From the Department of Allergology, First Medical Service, Sahlgrenska sjukhuset, 413 4 5 Gsteborg, Sweden Changes in the Course and Treatment of Asthma During a Decade, 1968 - 1978 BY Hans Formgren
Introduction Although there are great differences in details, the principles for treatment of bronchial asthma are actually the same today as ten years ago. The treatment is directed against a symptom-complex, a dysfunction of the regulation of bronchomotor tone with an increased responsiveness of the airways. The cause of this dysfunction varies and therefore the treatment cannot be standardized. Whilst this is obvious it must be kept in mind; therapy
of asthma is therefore by no means a pure pharmacological question (Table I). Air pollution can cause irritation and bronchoconstriction, asthmatics as a group are even more susceptible to the effects of air pollution (LOPEZ & SALVAGGIO 1978). Avoiding bronchial irritants and allergens is today even more difficult than ten years ago.
Table I. 1. 2.
3. 4.
5. 6. 7.
Elimination of allergens and bronchoirritants Prevention therapy Specific therapy - immunotherapy Symptomatic therapy a. Sympathomimetics b. Theophylline derivatives c. Corticosteroids d. Expectorants e. Antibiotics Physiotherapy Psychotherapy Information and education of the patient 54
Allergy is an important cause of asthma in childhood and in young adults.
chronic condition just like diabetes or hypertension (ENGSTRBM et al. 1978).
Although we have got much improved diagnostic measures regarding allergy, immunotherapy of asthma is still often disappointing, i.e. due to impure allergen extract.
The symptomatic treatment of asthma with drugs is today fundamentally the same as ten years ago though important modifications have been made.
Prophylactic treatment with drugs was an almost unknown concept until about ten years ago when Disodiumcromoglycate was introduced (COX 1967; ALTOUNYAN 1967; HARGREAVE et al. 1968). Since then numerous publications have documented the value of the drug in the prophylaxis of allergen-induced and excerciseinduced asthma, especially in children. The drug is, however, without value in most cases of the intrinsic - not IgE mediatedtype of asthma (ELGEFORS & FORMGREN 1970). Inhalation of the powder by the spinhaler is an unpractical mode of administration, especially in adults, and is a great drawback. Oral antiallergic drugs are presently under development and may be of value in the prophylaxis of asthma (LUWHAGEN et al. LUWHAGEN & LINDHOLM 1977). The policy in treatment is increasingly directed towards prophylaxis of attacks with the realization that the disease is a 55
Bronchodilating drugs Ephedrine and other non-selective beta-receptor agonists have in many countries been replaced by selective P2-receptor agonists. Only in the less developed countries ephedrine is still the dominating oral drug for asthma - for ecomomic reasons. Ephedrine is a very cheap substance in cpntrast to the B2-receptor stimulants. The oral P2-receptor stimulants salbutamol and terbutaline are both accepted in the first line, basic symptomatic treatment for asthma, and are superior to ephedrine (WILSON et al. 1976). The main drawback is the unpredictably occurring skeletal muscle tremor (FORMGREN 1975), which sometimes makes regular use hard. Therefore oral treatment is often replaced or combined with regular prophylactic aerosol treatment. The milder form of asthma can often be controlled by regular aerosol treatment (FORMGREN 1977).
Another new approach in the treatment of the more severe forms of asthma is high-dose inhalation therapy with salbutamol or terbutaline given with a nebulizer at home. Thereby the need for emergency treatment and hospitalization has diminished considerably. In pediatric practice this form of high-dose inhalation treatment of acute asthma has to a great extent replaced subcutaneous sympathomimetic therapy with adrenaline or terbutaline. In the treatment of severe asthma in hospital high., dose inhalation therapy with nebulizer or intermittent positive pressure breathing administered by a nebulizer with salbutamol or terbutaline, in combination with physiotherapy, has become routine in the clearingup of the bronchii. Theophylline is still a valuable drug in severe asthma, mainly given intravenously as injections or in drip. The drug is, however, hazardous if given in such high doses as recommended recently (PIAFSKY & OGILVIE 1975) if plasma concentrations are not monitored regularly. The drug acts synergistically with Breceptor agonists (SVEDMYR et al. 1977). This is the rationale for its oral use in combination with BZ-stimulants. Especially in patients who cannot tolerate 56
oral BZ-receptor stimulants theophylline is useful as it potentiates the effect of regular aerosol treatment with these drugs. Theophylline has thus got a more rational basis for use than hitherto. The number of synonyms in Sweden, both among sympathomimetic drugs and theophylline preparations, has diminished considerably. Corticosteroids are still necessary in the more severe cases of asthma, but the mode of use has changed considerably. In spite of the fact that the indication for steroids in asthma has not changed, introduction of steroid treatment is no longer so ominous with beclomethasone diproprionate (BDP), as patients usually can abandon steroids without trouble, when getting better. It has been shown that the need for corticosteroids was diminished by regular use of terbutaline (FORMGREN 1971, 1975) and furthermore disodiumcromoglycate also has a steroid sparing effect (ENGSTROM & KRAEPELIN 1971; ARNER et al. 1971).
BDP was introduced as the first steroid aerosol without resorptive effects in doses which gave a substantial relief of asthma symptoms. A great number of studies have shown that oral
steroids can be replaced by BDPinhalation or that the need of steroids diminishes (ERIKSSON et al. 1975 a, b; DASH 1974; CAMPBELL 1975). Furthermore, in the cases with withdrawal symptoms, regular BDP-inhalation has made alternate day oral steroid administration possible.
has decreased because they have very little documented therapeutic value. We have no better rationale to use expectorants than the traditional one. The widespread use of bromhexidine is more a result of successful marketing than of proven therapeutic effect and need.
The use of corticosteroids in the treatment of acute asthma and in status asthmatics has not changed much. Hydrocortisone, however, has been almost abandoned and replaced by betamethasone, mainly for practical and economic reasons, but partly as betamethasone has less mineral-corticoid effects with less water retention and less risk for potassium deprivation (ERIKSSON et al. 1972). ACTH has almost been abandoned in asthma therapy except in children as ACTH does not affect the height and skeletal maturation (TARANGER et al. 1973). The use of expectoratant drugs
The use of antibiotics has not changed much during the past decade. The main achievement is the introduction of cephalosporines and trimetoprim-sulfa. They have, however, not influenced the therapy of asthma on the whole. Own long-term studies of the course and therapy of chronic asthma. A group of patients with chronic asthma has been followed regularly for more than 12 years on regular symptomatic treatment. The patient material is presented in Table 11. During 1968-1969
Table 11.
-
1968
Number of patients Male/female Mean age (years) Range Longterm oral steroids Retired from work Dead
51
17/34 52 17-75 43 20
-
57
1969
1978 41 12/29 59.6 30-85 28 21 9
after an asthma duration of on average 1 2 years (range 4-50 years) the €ormer bronchodilating therapy consisting of compound ephedrine-theophylline tablets was replaced by regular oral terbutaline medication 5 mg t i d. They were then thoroughly followed for another 32 months' period. The results of this study have earlier been published elsewhere (FORMGREN 1975). Since then the patients have been continously controlled and treated at our department. In order to make a careful study of the course of the asthma, the changes in treatment and the severity of their asthma, these patients were followed-up in September 1978, i.e. ten years after the institution of terbutaline. Methods Case histories of the patients were reviewed with special emphasis on the drugs and doses used during the last twelve months. Furthermore the severity of the asthma was estimated and concomittant diseases taken into account. Spirometry (Vitalograph) was made in all patients still living in the area. Four patients have moved and nine have died from intercurrent diseases during the decade. 58
Results The present drug treatment is summarized in Table 111. 8 0 % of the patients still need longterm steroid treatment. However, the dose regimen of the steroid has altered. 25 % of the patients still needing oral corticosteroids now can manage on an alternate day regimen. The remaining patients on oral steroids (except one) are on one morning dose daily. Eight patients use prednisolone alone on an average dosage of 4 . 4 mg (+ 1.7) per day and 20 take BDP regularly in addition to prednisolone (average dosage of 6.0 mg (+ 3.1). Six patients have been successfully transferred to BDP. The oral prednisolone dosage has thus been reduced from 9.0 5 3.5 mg 1968-1978, to an average of 5.5 2.8 mg, i.e. by 39 %The . changed pattern of steroids is shown in Fig. 1. Of the 41 patients, 35 are still on regular oral B2-stimulants and four have preferred to return to compound (ephedrine-theophylline) bronchodilating tablets. Thirtythree patients use P2stimulating aerosols on a regular basis, 15 % terbutaline, 16 % salbutamol and 9 % fenoterol. Six patients of the 41 use the aerosol as the only antiasthmatic therapy. In eight patients the asthma is only occasionally
Table 111. Drug treatment of asthma 1978
Steroid dependent Single dose daily (oral) Alternate day therapy (oral) Oral steroids only BDP + oral steroids BDP No steroids
Number 33/41 20/28 7/28 8/33 20/33 6/33 7/41
80 71 25 24 61 18 17
Oral terbutaline Oral salbutamol Compound asthma tab1
34/41 1/41 4/41
83 2.4 10
Inhaled terbutaline Inhaled salbutamol Inhaled fenoterol.
5/33 25/33 3/33
15 76 9
6/4 1 6/41 8/41
15 15 20
" Pari 'I - nebu 1iz er at home No oral medication No therapy
present and no regular therapy is needed. Of the 41 patients with chronic disabling asthma 2 0 % have thus been "cured". Lung function Spirometry was carried out in 35 patients maintained on their normal every day treatment. They showed a varying degree of actual airway obstruction and responded to four inhalations of salbutamol. In no case was there any indication of tolerance to the bronchodilating effect, with the exception of the patients without spirometric evidence of actual broncho59
%
% % % % %
% % % % % %
% % % %
constriction in relation to predicted normal value or FEVlSO/FVC ratio (Table IV). No patient gave any history of lack of response to their inhaler or their oral B2-stimulants.
Table IV FEVlS0 values within pred. n.v. after aerosol
F E V 1 - O values within pred. n.v. before aerosol FEVl. 0
n before after %
13 2.47 2.61 5.6
S.D.
FEVl.0 10 1.74 2.11 24.1
0.55
0.66 5.2
S.D.
0.65 0.70 2 17
70-
FEVlS0 values below 2 S . D . of pred. n.v. FEVl. 0 12 1.20 1.42 19.3
S.D.
0.44 0.49 14 - 7
0 0 92.5rng
C l -2.5 55.0 D >5,0 s7,5
60-
-7.5
50-
SIO
mg
‘0
mg mg
I0
a>10 $20 mg
“41
10
30
30
20-
?*
10-
.I0
0-
1968 - 69 n-51 Prednisolone dosage mg day
30 f 346
P 1971-72 n = 51
7 3 5 f 345
1978 n41
5,54Q/a
Figure 1. The changing pattern of corticosteroid need and dosage during a decade in 51 asthmatic patients. 1968 before the use of terbutaline, 1971-72 after regular daily oral terbutaline therapy but before institution of beclometasonediproprionate (BSP) inhalation. 1978 patients show a considerably reduced need for oral steroids when on regular BSP inhalations. 60
Discussion In spite of the lack of a control patient yroup, the following conclusions can be drawn from this exceptionally long surveillance study. The regular use of oral D2-stimulants is a safe medication with beneficial effect on the course of asthma. No signs of resistance have been noted - no tendency of increasing the dose has been noted throughout the years. No reports of lessened effect of the dose aerosol have been noted. The need for oral corticosteroids has diminished significantly. Beclomethasone diproprionate aerosol has made it possible to institute alternate day regimen in the majority of the patients needing oral steroids. Oral steroids can in some patients be completely replaced by beclomethasone diproprionate inhalation. Some patients with chronic asthma who for years have had a documented need for regular therapy, can be "cured" by longterm vigorous therapy by B2-stimulants and BDP given prophylactically and become virtually symptom free. In about 20 %, therapy can be omitted totally without recurrent symptom of asthma which, to the author's knowledge, has not been reported earlier.
61
In summary, the newer drugs, i.e. D2-receptor stimulants and BDP, have been shown to be a great advance, and a substantial improvement of the prognosis of severe asthma has been achieved.
References Altounyan, R.: Inhibition of experimental asthma by a new compound. - Disodiumcromoglycate "Intal" Acta Allergol. 1967, 22, 487.
.
Arner, B., B. Berg, A . Bertler & S.G.O. Johansson: Steroid sparing effect of disodiumcromoglycate in chronic bronchial asthma. Acta Allergol. 1971, 2 , 383-399.
Campbell, I.A.: Inhaled corticosteroids compared with oral prednisone in patients starting long term corticosteroid therapy for asthma. Lancet, 1975, 2, 469-473
Cox, J.S.G.: Disodium cromoglycate (FPL 670) ("Intal): a specific inhibitor of reaginic antibody - antigen mechanisms. Nature (Lond.) 1967, 216, 1328-1329.
Dash, C.H.: Some observations on the use of corticosteroid aerosols in asthma. Postgrad. Med. J. 1974, 3,Suppl 4, 25-32
Elgefors, B. & H. Formgren: Disodium cromoglycate (Intal, Lomudal) in intrinsic asthma. Acta Allergol. 1970, 2,374-381.
Formgren, H.: Experiences of longterm treatment of asthma with terbutaline. Acta Allergal. 1971, 26, 81-89.
Engstrem, I. & S . Kraepelin: The corticoid sparing effect of disodium cromoglycate in children and adolescents with bronchial asthma. Acta Allergol. 1971, 26, 90-100.
Formgren, H.: The therapeutic value of oral long-term treatment with terbutaline (Bricanyl) in asthma. Scand. J. resp. Dis. 1975, 56, 321-328. Formgren, H.: Broncho- and cardioselective P-receptor active drugs in the treatment of asthmatic patients. Scand. J. resp. Dis. 1977, Suppl. 97, 25.
Engstr6m, I., H. Formgren & N. Svedmyr: Symptomatic treatment of asthma in Sweden. Asthma evaluation of drug therapy. A symposium of Glaxo, Sweden. Summary of a panel discussion. Scand. J. resp. D i s . 1977, Suppl 101, 201-208.
Hargreave, F.E., M. Chan & D.S. McCarthy: Inhibitory effects of disodium cromoglycate on allergen-inhalation tests. Lancet, 1968, 2, 134-137.
Eriksson, N.E., H. Formgren & S . Larsson: The infusion treatment of status asthmaticus. Lzkartidningen 1972, 69, suppl 111, 44-49
Lopez, M. & J.E. Salvaggio: Climate - weather - air pollution. A review. In Allergy, Principles and practice, 1978, 2, 965-976. Ed. Middleton, E., C.E. Reed & E.F. Ellis: The C.V. Mosby Company, Saint Louis.
Eriksson, N . E . , S . Lindgren & N. Lindholm: Longterm treatment of steroid-dependent patients with beclomethasone dipropionate. Allergol. et Immunopath. 1975 a, 111, 77-86.
LBwhagen, 0. & N. Lindholm: Bronchial challenge as an experimental model for evaluating anti-allergic drugs. In Asthma Evaluation of drug therapy. A symposium of Glaxo, Sweden. Ed. Berglund, E. and Svedmyr, N. Scand. J. resp. Dis. 1977, Suppl. 101, 43-47.
-
Eriksson, N.E., S . Lindgren & N. Lindholm: A double blind comparison of beclomethasone diproprionate aerosol and predn:solone in asthmatic patients. Postgrad. Med. J. 1975 b, Suppl 4, I , 67-70.
02
Ltjwhagen, O., B. Lindholm, B. Hegardt & N. Svedmyr. To be published. Piafsky, K.M. & R.J. Ogilvie: Dosage of theophylline in bronchial asthma. N. Engl. J. Med. 1975, 292, 1218-1222 Svedmyr, K., I. Mellstrand & N. Svedmyr: A comparison between effects of aminophylline, proxyphylline and terbutaline in asthmatics. Asthma Evaluation of drug therapy. A symposium of Glaxo, Sweden. Scand. J. resp. Dis. 1977, 101, 139-146
-
Taranger, J., K.L. M6ller & B. Bruning: Aspects of linear growth and skeletal maturation in asthmatic children treated with synthetic corticotropine. ACTH - a practical review of progress to date. Int. Symposium, Dubrovnic. Ed. R. Schuppli. 1973, 154-158. Wilson, A.F., H.S. Novey, P. Cloninger, J. Davies & P. White: Cardiopulmonary effects of longterm bronchodilator administration. J. Allergy clin. Immunology 1976, 204-212.
s,
.
63
Introduction Although there are great differences in details, the principles for treatment of bronchial asthma are actually the same today as ten years ago. The treatment is directed against a symptom-complex, a dysfunction of the regulation of bronchomotor tone with an increased responsiveness of the airways. The cause of this dysfunction varies and therefore the treatment cannot be standardized. Whilst this is obvious it must be kept in mind; therapy
of asthma is therefore by no means a pure pharmacological question (Table I). Air pollution can cause irritation and bronchoconstriction, asthmatics as a group are even more susceptible to the effects of air pollution (LOPEZ & SALVAGGIO 1978). Avoiding bronchial irritants and allergens is today even more difficult than ten years ago.
Table I. 1. 2.
3. 4.
5. 6. 7.
Elimination of allergens and bronchoirritants Prevention therapy Specific therapy - immunotherapy Symptomatic therapy a. Sympathomimetics b. Theophylline derivatives c. Corticosteroids d. Expectorants e. Antibiotics Physiotherapy Psychotherapy Information and education of the patient 54
Allergy is an important cause of asthma in childhood and in young adults.
chronic condition just like diabetes or hypertension (ENGSTRBM et al. 1978).
Although we have got much improved diagnostic measures regarding allergy, immunotherapy of asthma is still often disappointing, i.e. due to impure allergen extract.
The symptomatic treatment of asthma with drugs is today fundamentally the same as ten years ago though important modifications have been made.
Prophylactic treatment with drugs was an almost unknown concept until about ten years ago when Disodiumcromoglycate was introduced (COX 1967; ALTOUNYAN 1967; HARGREAVE et al. 1968). Since then numerous publications have documented the value of the drug in the prophylaxis of allergen-induced and excerciseinduced asthma, especially in children. The drug is, however, without value in most cases of the intrinsic - not IgE mediatedtype of asthma (ELGEFORS & FORMGREN 1970). Inhalation of the powder by the spinhaler is an unpractical mode of administration, especially in adults, and is a great drawback. Oral antiallergic drugs are presently under development and may be of value in the prophylaxis of asthma (LUWHAGEN et al. LUWHAGEN & LINDHOLM 1977). The policy in treatment is increasingly directed towards prophylaxis of attacks with the realization that the disease is a 55
Bronchodilating drugs Ephedrine and other non-selective beta-receptor agonists have in many countries been replaced by selective P2-receptor agonists. Only in the less developed countries ephedrine is still the dominating oral drug for asthma - for ecomomic reasons. Ephedrine is a very cheap substance in cpntrast to the B2-receptor stimulants. The oral P2-receptor stimulants salbutamol and terbutaline are both accepted in the first line, basic symptomatic treatment for asthma, and are superior to ephedrine (WILSON et al. 1976). The main drawback is the unpredictably occurring skeletal muscle tremor (FORMGREN 1975), which sometimes makes regular use hard. Therefore oral treatment is often replaced or combined with regular prophylactic aerosol treatment. The milder form of asthma can often be controlled by regular aerosol treatment (FORMGREN 1977).
Another new approach in the treatment of the more severe forms of asthma is high-dose inhalation therapy with salbutamol or terbutaline given with a nebulizer at home. Thereby the need for emergency treatment and hospitalization has diminished considerably. In pediatric practice this form of high-dose inhalation treatment of acute asthma has to a great extent replaced subcutaneous sympathomimetic therapy with adrenaline or terbutaline. In the treatment of severe asthma in hospital high., dose inhalation therapy with nebulizer or intermittent positive pressure breathing administered by a nebulizer with salbutamol or terbutaline, in combination with physiotherapy, has become routine in the clearingup of the bronchii. Theophylline is still a valuable drug in severe asthma, mainly given intravenously as injections or in drip. The drug is, however, hazardous if given in such high doses as recommended recently (PIAFSKY & OGILVIE 1975) if plasma concentrations are not monitored regularly. The drug acts synergistically with Breceptor agonists (SVEDMYR et al. 1977). This is the rationale for its oral use in combination with BZ-stimulants. Especially in patients who cannot tolerate 56
oral BZ-receptor stimulants theophylline is useful as it potentiates the effect of regular aerosol treatment with these drugs. Theophylline has thus got a more rational basis for use than hitherto. The number of synonyms in Sweden, both among sympathomimetic drugs and theophylline preparations, has diminished considerably. Corticosteroids are still necessary in the more severe cases of asthma, but the mode of use has changed considerably. In spite of the fact that the indication for steroids in asthma has not changed, introduction of steroid treatment is no longer so ominous with beclomethasone diproprionate (BDP), as patients usually can abandon steroids without trouble, when getting better. It has been shown that the need for corticosteroids was diminished by regular use of terbutaline (FORMGREN 1971, 1975) and furthermore disodiumcromoglycate also has a steroid sparing effect (ENGSTROM & KRAEPELIN 1971; ARNER et al. 1971).
BDP was introduced as the first steroid aerosol without resorptive effects in doses which gave a substantial relief of asthma symptoms. A great number of studies have shown that oral
steroids can be replaced by BDPinhalation or that the need of steroids diminishes (ERIKSSON et al. 1975 a, b; DASH 1974; CAMPBELL 1975). Furthermore, in the cases with withdrawal symptoms, regular BDP-inhalation has made alternate day oral steroid administration possible.
has decreased because they have very little documented therapeutic value. We have no better rationale to use expectorants than the traditional one. The widespread use of bromhexidine is more a result of successful marketing than of proven therapeutic effect and need.
The use of corticosteroids in the treatment of acute asthma and in status asthmatics has not changed much. Hydrocortisone, however, has been almost abandoned and replaced by betamethasone, mainly for practical and economic reasons, but partly as betamethasone has less mineral-corticoid effects with less water retention and less risk for potassium deprivation (ERIKSSON et al. 1972). ACTH has almost been abandoned in asthma therapy except in children as ACTH does not affect the height and skeletal maturation (TARANGER et al. 1973). The use of expectoratant drugs
The use of antibiotics has not changed much during the past decade. The main achievement is the introduction of cephalosporines and trimetoprim-sulfa. They have, however, not influenced the therapy of asthma on the whole. Own long-term studies of the course and therapy of chronic asthma. A group of patients with chronic asthma has been followed regularly for more than 12 years on regular symptomatic treatment. The patient material is presented in Table 11. During 1968-1969
Table 11.
-
1968
Number of patients Male/female Mean age (years) Range Longterm oral steroids Retired from work Dead
51
17/34 52 17-75 43 20
-
57
1969
1978 41 12/29 59.6 30-85 28 21 9
after an asthma duration of on average 1 2 years (range 4-50 years) the €ormer bronchodilating therapy consisting of compound ephedrine-theophylline tablets was replaced by regular oral terbutaline medication 5 mg t i d. They were then thoroughly followed for another 32 months' period. The results of this study have earlier been published elsewhere (FORMGREN 1975). Since then the patients have been continously controlled and treated at our department. In order to make a careful study of the course of the asthma, the changes in treatment and the severity of their asthma, these patients were followed-up in September 1978, i.e. ten years after the institution of terbutaline. Methods Case histories of the patients were reviewed with special emphasis on the drugs and doses used during the last twelve months. Furthermore the severity of the asthma was estimated and concomittant diseases taken into account. Spirometry (Vitalograph) was made in all patients still living in the area. Four patients have moved and nine have died from intercurrent diseases during the decade. 58
Results The present drug treatment is summarized in Table 111. 8 0 % of the patients still need longterm steroid treatment. However, the dose regimen of the steroid has altered. 25 % of the patients still needing oral corticosteroids now can manage on an alternate day regimen. The remaining patients on oral steroids (except one) are on one morning dose daily. Eight patients use prednisolone alone on an average dosage of 4 . 4 mg (+ 1.7) per day and 20 take BDP regularly in addition to prednisolone (average dosage of 6.0 mg (+ 3.1). Six patients have been successfully transferred to BDP. The oral prednisolone dosage has thus been reduced from 9.0 5 3.5 mg 1968-1978, to an average of 5.5 2.8 mg, i.e. by 39 %The . changed pattern of steroids is shown in Fig. 1. Of the 41 patients, 35 are still on regular oral B2-stimulants and four have preferred to return to compound (ephedrine-theophylline) bronchodilating tablets. Thirtythree patients use P2stimulating aerosols on a regular basis, 15 % terbutaline, 16 % salbutamol and 9 % fenoterol. Six patients of the 41 use the aerosol as the only antiasthmatic therapy. In eight patients the asthma is only occasionally
Table 111. Drug treatment of asthma 1978
Steroid dependent Single dose daily (oral) Alternate day therapy (oral) Oral steroids only BDP + oral steroids BDP No steroids
Number 33/41 20/28 7/28 8/33 20/33 6/33 7/41
80 71 25 24 61 18 17
Oral terbutaline Oral salbutamol Compound asthma tab1
34/41 1/41 4/41
83 2.4 10
Inhaled terbutaline Inhaled salbutamol Inhaled fenoterol.
5/33 25/33 3/33
15 76 9
6/4 1 6/41 8/41
15 15 20
" Pari 'I - nebu 1iz er at home No oral medication No therapy
present and no regular therapy is needed. Of the 41 patients with chronic disabling asthma 2 0 % have thus been "cured". Lung function Spirometry was carried out in 35 patients maintained on their normal every day treatment. They showed a varying degree of actual airway obstruction and responded to four inhalations of salbutamol. In no case was there any indication of tolerance to the bronchodilating effect, with the exception of the patients without spirometric evidence of actual broncho59
%
% % % % %
% % % % % %
% % % %
constriction in relation to predicted normal value or FEVlSO/FVC ratio (Table IV). No patient gave any history of lack of response to their inhaler or their oral B2-stimulants.
Table IV FEVlS0 values within pred. n.v. after aerosol
F E V 1 - O values within pred. n.v. before aerosol FEVl. 0
n before after %
13 2.47 2.61 5.6
S.D.
FEVl.0 10 1.74 2.11 24.1
0.55
0.66 5.2
S.D.
0.65 0.70 2 17
70-
FEVlS0 values below 2 S . D . of pred. n.v. FEVl. 0 12 1.20 1.42 19.3
S.D.
0.44 0.49 14 - 7
0 0 92.5rng
C l -2.5 55.0 D >5,0 s7,5
60-
-7.5
50-
SIO
mg
‘0
mg mg
I0
a>10 $20 mg
“41
10
30
30
20-
?*
10-
.I0
0-
1968 - 69 n-51 Prednisolone dosage mg day
30 f 346
P 1971-72 n = 51
7 3 5 f 345
1978 n41
5,54Q/a
Figure 1. The changing pattern of corticosteroid need and dosage during a decade in 51 asthmatic patients. 1968 before the use of terbutaline, 1971-72 after regular daily oral terbutaline therapy but before institution of beclometasonediproprionate (BSP) inhalation. 1978 patients show a considerably reduced need for oral steroids when on regular BSP inhalations. 60
Discussion In spite of the lack of a control patient yroup, the following conclusions can be drawn from this exceptionally long surveillance study. The regular use of oral D2-stimulants is a safe medication with beneficial effect on the course of asthma. No signs of resistance have been noted - no tendency of increasing the dose has been noted throughout the years. No reports of lessened effect of the dose aerosol have been noted. The need for oral corticosteroids has diminished significantly. Beclomethasone diproprionate aerosol has made it possible to institute alternate day regimen in the majority of the patients needing oral steroids. Oral steroids can in some patients be completely replaced by beclomethasone diproprionate inhalation. Some patients with chronic asthma who for years have had a documented need for regular therapy, can be "cured" by longterm vigorous therapy by B2-stimulants and BDP given prophylactically and become virtually symptom free. In about 20 %, therapy can be omitted totally without recurrent symptom of asthma which, to the author's knowledge, has not been reported earlier.
61
In summary, the newer drugs, i.e. D2-receptor stimulants and BDP, have been shown to be a great advance, and a substantial improvement of the prognosis of severe asthma has been achieved.
References Altounyan, R.: Inhibition of experimental asthma by a new compound. - Disodiumcromoglycate "Intal" Acta Allergol. 1967, 22, 487.
.
Arner, B., B. Berg, A . Bertler & S.G.O. Johansson: Steroid sparing effect of disodiumcromoglycate in chronic bronchial asthma. Acta Allergol. 1971, 2 , 383-399.
Campbell, I.A.: Inhaled corticosteroids compared with oral prednisone in patients starting long term corticosteroid therapy for asthma. Lancet, 1975, 2, 469-473
Cox, J.S.G.: Disodium cromoglycate (FPL 670) ("Intal): a specific inhibitor of reaginic antibody - antigen mechanisms. Nature (Lond.) 1967, 216, 1328-1329.
Dash, C.H.: Some observations on the use of corticosteroid aerosols in asthma. Postgrad. Med. J. 1974, 3,Suppl 4, 25-32
Elgefors, B. & H. Formgren: Disodium cromoglycate (Intal, Lomudal) in intrinsic asthma. Acta Allergol. 1970, 2,374-381.
Formgren, H.: Experiences of longterm treatment of asthma with terbutaline. Acta Allergal. 1971, 26, 81-89.
Engstrem, I. & S . Kraepelin: The corticoid sparing effect of disodium cromoglycate in children and adolescents with bronchial asthma. Acta Allergol. 1971, 26, 90-100.
Formgren, H.: The therapeutic value of oral long-term treatment with terbutaline (Bricanyl) in asthma. Scand. J. resp. Dis. 1975, 56, 321-328. Formgren, H.: Broncho- and cardioselective P-receptor active drugs in the treatment of asthmatic patients. Scand. J. resp. Dis. 1977, Suppl. 97, 25.
Engstr6m, I., H. Formgren & N. Svedmyr: Symptomatic treatment of asthma in Sweden. Asthma evaluation of drug therapy. A symposium of Glaxo, Sweden. Summary of a panel discussion. Scand. J. resp. D i s . 1977, Suppl 101, 201-208.
Hargreave, F.E., M. Chan & D.S. McCarthy: Inhibitory effects of disodium cromoglycate on allergen-inhalation tests. Lancet, 1968, 2, 134-137.
Eriksson, N.E., H. Formgren & S . Larsson: The infusion treatment of status asthmaticus. Lzkartidningen 1972, 69, suppl 111, 44-49
Lopez, M. & J.E. Salvaggio: Climate - weather - air pollution. A review. In Allergy, Principles and practice, 1978, 2, 965-976. Ed. Middleton, E., C.E. Reed & E.F. Ellis: The C.V. Mosby Company, Saint Louis.
Eriksson, N . E . , S . Lindgren & N. Lindholm: Longterm treatment of steroid-dependent patients with beclomethasone dipropionate. Allergol. et Immunopath. 1975 a, 111, 77-86.
LBwhagen, 0. & N. Lindholm: Bronchial challenge as an experimental model for evaluating anti-allergic drugs. In Asthma Evaluation of drug therapy. A symposium of Glaxo, Sweden. Ed. Berglund, E. and Svedmyr, N. Scand. J. resp. Dis. 1977, Suppl. 101, 43-47.
-
Eriksson, N.E., S . Lindgren & N. Lindholm: A double blind comparison of beclomethasone diproprionate aerosol and predn:solone in asthmatic patients. Postgrad. Med. J. 1975 b, Suppl 4, I , 67-70.
02
Ltjwhagen, O., B. Lindholm, B. Hegardt & N. Svedmyr. To be published. Piafsky, K.M. & R.J. Ogilvie: Dosage of theophylline in bronchial asthma. N. Engl. J. Med. 1975, 292, 1218-1222 Svedmyr, K., I. Mellstrand & N. Svedmyr: A comparison between effects of aminophylline, proxyphylline and terbutaline in asthmatics. Asthma Evaluation of drug therapy. A symposium of Glaxo, Sweden. Scand. J. resp. Dis. 1977, 101, 139-146
-
Taranger, J., K.L. M6ller & B. Bruning: Aspects of linear growth and skeletal maturation in asthmatic children treated with synthetic corticotropine. ACTH - a practical review of progress to date. Int. Symposium, Dubrovnic. Ed. R. Schuppli. 1973, 154-158. Wilson, A.F., H.S. Novey, P. Cloninger, J. Davies & P. White: Cardiopulmonary effects of longterm bronchodilator administration. J. Allergy clin. Immunology 1976, 204-212.
s,
.
63
