Allergy, 1990, 45, 209-212
Who will benefit from hyposensitization? Predictive parameters in house dust mite allergic asthmatics H. MOSBECH* Medical Department TTA, Allergy Unit 7511, State University Hospital, Copenhagen N, Denmark
The aim of this study was to assess the ability of various data collected before treatment to predict the therapeutic benefits of hyposensitization. Thirty-one asthmatics were hyposensitized with extract from the house dust mite Dermatophagoides pteronyssinus (Dp) for 2 years, 15 comparable patients served as controls. The treatment extract was either modified by coupling to monomethoxypolyethylene glycol (mPEG) or administered in a diluent containing A1(OH)3. Improvement would be either a S 10-fold increase in bronchial tolerance to Dp or an overall clinical effect judged from questionnaires plus diary cards. Patients improving in bronchial Dp-sensitivity after 1 year had been more sensitive to Dp pre-treatment in bronchi and in basophils, and had a lower FEV, compared with the patients not improving {P 15% and/or an increase in |32-agonist spray of at least 2 x 2 puffs should be necessary (9). The overall clinical effect after 2 years was determined by combining information from diary cards and from a retrospective judgement simply asking patients at the end of treatment whether they felt an effect or not. Improvement would mean improvement in symptom scores/ medication and in retrospective judgement - or in one of these parameters with no change in the other. A 10% reduction in symptom scores and/or medication was regarded as an improvement (8). Sixteen patients received mPEG-Dp-, and 15 Dp-extract. Fifteen served as controls. Since improvement rate in Dp- and mPEG-Dptreated groups did not differ with regard to the two effect parameters chosen (8, 9), treatment groups were not analysed separately. Analyses were performed on all data available, although for some parameters data from a few patients were missing (8) due to reasons not related to clinical state or treatment. Categorical data were analysed by Fisher's exact test (Table 2), whereas other variables were tested by Mann-Whitney or Kruskal-Wallis test (Table 1). If a pre-treatment parameter
PREDICTION OF EFFICACY OF HYPOSENSITIZATION showed a significant correlation to the effect in the hyposensitized patients, a similar analysis was made in the control group. RESULTS No pre-treatment parameter could discriminate completely between patients responding or not responding to HS. However, patients improving in bronchial sensitivity to Dp had the poorest lung function and bronchi, or basophils with the highest sensitivity to Dp (Table 1). If no late-phase bronchospasm had occurred after bronchial Dp challenge, the chance of improvement was reduced to approximately 1/3 of the chance in patients presenting with late reactions (Table 2). Patients improving clinically tended to have the highest bronchial sensitivity to histamine (Table 1). By additional analysis of the non-hyposensitized patients it was not possible to demonstrate similar connections between pre-treatment bronchial sensitivity to Dp or occurrence of late reactions, and the improvement in Dp-sensitivity or in clinicEii symptoms. For patients showing a general clinical improvement, the mean titre of Dp allergen in mattress dust was 32, equivalent to 1,000 mites/g fine dust (5). This was 5-6 times higher than in mattresses of unchanged or deteriorated patients, but variation was extensive {P = 0.1). In contrast, in the control group the spontaneous clinical improvement tended to be most pronounced in patients with low allergen exposure. Change in bronchial Dp-sensitivity was totally unrelated to the Dp-exposure. Patients classified according to either their clinical change or their change in Dp-sensitivity did not differ with regard to pre-treatment nasal, conjunctival or skin sensitivity to Dp, Dpspecific IgE, IgG, IgGl, IgG2, IgGj, IgG^, or to age, duration of pulmonary symtoms, pulmonary scores, Pj'^go'^ist consumption, or use of inhaled steroids. DISGUSSION The present study is the first prospective controlled study on HS with house dust mite allergens in asthmatics to demonstrate better thera14*
211
peutic effects in highly Dp-sensitive individuals compared with patients with a clearly demonstrated but less pronounced sensitivity. Previously, high pre-treatment nasal sensitivity to Dp-extract in rhinitis patients was correlated to improvement in nasal Dp-sensitivity and in symptoms (3). However, in an early study demonstrating effect of HS with house dust, this was not correlated to pre-treatment bronchial sensitivity (7). Results from HS with other allergens have been similarly conflicting, demonstrating correlations to pre-treatment allergen sensitivity in some (2, 6), but not in others (4). The course of the asthma disease is fluctuating due to known and unknown mechanisms, and the higher improvement rate seen in more severely afflicted patients might have reflected simply a regression towards the mean. In the present study this explanation was, however, less likely, since the improvement seen in nonhyposensitized patients was correlated neither to initial bronchial Dp or histamine sensitivity nor to the occurrence of late-phase bronchial reactions. As proposed (H), the better effect in the most sensitive patients might be ascribed to a much higher allergen stimulation received relative to their sensitivity - than in patients with low sensitivity. Disappointingly, the majority of parameters tested did not contain any information useful in selecting patients readily benefiting clinically from HS. The asthma disease is, however, influenced by severail factors not related to HS, as reflected in the high proportion of patients reporting spontaneous clinical improvement when followed for 2 years (8). Even with these problems, a trend was in fact demonstrated in the present study towards a better clinical effect in patients with extreme bronchial sensitivity to Dp and histamine. This trend supported the significant correlations demonstrated for the change in Dp-specific bronchial sensitivity. In conclusion, HS with Dp-extract should be given preferentially to patients with high bronchial Dp-sensitivity and late-phase bronchial reactions. The study does not support the idea of restricting therapy to young patients or to patients with almost normal basic lung function (1, 10).
212
H. MOSBECH
REFERENCES 1. Bousquet, J., Hejjaoui, A., Clauzel, A.-M., et al.: Specific immunotherapy with a standardized Dermatophagoides pteronyssinus extract. II. Prediction of efficacy of immunotherapy. J. Allergy Clin. Immunol. 82, 971-977, 1988. 2. Bucur, J., Dreborg, S., Einarsson, R., Ljungstedt-Pahlman, I., Nilsson, J.-E. & Persson, G.: Immunotherapy with dog and cat allergen preparations in dog-sensitive and cat-sensitive asthmatics. Ann. Allergy 62, 355-361, 1989. 3. D'Souza, M. F., Pepys, J., Wells, I. D., et al.: Hyposensitization with Dermatophagoides pteronyssinus in house dust allergy: a controlled study of clinical and immunological effects. Clin. Allergy 3, 177-193, 1973. 4. Dreborg, S., Agrell, B., Foucard, T., Kjellman, N.-I. M., Koivikko, A. & Nilsson, S.: A double-blind, multicenter immunotherapy trial in children, using a purified and standardized Cladosporium herbarum preparation. I. Clinical results. Allergy 41, 131-140, 1986. 5. Lind, P., Korsgaard, J. & Lcwenstein, H.: Detection and quantitation of Dermatophagoides in house-dust by immunochemical techniques. Allergy 34, 319-327, 1979. 6. Mailing, H.-J., Dreborg, S. & Weeke, B.: Diagnosis and immunotherapy of mould allergy. VL IgE-mediated parameters during a one-year placebo controlled study of immunotherapy with Cladosporium. Allergy 42, 305-314, 1987.
7. McAUen, M. K.: Bronchial sensitivity testing in asthma. An assessment of the effect of hyposensitization in house-dust and pollen-sensitive asthmatic subjects. Thorax 16, 30-35, 1961. 8. Mosbech, H., Dreborg, S., Frolund, L., et al.: Hyposensitization in asthmatics with mPEG modified and unmodified house dust mite extract. I. Clinical effect evaluated by diary cards and a retrospective assessment. Allergy 44, 487-498, 1989. 9. Mosbech, H., Dreborg, S., Frolund, L., et al.: Hyposensitization in asthmatics with mPEG modified and unmodified house dust mite extract. IL Effect evaluated by challenges with allergen and histamine. Allergy 44, 499-509, 1989. 10. Perrin, L. F., Scroussi, J., Cea-Gil, F., Deviller, P. & Lasne, Y.: Serum IgE levels and specific IgE antibodies in house dust mite allergy: predictive value. J. Asthma 20, 93-96, 1983. 11. 0sterballe, O.: Nasal and skin sensitivity during immunotherapy with two major allergens 19, 25 and partially purified extract of timothy grass pollen. Allergy 37, 169-177, 1982. Address: Holger Mosbech, M.D.
Medical Department TTA Allergy Unit 7511 State University Hospital Tagensvej 20 DK-2200 Copenhagen N Denmark
Who will benefit from hyposensitization? Predictive parameters in house dust mite allergic asthmatics H. MOSBECH* Medical Department TTA, Allergy Unit 7511, State University Hospital, Copenhagen N, Denmark
The aim of this study was to assess the ability of various data collected before treatment to predict the therapeutic benefits of hyposensitization. Thirty-one asthmatics were hyposensitized with extract from the house dust mite Dermatophagoides pteronyssinus (Dp) for 2 years, 15 comparable patients served as controls. The treatment extract was either modified by coupling to monomethoxypolyethylene glycol (mPEG) or administered in a diluent containing A1(OH)3. Improvement would be either a S 10-fold increase in bronchial tolerance to Dp or an overall clinical effect judged from questionnaires plus diary cards. Patients improving in bronchial Dp-sensitivity after 1 year had been more sensitive to Dp pre-treatment in bronchi and in basophils, and had a lower FEV, compared with the patients not improving {P 15% and/or an increase in |32-agonist spray of at least 2 x 2 puffs should be necessary (9). The overall clinical effect after 2 years was determined by combining information from diary cards and from a retrospective judgement simply asking patients at the end of treatment whether they felt an effect or not. Improvement would mean improvement in symptom scores/ medication and in retrospective judgement - or in one of these parameters with no change in the other. A 10% reduction in symptom scores and/or medication was regarded as an improvement (8). Sixteen patients received mPEG-Dp-, and 15 Dp-extract. Fifteen served as controls. Since improvement rate in Dp- and mPEG-Dptreated groups did not differ with regard to the two effect parameters chosen (8, 9), treatment groups were not analysed separately. Analyses were performed on all data available, although for some parameters data from a few patients were missing (8) due to reasons not related to clinical state or treatment. Categorical data were analysed by Fisher's exact test (Table 2), whereas other variables were tested by Mann-Whitney or Kruskal-Wallis test (Table 1). If a pre-treatment parameter
PREDICTION OF EFFICACY OF HYPOSENSITIZATION showed a significant correlation to the effect in the hyposensitized patients, a similar analysis was made in the control group. RESULTS No pre-treatment parameter could discriminate completely between patients responding or not responding to HS. However, patients improving in bronchial sensitivity to Dp had the poorest lung function and bronchi, or basophils with the highest sensitivity to Dp (Table 1). If no late-phase bronchospasm had occurred after bronchial Dp challenge, the chance of improvement was reduced to approximately 1/3 of the chance in patients presenting with late reactions (Table 2). Patients improving clinically tended to have the highest bronchial sensitivity to histamine (Table 1). By additional analysis of the non-hyposensitized patients it was not possible to demonstrate similar connections between pre-treatment bronchial sensitivity to Dp or occurrence of late reactions, and the improvement in Dp-sensitivity or in clinicEii symptoms. For patients showing a general clinical improvement, the mean titre of Dp allergen in mattress dust was 32, equivalent to 1,000 mites/g fine dust (5). This was 5-6 times higher than in mattresses of unchanged or deteriorated patients, but variation was extensive {P = 0.1). In contrast, in the control group the spontaneous clinical improvement tended to be most pronounced in patients with low allergen exposure. Change in bronchial Dp-sensitivity was totally unrelated to the Dp-exposure. Patients classified according to either their clinical change or their change in Dp-sensitivity did not differ with regard to pre-treatment nasal, conjunctival or skin sensitivity to Dp, Dpspecific IgE, IgG, IgGl, IgG2, IgGj, IgG^, or to age, duration of pulmonary symtoms, pulmonary scores, Pj'^go'^ist consumption, or use of inhaled steroids. DISGUSSION The present study is the first prospective controlled study on HS with house dust mite allergens in asthmatics to demonstrate better thera14*
211
peutic effects in highly Dp-sensitive individuals compared with patients with a clearly demonstrated but less pronounced sensitivity. Previously, high pre-treatment nasal sensitivity to Dp-extract in rhinitis patients was correlated to improvement in nasal Dp-sensitivity and in symptoms (3). However, in an early study demonstrating effect of HS with house dust, this was not correlated to pre-treatment bronchial sensitivity (7). Results from HS with other allergens have been similarly conflicting, demonstrating correlations to pre-treatment allergen sensitivity in some (2, 6), but not in others (4). The course of the asthma disease is fluctuating due to known and unknown mechanisms, and the higher improvement rate seen in more severely afflicted patients might have reflected simply a regression towards the mean. In the present study this explanation was, however, less likely, since the improvement seen in nonhyposensitized patients was correlated neither to initial bronchial Dp or histamine sensitivity nor to the occurrence of late-phase bronchial reactions. As proposed (H), the better effect in the most sensitive patients might be ascribed to a much higher allergen stimulation received relative to their sensitivity - than in patients with low sensitivity. Disappointingly, the majority of parameters tested did not contain any information useful in selecting patients readily benefiting clinically from HS. The asthma disease is, however, influenced by severail factors not related to HS, as reflected in the high proportion of patients reporting spontaneous clinical improvement when followed for 2 years (8). Even with these problems, a trend was in fact demonstrated in the present study towards a better clinical effect in patients with extreme bronchial sensitivity to Dp and histamine. This trend supported the significant correlations demonstrated for the change in Dp-specific bronchial sensitivity. In conclusion, HS with Dp-extract should be given preferentially to patients with high bronchial Dp-sensitivity and late-phase bronchial reactions. The study does not support the idea of restricting therapy to young patients or to patients with almost normal basic lung function (1, 10).
212
H. MOSBECH
REFERENCES 1. Bousquet, J., Hejjaoui, A., Clauzel, A.-M., et al.: Specific immunotherapy with a standardized Dermatophagoides pteronyssinus extract. II. Prediction of efficacy of immunotherapy. J. Allergy Clin. Immunol. 82, 971-977, 1988. 2. Bucur, J., Dreborg, S., Einarsson, R., Ljungstedt-Pahlman, I., Nilsson, J.-E. & Persson, G.: Immunotherapy with dog and cat allergen preparations in dog-sensitive and cat-sensitive asthmatics. Ann. Allergy 62, 355-361, 1989. 3. D'Souza, M. F., Pepys, J., Wells, I. D., et al.: Hyposensitization with Dermatophagoides pteronyssinus in house dust allergy: a controlled study of clinical and immunological effects. Clin. Allergy 3, 177-193, 1973. 4. Dreborg, S., Agrell, B., Foucard, T., Kjellman, N.-I. M., Koivikko, A. & Nilsson, S.: A double-blind, multicenter immunotherapy trial in children, using a purified and standardized Cladosporium herbarum preparation. I. Clinical results. Allergy 41, 131-140, 1986. 5. Lind, P., Korsgaard, J. & Lcwenstein, H.: Detection and quantitation of Dermatophagoides in house-dust by immunochemical techniques. Allergy 34, 319-327, 1979. 6. Mailing, H.-J., Dreborg, S. & Weeke, B.: Diagnosis and immunotherapy of mould allergy. VL IgE-mediated parameters during a one-year placebo controlled study of immunotherapy with Cladosporium. Allergy 42, 305-314, 1987.
7. McAUen, M. K.: Bronchial sensitivity testing in asthma. An assessment of the effect of hyposensitization in house-dust and pollen-sensitive asthmatic subjects. Thorax 16, 30-35, 1961. 8. Mosbech, H., Dreborg, S., Frolund, L., et al.: Hyposensitization in asthmatics with mPEG modified and unmodified house dust mite extract. I. Clinical effect evaluated by diary cards and a retrospective assessment. Allergy 44, 487-498, 1989. 9. Mosbech, H., Dreborg, S., Frolund, L., et al.: Hyposensitization in asthmatics with mPEG modified and unmodified house dust mite extract. IL Effect evaluated by challenges with allergen and histamine. Allergy 44, 499-509, 1989. 10. Perrin, L. F., Scroussi, J., Cea-Gil, F., Deviller, P. & Lasne, Y.: Serum IgE levels and specific IgE antibodies in house dust mite allergy: predictive value. J. Asthma 20, 93-96, 1983. 11. 0sterballe, O.: Nasal and skin sensitivity during immunotherapy with two major allergens 19, 25 and partially purified extract of timothy grass pollen. Allergy 37, 169-177, 1982. Address: Holger Mosbech, M.D.
Medical Department TTA Allergy Unit 7511 State University Hospital Tagensvej 20 DK-2200 Copenhagen N Denmark
