence of specific IgE at entry.
DISCUSSION The number of patients recruited for the trial was small, despite repeated efforts. There seemed to be several reasons for this. Monthly attendances for two years were demanding for patients and doctors. Some were reluctant to countenance injections of a placebo for 18 months. Inhaled corticosteroids had become widely used shortly before the intake began and there may have been a dearth of patients whose asthma appeared to be due to mite allergy and who still had residual symptoms of sufficient severity to be eligible. The small numbers clearly reduce the sensitivity of the trial. Alterations in treatment during the trial were rather frequent. Doctors were advised to reduce medicaments if the asthma improved but they were asked to avoid introducing sodium cromoglycate and corticosteroids in those not already on them, unless the indications were strong. Four patients were started on cromoglycate and five on corticosteroids during the trial and it is difficult to assess how necessary this was. Introductions and withdrawals of these drugs were evenly spread among the groups and all changes in medicines were taken into account in the physicians’ assessments. The house dust mite extract (Bencard) used in this trial was three times as strong as the commercial preparation available in Britain. This was a deliberate choice so that if no difference was found between the treated and controls it could not be attributed to low dosage. The strength of the preparation was probably responsible for the rather frequent reactions which caused the withdrawal of seven of the 43 patients receiving it. As it has also been suggested that lengthy treatment is necessary for good results (Aas 1971; Assem & McAllen 1973) one group was treated for 18 months. From one study it is suggested that in allergic rhinitis mite extract injections for 18 weeks are ineffective, but that they might produce some improvement when continued for a year (Gabriel et al. 1977). In trials which use a treatment with substantial side-effects alongside a placebo it is impossible to maintain entirely satisfactory double-blind conditions. There were further difficulties in that there was a change to control solutions in one group after 18 weeks. It is possible that those having local reactions would have little difficulty in spotting the change but there is nothing to suggest that this affected the results. Early trials with aqueous house dust mite extract showed some benefit (Smith 1971; D’Souza et al. 1973 ; Bessot et al. 1975) though no improvement was seen with an alumprecipitated extract (Newton et al. 1978) nor a short period of treatment with a depot preparation (Gaddie et al. 1976). The patients in this trial were a heterogeneous group of atopic asthmatics with a history suggesting an association between their asthma and house dust mite, and who showed evidence of house dust hypersensitivity by skin and nasal tests. It is possible that there are people whose asthma is more closely related to
House Dust Mite Extract in Asthma
269
mite allergy who might respond to hyposensitization. We failed to identify such a group in this trial. In our patients treatment at best produced but marginal improvement. Judged by asthma scores, patients in Group A given active material for 18 months and not taking corticosteroids showed some improvement at night. They did so during the first six months when patients in Group B failed to improve although on the same treatment. There was no difference in corticosteroid usage between the groups but more patients on active treatment discontinued bronchodilators. The combined assessments by the physicians on the subcommittee took individual changes in medication into account and found that in patients not on corticosteroids the group treated with active material did better than the controls. The difference was not significant (0.1~ P > 0.05) at six months and even less evident at 24 months. No additional benefit was shown by prolonging injections from 18 weeks to 18 months. In contrast, patients on corticosteroids did slightly better on placebo injections than active material. They may represent a more severe group of asthmatics in whom the extract may have an adverse effect. But it also raises doubt about the importance of the minor improvement found in patients not on corticosteroids and given the active preparation. Forty-three patients started injections of active material and seven of these had side effects severe enough to cause the injections to be stopped; in only one case could these be clearly blamed on neglect of warning signs. Side-effects could be reduced by using weaker solutions. In the light of the marginal benefit which was found only in the patients not on corticosteroids it seems doubtful whether treatment in this form is suitable for general use. ACKNOWLEDGEMENTS
This trial was made possible by a generous grant from the Asthma Research Council of Great Britain. We are grateful to the Bencard Allergy Unit of Beecham Research Laboratories for providing the material used in the trial, to Professor Pepys’ laboratory at Institute of Diseases of the Chest, Brompton Hospital, London, where serological work was carried out, and to the following physicians for submitting patients: Dr R. A. L. Agnew, Liverpool; Dr J. R. Carter, Hull; Dr A. G. Chappell, Bridgend; Dr R. A. Clark, Sheffield; Dr G. K. Crompton, Edinburgh; Dr J. Dawson, Plymouth; Dr E. Hills, Aylesbury; Dr J. N. Hoffman, Bristol; Dr S. Lal, Bury; Dr D. J. Lane, Oxford; Dr A. Mithal, Lincoln; Dr D. O’D riscoll, Galway; Professor J. Pepys, Brompton; Dr W. H. R. Smith, Nottingham; Dr C. J. Stewart, Ipswich; Dr A. R. Tanser, Trowbridge; Dr b57. H. Tattersall, Bournemouth; and Dr R. H. Townshend, Sheffield. REFERENCES AAS, K. (1971) Hyposensitization in house dust allergy asthma: a double-blind controlled study with evaluation of the effect on bronchial sensitivity to house dust. Acta paediat. wand. 60, 264. ASSEM, E. S. K. & MCALLEN, M. K. (1973) Changes in challenge tests following hyposensitization with mite extract. Clin. Allergy 3, 161. BESOT, J.-CL., MOREAU, G., LENZ, D., PARINI, J.-P., ARAUJO-FONTAINE, A. & PAULI, G. (1975) l?tude comparative dun essai de desensibilisation ‘en double insu’ aux extraits de poussiere et aux extraits d’acariens. Reu. fr. allerg. 15, 73.
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British Thoracic Association
BRITISH TUBERCULOSIS ASSOCIATION (1968) Treatment of house dust allergy. Br. med. J. 3, 774. CESKA, M., ERIKSSON, R. & VARGA, J. M. (1972) Radioimmunosorbent assay of al1ergens.J. Allergy din. Immunol. 49, 1. D’SOUZA, M. F., PEPYS, J., WELLS, I. D., TAI, E., PALMER, F., OVERELL, B. G., MCGRATH, I. T., & MEGSON, M. (1973) Hyposensitization with Dermatophagoides pteronyssinus in house dust allergy. Clin. Allergy 3, 177. GADDIE, J., SKINNER, C. & PALMER, K. N. V. (1976) Hyposensitization with house dust mite vaccine in bronchial asthma. BY. med, J. 2, 561. GABRIEL, M., ALLAN, W. G. L., HILL, L. E. & NUNN, A. J. (1977) Study of prolonged hyposensitization with D. pteronyssinus extract in allergic rhinitis. Clin. Allergy 7, 325. NEWTON, D. A. G., MABERLEY, D. J. & WILSON, R. (1978) H ouse dust mite hyposensitization. Br. J. Dis. Chest 72, 21. SCHEIDEGGER, J. J. (1955) Une micro-methode d’immune-electrophorese. bzt. Archs Allergy appl. Immunol. 7, 103. SMITH, A. P. (1971) Hyposensitization with Dermatophagoidespteronyssinus antigen: Trialin asthma induced by house dust. Br. med. J. 4, 204.
A TRIAL
MITE
ALLERGY
OF HOUSE DUST MITE EXTRACT IN BRONCHIAL ASTHMA SUBCOMMITTEE OF THE RESEARCH COMMITTEE BRITISH THORACIC ASSOCIATION*
OF THE
Summary Patients with asthma considered to be due to house dust mite allergy were allocated at random to treatment with (a) increasing weekly injections of house dust mite extract for 18 weeks followed by monthly injections to complete 18 months of treatment; (6) similar injections for 18 weeks followed by placebo injections up to 18 months or (c) placebo injections for 18 months. Fifty-six patients completed at least six months of observation. In patients not on corticosteroids the treated group did a little better than the controls, as judged by night asthma scores, discontinuation of bronchodilators and overall blind assessment of the records by a panel of independent physicians. No benefit was apparent by extending treatment from 18 weeks to 18 months. In contrast, patients on corticosteroids given placebo injections did a little better than the treated group. The extract used was stronger than the commercially available preparation and the injections had to be stopped in one-sixth of the patients because of side-effects. The improvement in patients not on corticosteroids in this trial was of doubtful clinical importance.
Some physicians believe that attempts at hyposensitization to house dust extract are worth while in asthmatics who become more wheezy when exposed to house dust. The British Tuberculosis Association trial in 1968, however, found no difference between a commercially available preparation and placebo injections. By the time the results were published it had become recognized that the major allergen in house dust was the house dust mite, Dermatophagoidespteronyssinus. Aqueous extracts of the mite later became available for treatment and in 1972 the Research Committee of the British Thoracic Association resolved to carry out a further multicentre double blind controlled study in patients with asthma. Materials
and Methods
Patients Physicians with an interest in asthma in the British Isles were asked to submit patients with asthma which they considered to be caused by house dust mite allergy. The patients had to have (a) a positive skin prick test with a 1.2% (w/v) solution of D. pteronyssinus extract, together with (b) a * Members of the Mite Allergy Subcommittee were: D. Davies (Chairman), G. Berry tician), E. Hills, S. La1 (Coordinator), M. McAllen, J. Morrison Smith and J. Pepys.
(Statis-
House Dust Mite Extract in Asthma
261
worsening of asthma after exposure to dust from house cleaning or bed making and/or a positive nasal provocation test with one of three strengths (0.005, 0.04 or 0.3%) of D. pteronyssinus extract. Eligible patients were aged 16 to 50 years, born in the British Isles of any racial group and with dyspnoea and wheezing at least once a week in the previous year and severe enough at times to interfere with normal activities. Excluded were patients (a) likely to have seasonal exacerbations of asthma, (b) with symptoms due to animal danders when continued exposure was likely, (c) with other recognizable unavoidable triggers, except exercise, (d) previously given a course of dust or mite extract injections, and (e) who were pregnant. The consent of the patient was obtained. In the initial weeks they were taught to keep a daily record card. This recorded the severity of day and night asthma, nasal symptoms and the use of bronchodilators, sodium cromoglycate and corticosteroid tablets and aerosols. Skin prick tests with nine other common allergens were done and the forced expiratory volume in one second (FEV1) before and after the inhalation of a bronchodilator was recorded. All subjects were given advice about house dust suppression, the details being left to individual physicians. Treatment An aqueous extract of D. pteronyssinus which had been grown on animal tissue of non-dermal origin (Bencard) was put up in strengths of 0.005, 0.04 and 0.3%. The control solution contained the vehicle only (glycerated extraction medium). Group A patients were given weekly injections of 0.1, 0.2, 0.3, 0.5, 0.7 and 1 ml, starting with the lowest concentration and increasing to higher ones. The schedule was modified to deal with local or generalized reactions. When the top dose had been reached (usually after 18 weeks) or, in a few cases, the maximum tolerated dose, this was continued at monthly intervals until 18 months’ treatment had been completed. Group B were given similar injections for 18 weeks but, when the maximum or maximumtolerated dose was reached, placebo injections were given at monthly intervals to complete 18 months. Group C were given placebo injections for 18 months. Patients were allocated randomly to one of the three treatments separately within centres and according to whether or not they were receiving corticosteroids (orally or by inhalation). When the patients had kept satisfactory records for four weeks, injections were started. They were seen by their physician at monthly intervals for two years. He issued new diary cards and recorded changes in severity of asthma and medicaments, absence from work and the FEV1. Every six months he also repeated skin and nasal tests with D. pteronyssinus extract, assessed changes in asthma severity and checked whether dust suppression measures were still being carried out. Total IgE and IgE and IgG specific to D. pteronyssinus were measured before the start of treatment and every six months for a total of two years. IgE specific to mite extract was measured by the radioallergosorbent test (RAST) (Ceska et al. 1972) and specific IgG by radio-immunoelectrophoresis, amodification of the method of Scheidegger (1955). All measurements were done in one batch at the end. Assessment
of progress
The serial records were used to assess the changes in every patient in two ways: 1. The mean values of the day and night asthma scores, use of bronchodilators, sodium cromoglycate and corticosteroids and FEVi expressed as a percentage of the predicted value were all calculated for the pre-treatment period (entry values and month 1). The same parameters were calculated again for months 2 and 3 and thereafter for each three month period up to 24 months. The changes in each variable from the pre-treatment value were calculated and the effects of treatment were assessed by analysis of variance on each variable separately and for each of the eight time periods from months 2-3 to months 21-24. 2. The six physicians on the subcommittee considered all the variables together in making a combined assessment of each patient’s progress. For every patient they used the mean values of each variable grouped into the time periods used in the first method of assessment and also the
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262
six-monthly assessments by the patient’s own doctor. Two print-outs were prepared for every patient, one to cover the first six months, i.e. up to the end of the weekly injection schedule, and the other to cover all 24 months of the trial. The trial regimen was not included in the print-outs which were distributed in random order to all six physicians on the subcommittee. Each physician independently made an assessment of every patient’s progress using five categories: much better, better, no change, worse and much worse. In making the assessments the physicians used their judgement to eliminate the effects of change in bronchodilator, sodium cromoglycate or corticosteroid treatment. For example, if a patient’s asthma score and FEVl had not altered but he had reduced his dose of corticosteroid then this would be judged as an improvement. The assessments of the six physicians were combined by assigning scores 2, 1, 0, - 1 and - 2 to the five categories and averaging the scores for every patient. The average scores were analysed by analysis of variance.
RESULTS
A total of 70 patients were submitted from 17 centres. completing six months in the trial, another five before 24 months. Seven of the patients withdrawn early did because they either changed their minds or proved Table I. Number
of patients
Fourteen patients withdrew before 12 months and another five before not start their injections (Table I), uncooperative. The other seven in trial
Treatment No.
of patients
Entering trial Withdrawals in Did not start Reactions to Other reasons Completing six Completing 12 Completing 24
first year injections injections months months months
A
B
c
Total
24
24
22
70
5 5 0 15 14 14
0 2 3 22 19 15
2 1 1 19 18 17
7 8 4 56 51 46
withdrawals in the first six months resulted from reactions to the injections; one had received placebo injections. In one case a severe reaction occurred after the dose had been increased three times despite local reactions, contrary to the protocol. One patient required hospital treatment after a reaction to an injection. Between six and twelve months five patients withdrew. One had a severe anaphylactic reaction in month 8, one suffered a bereavement, another became pregnant and the other two gave no reason. Only the 56 patients who remained in the trial for at least six months were included in the analysis. Those who withdrew later were retained in the analysis until the time of withdrawal. However, in the combined assessment at 24 months all the records were considered for patients remaining in the trial for 12 months or longer. Completion of injection courses If there were no local or generalized reactions a dose of 1 ml of the 0.3% extract should have been achieved in 18 weeks. In Groups A and B one patient in each took longer than 20 weeks and three in each never achieved the full dose. In the control group (C) two
263
House Dust Mite Extract in Asthma took longer than 20 weeks but all achieved the full dose. Information seven patients (three A, one B and three C).
was incomplete for
Initial characteristics of patients The features of the 56 patients who continued in the trial for at least six months are shown in Table II. There were some quite large differences between the treatment groups arising from the small numbers in the trial. For example, the percentage of males ranged from 37% to 73%. Since some of the factors may be of prognostic importance they were included as co-variates in the analysis in order to assesswhether the response was dependent on them and to make allowance for them in treatment comparisons. Table II.
Characteristics
at entry
to trial
of the
56 patients
who
completed
six months
Treatment Characteristic A Number Male Aged 30 or over Duration of asthma, 10 years or more* Provoking factors other than house dust Smokers Off work due to asthma in last six months Attacks of asthma every day in last six months FEVr less than 75% predicted Prick test positive for house dust/D. pteronyssinus only? for one other for two or more others Mean Day Night
asthma
scores1
before
treatment
15 11 10 11 4 3 7 6 9
(73%) (67%) (73%) (27%) (20%) (47%) (40%) (60%)
2 (13%) 4 (27%) 9 (60%)
B
22 12 (55%) 12 (55%) 14 (74%) 12 (55%) 5 (23%) 11 (50%) 10 (45%) 8 (36%) 6 (27%) 1 (5%) 15 (68%)
C
19 7 (37%) 1.5 (79%) 8 (50%) 11 (58%) 1 (5%) 15 (79%) 12 (63%) 12 (63%)
5 (26%) 5 (26%) 9 (47%)
(range) 0.8
(0.1-1.8)
0.7 (O-1.7)
0.6 (O-l .6) 0.3 (O-l .3)
0.9 (O-2.1) 0.4 (O-l .4)
* Not available on all patients. t Weal diameter at least 3 mm more than with control solution. 1 Asthma scores were noted daily on the record card. The day score was : 0 = free of wheezing and shortness of breath; 1 =short of breath on hurrying; 2=short of breath at normal pace; 3 = unable to work. The night score was : 0 = not woken by asthma; 1 = woken once or twice; 2 = awake a lot.
Asthma scores The change in day and night asthma scores are shown in Fig. 1. For patients on corticosteroids the control group did better than those on active treatment during the first few months. The difference was significant (PC 0.05) for the day score in months 4-9 and for the night score in months 4-6. Later the differences between treated and controls were smaller and not significant. For those not on corticosteroids there were no differences between treatments except that those in Group A had a better improvement in night score than those in Groups B and C. However, this difference between groups A and B was observed in the first six
British Thoracic Association
264 STEROID
GROUP
NON-STEROID
GROUP
11’.
-A --mL---
8
Treatment
.3 0
6
12
18
24
I 0
I
1
I
1
6
12
18
24
1
Months
Night asthma score
0 6
0
12
18
24
d
Ii
1;
I 18
2:
Fig. 1. Changes
in day and night asthma scores over trial period for 56 patients. Day scores: 0 = free of wheezing and shortness of breath; 1 = short of breath on hurrying; 2 = short of breath at normal pace; 3 =unable to work due to asthma. Night scores: 0 =not woken by asthma; 1 = woken once or twice; 2 = awake a lot
months when treatment chance,
patients
on
A and B were the same. This may have occurred because, by A had higher initial night scores.
treatment
Changes in medication Sodium cromoglycate was taken at some stage during the trial by 25 of the 32 patients not on corticosteroids and by 9 of the 24 on corticosteroids. Four patients (one A, one B,
House Dust Mite Extract in Asthma
265
:wo C) who did not take cromoglycate during the first three months were taking it at the :nd of the trial. Conversely, 11 patients (four A, three B, four C) who took it during the irst three months were not taking it at the end. In the non-corticosteroid group five patients (two A, one B, two C) took steroids at some stage during the trial. In the corticosteroid group (oral or inhaled) only two patients were not taking steroids at the end and both were in the control group. The mean number of cromoglycate capsules used initially and their subsequent changes and the mean corticosteroid dosage during the trial did not differ significantly between groups. Use of bronchodilators Bronchodilators were taken at some time by 49 of the 56 patients. Two patients (both B) who did not take bronchodilators during the first three months were taking them at the end. Seven patients (three A, four B) who took bronchodilators during the first three months were not taking them at the end. The difference in the proportions on active treatment and on placebo discontinuing bronchodilators (7/27 compared with O/17) was significant (P=O.O3, exact test). However, two of these patients went on to inhaled
mch better 0
n
Better
0
mm
ma 0
n nnnn
0
T-0
0
n 0 00
No change
00
mm
nnnn
00 0
00 u000
o:oo
mm
0
--
0
0 0
q n
n
0
Worst
n 0
Much worse
A STEROID
Fig. 22
2. Progress
in trial
assessed
C
B
A
GROUP at six months
c
B
NON-STEROID by
the
physicians
GROUP
on the
subcommittee
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266
corticosteroids during the trial and two others never averaged more than one bronchodilator tablet a day at peak usage. If these are excluded the difference between the active and placebo groups becomes insignificant.
The mean values (% predicted) for patients were calculated and there was no statistical difference between the groups. Combined assessment by physicians on the subcommittee In the second method of analysis an assessment was made taking into account all factors. The results, averaged over the six physicians, are shown in Figs 2 and 3. Agreement between the physicians was good. Every one made 107 assessments and on average over the 1.5 physician pairs there was exact agreement in 63 cases and agreement within one category in 103 cases. Such agreement would have been expected by chance in only 3.5 and 84 cases respectively. Comparing the patient’s own doctor’s assessment with that of the six physicians, there was exact agreement in only 32 cases and agreement within one category in 80 cases. Agreement could be expected by chance in 24 and 69 cases respectively. Much better
0
n 0 Better
00
0 No change
4
00
-
-
00
0
:.. w n
Worse
00
0 0
0
Much worse
B
A STEROID
Fig.
3. Progress
in trial
assessed
at end
c GROUP (24
months)
R
A
NON-STEROID by the
physicians
C GROUP on the
subcommittee
House Dust Mite Extract in Asthma
267
At six months, patients not on corticosteroids had done better than those on corticosteroids (PC 0.001). Differences between treatments were much less. In patients not on :orticosteroids the treated did better than the controls and in those on corticosteroids he controls did better. These differences were not statistically significant (0.1~ P> 0.05). At 24 months the differences between the groups followed a similar pattern but were smaller. The difference between patients on corticosteroids and those not on corticosteroids, and between treated and controls in the non-steroid group were both not significant (0.2> P> 0.1). Those on maintenance therapy for 18 months (Group A ~1 Zroup B) did not show any additional benefit. None of the individual characteristics (Table II) was significantly associated with the 3rogress at either six months or 24 months. At six months patients who had been off ,york due to asthma in the six months before entering the trial did better than those who nad not, but the difference was not significant (P> 0.1). The differences between the treatment groups were assessed after making allowances for each individual characteristic separately and also for groups of characteristics simultaneously. The conclusions given earlier were unchanged except that for patients on corticosteroids the advantage from placebo injections at six months was (0.2 > P> 0.1). Thus, the small beneficial effect of active injections for patients not on corticosteroids was not a consequence of the differences between the groups in types of patients, but the non-beneficial effect for patients on corticosteroids could have been due to such differences. Changes in skin and nose tests The weal diameters following the skin test with D. pteronyssinus were similar for all the treatment groups at entry (average 8 mm, range 3-17 mm), and there were no significant changes. Nasal challenge tests were not carried out on all patients and for others the results were difficult to interpret. However, within these limitations there was no noticeable effect of treatment. Serological tests Serological tests were carried out on entry to the trial and thereafter at six-monthly intervals. The results are summarized in Table III which shows the number of patients Table
111.
IgG
antibody
Treatment At A B C * Specific IgE 2500 per minute it was considered least 500.
entry 6115 3/21 7118
Serological
results Specijk
Increase by six months 7114 4116 3117
was considered compared with to have increased
At
entry 12jlS 15121 11/18
IgE
antibody* Increase by six months 3114 5116 2117
positive if the count exceeded the background count of 1500; if the count had increased by at
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British Thoracic Association
with IgG antibody to the mite extract or specific IgE antibody, and also the number of patients whose antibody levels had increased after six months. The proportion of patients on active injections who increased their antibody levels was twice that of control patients for both IgG and specific IgE. However, the numbers were small and the difference could have easily been due to chance. There was no association between patient’s progress and the presence of specific IgE at entry.
DISCUSSION The number of patients recruited for the trial was small, despite repeated efforts. There seemed to be several reasons for this. Monthly attendances for two years were demanding for patients and doctors. Some were reluctant to countenance injections of a placebo for 18 months. Inhaled corticosteroids had become widely used shortly before the intake began and there may have been a dearth of patients whose asthma appeared to be due to mite allergy and who still had residual symptoms of sufficient severity to be eligible. The small numbers clearly reduce the sensitivity of the trial. Alterations in treatment during the trial were rather frequent. Doctors were advised to reduce medicaments if the asthma improved but they were asked to avoid introducing sodium cromoglycate and corticosteroids in those not already on them, unless the indications were strong. Four patients were started on cromoglycate and five on corticosteroids during the trial and it is difficult to assess how necessary this was. Introductions and withdrawals of these drugs were evenly spread among the groups and all changes in medicines were taken into account in the physicians’ assessments. The house dust mite extract (Bencard) used in this trial was three times as strong as the commercial preparation available in Britain. This was a deliberate choice so that if no difference was found between the treated and controls it could not be attributed to low dosage. The strength of the preparation was probably responsible for the rather frequent reactions which caused the withdrawal of seven of the 43 patients receiving it. As it has also been suggested that lengthy treatment is necessary for good results (Aas 1971; Assem & McAllen 1973) one group was treated for 18 months. From one study it is suggested that in allergic rhinitis mite extract injections for 18 weeks are ineffective, but that they might produce some improvement when continued for a year (Gabriel et al. 1977). In trials which use a treatment with substantial side-effects alongside a placebo it is impossible to maintain entirely satisfactory double-blind conditions. There were further difficulties in that there was a change to control solutions in one group after 18 weeks. It is possible that those having local reactions would have little difficulty in spotting the change but there is nothing to suggest that this affected the results. Early trials with aqueous house dust mite extract showed some benefit (Smith 1971; D’Souza et al. 1973 ; Bessot et al. 1975) though no improvement was seen with an alumprecipitated extract (Newton et al. 1978) nor a short period of treatment with a depot preparation (Gaddie et al. 1976). The patients in this trial were a heterogeneous group of atopic asthmatics with a history suggesting an association between their asthma and house dust mite, and who showed evidence of house dust hypersensitivity by skin and nasal tests. It is possible that there are people whose asthma is more closely related to
House Dust Mite Extract in Asthma
269
mite allergy who might respond to hyposensitization. We failed to identify such a group in this trial. In our patients treatment at best produced but marginal improvement. Judged by asthma scores, patients in Group A given active material for 18 months and not taking corticosteroids showed some improvement at night. They did so during the first six months when patients in Group B failed to improve although on the same treatment. There was no difference in corticosteroid usage between the groups but more patients on active treatment discontinued bronchodilators. The combined assessments by the physicians on the subcommittee took individual changes in medication into account and found that in patients not on corticosteroids the group treated with active material did better than the controls. The difference was not significant (0.1~ P > 0.05) at six months and even less evident at 24 months. No additional benefit was shown by prolonging injections from 18 weeks to 18 months. In contrast, patients on corticosteroids did slightly better on placebo injections than active material. They may represent a more severe group of asthmatics in whom the extract may have an adverse effect. But it also raises doubt about the importance of the minor improvement found in patients not on corticosteroids and given the active preparation. Forty-three patients started injections of active material and seven of these had side effects severe enough to cause the injections to be stopped; in only one case could these be clearly blamed on neglect of warning signs. Side-effects could be reduced by using weaker solutions. In the light of the marginal benefit which was found only in the patients not on corticosteroids it seems doubtful whether treatment in this form is suitable for general use. ACKNOWLEDGEMENTS
This trial was made possible by a generous grant from the Asthma Research Council of Great Britain. We are grateful to the Bencard Allergy Unit of Beecham Research Laboratories for providing the material used in the trial, to Professor Pepys’ laboratory at Institute of Diseases of the Chest, Brompton Hospital, London, where serological work was carried out, and to the following physicians for submitting patients: Dr R. A. L. Agnew, Liverpool; Dr J. R. Carter, Hull; Dr A. G. Chappell, Bridgend; Dr R. A. Clark, Sheffield; Dr G. K. Crompton, Edinburgh; Dr J. Dawson, Plymouth; Dr E. Hills, Aylesbury; Dr J. N. Hoffman, Bristol; Dr S. Lal, Bury; Dr D. J. Lane, Oxford; Dr A. Mithal, Lincoln; Dr D. O’D riscoll, Galway; Professor J. Pepys, Brompton; Dr W. H. R. Smith, Nottingham; Dr C. J. Stewart, Ipswich; Dr A. R. Tanser, Trowbridge; Dr b57. H. Tattersall, Bournemouth; and Dr R. H. Townshend, Sheffield. REFERENCES AAS, K. (1971) Hyposensitization in house dust allergy asthma: a double-blind controlled study with evaluation of the effect on bronchial sensitivity to house dust. Acta paediat. wand. 60, 264. ASSEM, E. S. K. & MCALLEN, M. K. (1973) Changes in challenge tests following hyposensitization with mite extract. Clin. Allergy 3, 161. BESOT, J.-CL., MOREAU, G., LENZ, D., PARINI, J.-P., ARAUJO-FONTAINE, A. & PAULI, G. (1975) l?tude comparative dun essai de desensibilisation ‘en double insu’ aux extraits de poussiere et aux extraits d’acariens. Reu. fr. allerg. 15, 73.
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British Thoracic Association
BRITISH TUBERCULOSIS ASSOCIATION (1968) Treatment of house dust allergy. Br. med. J. 3, 774. CESKA, M., ERIKSSON, R. & VARGA, J. M. (1972) Radioimmunosorbent assay of al1ergens.J. Allergy din. Immunol. 49, 1. D’SOUZA, M. F., PEPYS, J., WELLS, I. D., TAI, E., PALMER, F., OVERELL, B. G., MCGRATH, I. T., & MEGSON, M. (1973) Hyposensitization with Dermatophagoides pteronyssinus in house dust allergy. Clin. Allergy 3, 177. GADDIE, J., SKINNER, C. & PALMER, K. N. V. (1976) Hyposensitization with house dust mite vaccine in bronchial asthma. BY. med, J. 2, 561. GABRIEL, M., ALLAN, W. G. L., HILL, L. E. & NUNN, A. J. (1977) Study of prolonged hyposensitization with D. pteronyssinus extract in allergic rhinitis. Clin. Allergy 7, 325. NEWTON, D. A. G., MABERLEY, D. J. & WILSON, R. (1978) H ouse dust mite hyposensitization. Br. J. Dis. Chest 72, 21. SCHEIDEGGER, J. J. (1955) Une micro-methode d’immune-electrophorese. bzt. Archs Allergy appl. Immunol. 7, 103. SMITH, A. P. (1971) Hyposensitization with Dermatophagoidespteronyssinus antigen: Trialin asthma induced by house dust. Br. med. J. 4, 204.