Archives of Disease in Childhood, 1976, 51, 905.
Significance of late reactions after bronchial challenge with house dust mite J. 0. WARNER From the Respiratory Unit, The Hospitalfor Sich Children, Great Ormond Street, London Warner, J. 0. (1976). Archives of Disease in Childhood, 51, 905. Significance of late reactions after bronchial challenge with house dust mite. Sixty-nine children with moderately severe perennial asthma were submitted to bronchial provocation tests using aqueous extracts of Dermatophagoides pteronyssinus (house dust mite). 60 (87%) had immediate positive reactions. 73% also had late reactions occurring 4 to 8 hours after the challenge. A significant correlation was found between frequent attacks of asthma in the year before bronchial challenge and the occurrence of late reactions. The late reaction was more prolonged and severe than the immediate reaction. The changes in lung mechanics during a late reaction were similar to those found in severe naturally occurring asthma. The possible relevance of the late reaction in antigen-induced asthma is discussed.
BPTs are rarely considered to be an essential part of the investigation of bronchial asthma in childhood. There are misgivings about the safety of such procedures (Bristow, 1974). The specificity of the reactions is doubted in a disease where nonspecific airways lability is a frequent problem. It is also possible that hypersensitivity or primary sensitization might be produced by the test. However, in a situation where major family upheaval is often necessary to achieve adequate antigen avoidance, or where hyposensitization is contemplated, clinical histories and prick skin testing are inadequate methods of allergen identification (Aas, 1970; Spector and Farr, 1974). Unfortunately BPTs neither mimic the conditions which occur during natural allergen exposure
BPT:
PEF:
FEV0.7:
FVC: TGV: RV: TLC: SGaw:
Abbreviations bronchial provocation tests peak expiratory flow forced expiratory volume at 075 s forced vital capacity thoracic gas volume residual volume total lung capacity specific conductance
Received 1 April 1976.
(Kim, 1965; Bronsky and Ellis, 1969), nor produce a reaction which could be equated with severe asthmatic attacks (Engstr6m, 1964). However, pulmonary allergy may be associated with immediate and late responses to the inhalation of allergens (Pepys, 1973) and the relevance of these two reactions to symptoms in different diseases is not clear. Bronchial responses to direct Dermatophagoides pteronyssinus (house dust mite) challenge were studied to investigate the relevance of late reactions in childhood asthma, and to answer some of the criticisms of BPTs. Methods D. pteronyssinus provocation test solutions. The test solutions of D. pteronyssinus were kindly supplied by Bencard Ltd. 1-2 g of mite raw material (mite bodies and excreta) were extracted into 100 ml glycerinated extraction medium, dialysed, concentrated under vacuum, reconstituted as a glycerinated extract, and sterilized by filtration. Quality control tests included measurement of protein nitrogen and polysaccharide, skin test activity compared with freezedried standards in sensitive human volunteers, and tests for acute toxicity by intraperitoneal injection into mice and for irritancy by intradermal injection in guinea pig skin. Serial dilutions of the extract were prepared aseptically diluting in sterile 0 5% phenol saline. Three strengths, 0 001%, 0 * 01%, and 0 1% were dispensed in 10 ml amber vials and stored at 4°C. A single batch was used throughout. 905
J. O. warner
906
Bronchial provocation test. The allergen extracts were inhaled through a mouth piece after nebulization by a Wright nebulizer, containing 2 ml of fluid, with an from an air cylinder. Expired air, airflow of 8 containing allergen, was removed from the room by a closed circuit to an extractor fan system, so that the room atmosphere was not contaminated by the allergen. Children were admitted to hospital 24 hours before
I/min
Patients Sixty-nine children (51 males, 18 females) between the ages of 5 and 14 years completed the tests. All had been selected from medical clinics in the hospital as having asthma of sufficient severity to warrant further investigation and treatment. All had at least 6 attacks of wheezing per year and none was satisfactorily controlled on bronchodilators alone; 38 were on prophylactic disodium cromoglycate and 17 on inhaled steroid preparations. All had perennial asthma with a predominance of nocturnal attacks. 34 had coexistent eczema and 42 had symptoms suggestive of allergic rhinitis (11 seasonal, 31 perennial). 10 additional children did not complete the tests because they had positive reactions to the control solution (0 500 phenosaline) and were excluded; none reacted to the mite culture medium.
the procedure so that bronchodilators, antihistamines, disodium cromoglycate, and occasionally inhaled steroids, could be discontinued in a stable environment where there was no further exposure to the house mite (Sarsfield, 1974). PEF measurements, using a Wright Peak Flow Meter, were recorded hourly during waking hours for comparison with similar readings after provocation (to establish a stable baseline record). The BPT only proceded if the baseline PEF was greater than 50% of the normal value. Clinical histories were obtained from the parents at Results the time of admission using a standard questionnaire. Patients were selected for study because they had a Sixty (87%) of the 69 patients completing the history suggestive of house mite allergy. The children tests had an immediate bronchial sensitivity to were prick skin tested with the different dilutions of the D. pteronyssinus. None of the 69 children reacted D. pteronyssinus extract and the highest concentration to the control solutions. 9 had no bronchial rewhich failed to elicit a skin reponse was used as the starting dose for inhalation. Each patient had two 5- sponse to D. pteronyssinus, but 5 had positive reminute control inhalations, one with 0 5% phenol sponses to other allergens (1 to cat fur, 2 to Timothy saline and the second with an extract of the mite culture grass pollen, 1 to Alternaria mould, and 1 to medium. Provided there was no response to these in- Cladosporium mould). 4 of the negative D. halations, the allergen extracts were then inhaled first pteronyssinus BPT patients had positive prick skin for 1 minute and, if no response after 20 minutes, for tests to the standard 1 * 2% skin testing solution and 5 minutes, in increasing concentrations until the top only 3 of these reacted to the 0a 1% dilution. dose was reached or a positive response obtained. Only 5 positive BPT patients had negative skin Patients with a negative bronchial response to D.pteronys- responses to the 0 1% dilution (Table I). The sinus were challenged with a further allergen selected on correlation between skin test and BPT result the basis ofthe skin test results. Each inhalation was followed by a 20-minute interval was 94%. Many children had a late skin response to 1 2% to allow detection of a response, a fall in PEF of 20% or greater at both 10 and 20 minutes after inhalation being D. pteronyssinus solution and occasionally to 0 1% considered positive. After a positive reaction various but not to the more dilute solutions, with indurarespiratory function parameters were measured at frequent tion and erythema developing at the site of the intervals for the next 24 hours before the patient was immediate response 3 to 4 hours after it had disdischarged. FEV0.75 and VC were measured using the appeared. 24 of 39 (62%) patients had late skin Vitalograph, and TGV, RV, TLC, and SGaw were reactions and all these had positive BPTs to D. measured by total body plethysmograph (DuBois et al., 1956). The results are presented as changes from pteronyssinus. 36 (73%) of the 49 children with baseline expressed as a percentage of the normal pre- positive BPTs to D. pteronyssinus also had late dicted values for height using our own published normal bronchial reactions beginning 4 to 8 hours after inhalation challenge and lasting for at least 12 hours. data (Cogswell et al., 1975).
TABLE I D. pteronyssinus prick skin test threshold in bronchial provocation positive and negative children Skin test threshold dilution giving a positive reaction (%) 0001 Bronchial provocation positive Bronchial provocation negative
7 0
001
01
1 2
31 0
17 3
5 1
Skin test negative at all dilutions 0 5
Signmficance of late reactions after bronchial challenge with house dust mite In addition, 4 of 9 patients who continued inhaled steroids on the day they were tested had late reactions. There was a significant correlation (P
Significance of late reactions after bronchial challenge with house dust mite J. 0. WARNER From the Respiratory Unit, The Hospitalfor Sich Children, Great Ormond Street, London Warner, J. 0. (1976). Archives of Disease in Childhood, 51, 905. Significance of late reactions after bronchial challenge with house dust mite. Sixty-nine children with moderately severe perennial asthma were submitted to bronchial provocation tests using aqueous extracts of Dermatophagoides pteronyssinus (house dust mite). 60 (87%) had immediate positive reactions. 73% also had late reactions occurring 4 to 8 hours after the challenge. A significant correlation was found between frequent attacks of asthma in the year before bronchial challenge and the occurrence of late reactions. The late reaction was more prolonged and severe than the immediate reaction. The changes in lung mechanics during a late reaction were similar to those found in severe naturally occurring asthma. The possible relevance of the late reaction in antigen-induced asthma is discussed.
BPTs are rarely considered to be an essential part of the investigation of bronchial asthma in childhood. There are misgivings about the safety of such procedures (Bristow, 1974). The specificity of the reactions is doubted in a disease where nonspecific airways lability is a frequent problem. It is also possible that hypersensitivity or primary sensitization might be produced by the test. However, in a situation where major family upheaval is often necessary to achieve adequate antigen avoidance, or where hyposensitization is contemplated, clinical histories and prick skin testing are inadequate methods of allergen identification (Aas, 1970; Spector and Farr, 1974). Unfortunately BPTs neither mimic the conditions which occur during natural allergen exposure
BPT:
PEF:
FEV0.7:
FVC: TGV: RV: TLC: SGaw:
Abbreviations bronchial provocation tests peak expiratory flow forced expiratory volume at 075 s forced vital capacity thoracic gas volume residual volume total lung capacity specific conductance
Received 1 April 1976.
(Kim, 1965; Bronsky and Ellis, 1969), nor produce a reaction which could be equated with severe asthmatic attacks (Engstr6m, 1964). However, pulmonary allergy may be associated with immediate and late responses to the inhalation of allergens (Pepys, 1973) and the relevance of these two reactions to symptoms in different diseases is not clear. Bronchial responses to direct Dermatophagoides pteronyssinus (house dust mite) challenge were studied to investigate the relevance of late reactions in childhood asthma, and to answer some of the criticisms of BPTs. Methods D. pteronyssinus provocation test solutions. The test solutions of D. pteronyssinus were kindly supplied by Bencard Ltd. 1-2 g of mite raw material (mite bodies and excreta) were extracted into 100 ml glycerinated extraction medium, dialysed, concentrated under vacuum, reconstituted as a glycerinated extract, and sterilized by filtration. Quality control tests included measurement of protein nitrogen and polysaccharide, skin test activity compared with freezedried standards in sensitive human volunteers, and tests for acute toxicity by intraperitoneal injection into mice and for irritancy by intradermal injection in guinea pig skin. Serial dilutions of the extract were prepared aseptically diluting in sterile 0 5% phenol saline. Three strengths, 0 001%, 0 * 01%, and 0 1% were dispensed in 10 ml amber vials and stored at 4°C. A single batch was used throughout. 905
J. O. warner
906
Bronchial provocation test. The allergen extracts were inhaled through a mouth piece after nebulization by a Wright nebulizer, containing 2 ml of fluid, with an from an air cylinder. Expired air, airflow of 8 containing allergen, was removed from the room by a closed circuit to an extractor fan system, so that the room atmosphere was not contaminated by the allergen. Children were admitted to hospital 24 hours before
I/min
Patients Sixty-nine children (51 males, 18 females) between the ages of 5 and 14 years completed the tests. All had been selected from medical clinics in the hospital as having asthma of sufficient severity to warrant further investigation and treatment. All had at least 6 attacks of wheezing per year and none was satisfactorily controlled on bronchodilators alone; 38 were on prophylactic disodium cromoglycate and 17 on inhaled steroid preparations. All had perennial asthma with a predominance of nocturnal attacks. 34 had coexistent eczema and 42 had symptoms suggestive of allergic rhinitis (11 seasonal, 31 perennial). 10 additional children did not complete the tests because they had positive reactions to the control solution (0 500 phenosaline) and were excluded; none reacted to the mite culture medium.
the procedure so that bronchodilators, antihistamines, disodium cromoglycate, and occasionally inhaled steroids, could be discontinued in a stable environment where there was no further exposure to the house mite (Sarsfield, 1974). PEF measurements, using a Wright Peak Flow Meter, were recorded hourly during waking hours for comparison with similar readings after provocation (to establish a stable baseline record). The BPT only proceded if the baseline PEF was greater than 50% of the normal value. Clinical histories were obtained from the parents at Results the time of admission using a standard questionnaire. Patients were selected for study because they had a Sixty (87%) of the 69 patients completing the history suggestive of house mite allergy. The children tests had an immediate bronchial sensitivity to were prick skin tested with the different dilutions of the D. pteronyssinus. None of the 69 children reacted D. pteronyssinus extract and the highest concentration to the control solutions. 9 had no bronchial rewhich failed to elicit a skin reponse was used as the starting dose for inhalation. Each patient had two 5- sponse to D. pteronyssinus, but 5 had positive reminute control inhalations, one with 0 5% phenol sponses to other allergens (1 to cat fur, 2 to Timothy saline and the second with an extract of the mite culture grass pollen, 1 to Alternaria mould, and 1 to medium. Provided there was no response to these in- Cladosporium mould). 4 of the negative D. halations, the allergen extracts were then inhaled first pteronyssinus BPT patients had positive prick skin for 1 minute and, if no response after 20 minutes, for tests to the standard 1 * 2% skin testing solution and 5 minutes, in increasing concentrations until the top only 3 of these reacted to the 0a 1% dilution. dose was reached or a positive response obtained. Only 5 positive BPT patients had negative skin Patients with a negative bronchial response to D.pteronys- responses to the 0 1% dilution (Table I). The sinus were challenged with a further allergen selected on correlation between skin test and BPT result the basis ofthe skin test results. Each inhalation was followed by a 20-minute interval was 94%. Many children had a late skin response to 1 2% to allow detection of a response, a fall in PEF of 20% or greater at both 10 and 20 minutes after inhalation being D. pteronyssinus solution and occasionally to 0 1% considered positive. After a positive reaction various but not to the more dilute solutions, with indurarespiratory function parameters were measured at frequent tion and erythema developing at the site of the intervals for the next 24 hours before the patient was immediate response 3 to 4 hours after it had disdischarged. FEV0.75 and VC were measured using the appeared. 24 of 39 (62%) patients had late skin Vitalograph, and TGV, RV, TLC, and SGaw were reactions and all these had positive BPTs to D. measured by total body plethysmograph (DuBois et al., 1956). The results are presented as changes from pteronyssinus. 36 (73%) of the 49 children with baseline expressed as a percentage of the normal pre- positive BPTs to D. pteronyssinus also had late dicted values for height using our own published normal bronchial reactions beginning 4 to 8 hours after inhalation challenge and lasting for at least 12 hours. data (Cogswell et al., 1975).
TABLE I D. pteronyssinus prick skin test threshold in bronchial provocation positive and negative children Skin test threshold dilution giving a positive reaction (%) 0001 Bronchial provocation positive Bronchial provocation negative
7 0
001
01
1 2
31 0
17 3
5 1
Skin test negative at all dilutions 0 5
Signmficance of late reactions after bronchial challenge with house dust mite In addition, 4 of 9 patients who continued inhaled steroids on the day they were tested had late reactions. There was a significant correlation (P
