Clinical Allergy, 1977, Volume 7, pages 485-496
Controlled trials with four per cent cromolyn spray in seasonal allergic rhinitis* W. C. POSEY and H. S. NELSON Department of Allergy-CUnical Immunology, Fitzaimons Army Medical Center, Denver, Colorado^ U.S.A.
Summary Thirty-two patients with seasonal allergic rhinitis due to weed pollen were treated beginning prior to the weed pollen season of 1974 with either 4/^ cromolyn sodium or placebo nasal spray. The patients were followed on treatment with symptom diary cards and bi-weekly physician examinations for a period of 10 weeks. Radioallergosorbent (RAST) titres for the major weeds in the Denver area (ragweed, Russian thistle, and sage) were determined before the weed pollen season, and one and three months after the weed pollen season. There was no significant difference in symptom scores between the 4% cromolyn sodium- and placebo-treated groups, nor objective evidence on bi-weekly examinations by a physician to suggest differences in the two groups. Significant differences in favor of the 4% cromolyn-treaicd group were noted in the amount of antihistamines taken for symptomatic relief during the weed pollenating season, suggesting some protective effect ofthe drug. The clinical significance of this finding is not clear. Selecting patients with high baseline RAST titres for one or more of the major weeds did not alter the results of the study. In a second double-blind study twenty-two patients reporting to the allergy clinic with symptomatic seasonal allergic rhinitis due to weeds were randomly assigned to receive 4% cromolyn sodium or placebo nasal spray and followed through the weed pollen season. There was no difference between the two groups in either symptom scores or use of antihistamines for asymptomatic relief. Introduction Cromolyn sodium has been used extensively in the treatment of bronchial asthma since its introduction in England by Altounyan in 1967. Because of its action of blocking immunological release of mediators from mast cells, and its proven cffecliveness in blocking nasal and bronchial challenges as well as in treating reagin-mcdiutcd asthma, it was natural to try cromolyn for the treatment of allergic rhinitis. *The opinions or assertions herein are those of the author and are not to be construed as official or as reflecting the view of Ihe Department of the Air Fore: or Army. Correspondence: Lt Col William C. Posey, Allergy-Clinical Immunology Service (SGH/MAC), Wilford Hall USAF Medical Ccnicr. San Antonio, Texas 78236. U.S.A.
485
486
W. C. Posey and H. S. Nelson
In I%9 Orie and associates reported that the oral inhalation of 1°;', cromolyn sodium solution hlocked the nasal etTects of bronchial antigen challenge. These same authors (Pelikan ei ai., 1970) later reporled that i% cromolyn sodium applied directly to the nasal mucosa blocked nasal antigen challenge. The ability of cromolyn sodium to block nasal antigen challenge was confirmed by Taylor & Shivalkar (1971) using I and 10 mg cromolyn sodium powder. Connell (1972) reported that 4% cromolyn sodium was more elTective than 2",', solution in preventing the expected increase in nasal airways resistance after ragweed nasal challenge in ragweed-sensitive individuals. Clinical trials with cromolyn sodium in seasonal allergic rhinitis have yielded conflicting results. Knight & Underdown (1975) and Leiferman et al. (1975) have reported significant reduction in symptoms of ragweed pollenosis in patients treated with cromolyn sodium powder compared with placebo-treated groups. Because administration of cromolyn powder by nasal insulHator is inconvenient and because there is a question as to how etfectively the drug is distributed over the entire nasal mucosa, several clinical trials have been undertaken to test the effectiveness of 1%. 2% and 4% cromolyn sodium solutions. Blair & Herbert (1973) noted a decided patient and physician preference for 2% cromolyn sodium solution in a double-blind controlled study in forty patients with seasonal allergic rhinitis. Manners & Ezeoke (1973). however, in a similar study involving forty-six patients with seasonal allergic rhinitis could not demonstrate theelfectivenessof 2",, cromolyn sodium nasal solution. This study reports the results of clinical trials with 4" „ cromolyn sodium in patients with summer weed pollenosis., and further compares the results of using the drug prophylactically before the weed pollen season with its use in patients already symptomatic during the weed pollen season. Malerials and methods Selection and testing of patients The study was designed as a double-blind group comparative trial carried out during the ragweed pollen season of 1974. Thirty-four patients participated in the preseasonal study, eighteen males and sixteen females, ranging in age from 12 to 54 years. The patients were selected on the basis of a clear-cut history of acute late summer hay fever symptoms presumably due to weed pollen; all had had symptoms for at least 2 years, with the duration of symptoms ranging from 2 to 40 years. Weed sensitivity was confirmed by titrated skin tests and nasal challenges. The presence of perennial rhinitis, nasal polyps, significant nasal septal deviation or sinusitis was reason for exclusion from the study. Adniinistration of systemic corticosteroids within the preceding 3 months or topical steroids within the preceding month was also reason for exclusion. Previous hyposensitization was not a reason for exclusion but the dose of extract was not altered during the course of the study. Titrated skin tests were performed using glycerinated aqueous extracts of ragweed mix (25% giant ragweed, 25% short ragweed. 25% western ragweed. 25"o burweed marshelder), chenopod mix (50% Russian thistle. 50% kochia) and sage mix (40% common sage, 40";^ white sage, 20";, pasture sage), beginning with an intradernial injection of 0 02 ml of 1:100,000 w/v concentration of each antigen and progressing up to 0-02 ml of I; 100 w/v concentration. A positive reaction consisted of a weal at least 10 mm in diameter within 15 min after injection of the antigen.
Four per cent nasal cromolyn in allergic rhinitis
487
The nasal challenges consisted of spraying 010 ml of serial dilutions of mixed weed extract beginning with 100 PNU/ml and progressing up to a maximum concentration of 10.000 PNU/ml after first obtaining a negative challenge with glycerine -saline diluent control, A positive nasal challenge consisted of the appearance of nasal symptoms within 15 min of the challenge. Patients were carefully paired and assigned to 4% cromolyn sodium solution or placebo solution treatment group on the basis of (a) age; (b) sex; (c) the results of titrated skin tests; (d) the degree of anticipated exposure to weed pollen; and (e) hyposensitization therapy. The pairing of patients was performed by a third party who was also responsible for the packaging and distribution ofthe medication or placebo solutions. Treatment Patients in the active drug group received a solution containing 4% w/v cromolyn sodium with 0 01% disodium edetate and OOI"f, benzylkonium chloride diluted in sterile water in 12 ml glass bottles, for use in a special metered-dose nebulizer delivering approximately 0-13 ml/spray, equivalent to approximately 5 mg cromolyn sodium per spray. The patients in the control group received a placebo solution containing only the preservatives in the same concentration as the active drug solution. The patients were asked to spray each nostril every 3 hr six times a day. Both groups of patients were provided with an antihistamine (4 mg chlorplieniramine maleate tablets) to be taken only as needed for severe hay fever symptoms, and not to exceed six tablets per day Met hoc/ of study Symptom diary cards were provided for each week of the study with patients requested to record separately the severity of eye, throat, and nasal symptoms twice daily, utilizing a scale from 0 to 4, ranging from no symptoms to incapacitating symptoms. Patients were also requested to record the number of times the spray was used each day and the number of antihistamines taken. After a 1 week baseline period the patients began using the spray every 3 hr. Treatment began during the week of July 13, 1974 and concluded 8 weeks later on September 14. Patients were examined and diary cards collected at the end of the baseline and every 2 weeks thereafter. Unused spray and antihistamines were collected and a new supply of each was issued to each patient, and the amount of spray and antihistamines remaining was then measured to check for patient compliance and accuracy of recording of antihistamines in the diary. Pollen counts Semi-quantitative weed pollen counts were obtained daily throughout the study with a Rotoslide sampler, and expressed as the number of weed pollen grains per square centimeter slide surface area. Analysis of serum for specific IgE antibodies Serum samples were obtained from each patient at the start of the study (July 6), at the end of the treatment period (September 14) and 4 weeks after the end of the study (October 11). [gE antibody titres specific for short ragweed (Ambrosia elator), Russian thistle (Salsola pestifer) and sage (Artemesia vulgaris) were measured by the
488
IV. C. Posey and H. S. Nelson
radioallergosorbent (RAST) test. Ragweed-speciTcIgEantibody titres were performed by Dr Gerald Gleich at the Mayo Clinic. Rochester. Minnesota. Russian thistle and sage IgE antibody titres were performed in our own laboratory employing commercially available reagents (Pharmacia Corporation). Serum samples were stored at — 70"C and all three samples were analysed at the same time. Baseline RAST titres to the three weeds were therefore not available for the purpose of pairing patients at the start of the study. The levels of IgE antibody were expressed as the percentage of total added counts bound. A level greater than 5% counts bound was considered indicativeof sensitivity for ragweed. A value that was "clearly positive', i.e. greater than the ' C standards provided by Pharmacia Corporation was considered indicative of sensitivity to Russian thistle and sage. Statistical analysis The effects of treatment for each week of the study with 4% cromolyn sodium vs placebo was compared using two-tailed tests of significance (conlidence limits). Average symptoms scores and the amount of antihistamines used were analysed separately. Differences between the active drug group and the placebo group existing at baseline were corrected by the method of covariate analysis. Patients' and physicians' overall assessment for each group were analysed by the x^ test for frequency data. Coseasona! study A second study was carried out the same summer to evaluate the effectiveness of 4% cromolyn sodium treatment begun following the onset of symptoms of seasonal allergic rhinitis. Twenty-two patients reporting to the allergy clinic with symptomatic hay fever due to weeds were randomly assigned to a 4% cromolyn sodium or placebo treatment group. This was also a double-blind study, and the patients were evaluated and followed in a manner similar to that described for the preseasonal study. However, no attempt was made to produce matched pairs. The patients began using the 4% cromolyn sodium or placebo spray during the week of August 16, 1974. 5 weeks after the patients in the preseasonal study, and at the peak of the weed pollen season. Results Preseasonal study Table I shows the results of the titrated skin tests and nasal challenges. Skin test threshold and nasal challenge threshold are recorded as the reciprocal of the log,o Table 1. Results of tilratcd skin tests and nasal challenges of palienis in preseasonal study Skin test threshold* Treated group 4% cromolyn Placebo soluliun
Documented grass sensitivity 14/17 14'17
Ragweed
Chenopod
Sage
49
45
50
Nasal challenge threshold*
* Skin test threshold and nasal challenge threshold are given as the reciprocal of the dilution giving a positive reaction.
3-6 17
Four per cent nasal cromolyn in allergic rhinitis
489
dilution giving a positive test. It should be noted that about 80% of the patients in each group were sensitive to grass as well as weeds. Most of the patients were sensitive to two or all three of the weeds. Al! the patients were sensitive to ragweed, but patients with pure ragweed sensitivity are uncommon in the Denver area. The clinical data on the patients in each group is shown in Table 2. Thirty-two ofthe thirty-four patients completed the preseasonal study. One patient was dropped during the baseline week because of severe symptoms which could not be controlled with antihistamines and required the use of steroids. Another patient in the placebo group was dropped because ofthe development of severe chemical rhinitis. Table 2. Details of patients in the preseasonal study Details No. of patients Age (years) Ratige Mean Sex (Male/Female) Duration of hayfever symptoms Range Mean No. on hyposensitization
Placebo
4% Cromolyn
17
t7
13-54 32 9/8
12-44
1-M 15
3^0 13
5
6
29 9/8
The results of the analysis of the symptom diary cards for eacb week of the study are shown in Fig. I. The asnount of antihistamines was not included in this symptom score, but instead was analysed separately. Average weekly weed pollen counts are sbown in the lower part of Fig. I and correlate well with the rise in symptoms, peaking during weeks 7 and 8 of the study. Analysis of the average daily symptom scores for all symptoms for each group reveals a trend towards fewer symptoms at the peak of the weed pollen season for patients on tbe 4% cromolyn sodium solution, but this difference is not statistically significant. Although the nasal spray was begun before tbe weed pollen season, tbe baseline period was not an asymptomatic period. This may be explained by the fact that more than 80% ofthe patients in each group were also sensitive to grass and were just recovering from the effects of the MayJune grass pollen season in Denver. In as much as tbe baseline was not an asymptomatic period, and particularly since there was substantially greater symptomatology in tbe placebo group than the 4% cromolyn sodium group during the baseline, each individual symptom was analysed separately and adjusted by covariate analysis to correct the differences existing at baseline. Again, there was no statistical difference between any of the symptoms reported by the two groups: wherever a difference between the two groups was found during the study, tbat difference appears to have existed prior to initiation of treatment. Fig. 2 shows the amount of antihistamines taken for symptomatic relief by the two groups. A striking and statistically significant difl'erence in favor of the 4% cromoiyn sodium is noted throughout most of the weed pollen season, and is most pronounced (P
Controlled trials with four per cent cromolyn spray in seasonal allergic rhinitis* W. C. POSEY and H. S. NELSON Department of Allergy-CUnical Immunology, Fitzaimons Army Medical Center, Denver, Colorado^ U.S.A.
Summary Thirty-two patients with seasonal allergic rhinitis due to weed pollen were treated beginning prior to the weed pollen season of 1974 with either 4/^ cromolyn sodium or placebo nasal spray. The patients were followed on treatment with symptom diary cards and bi-weekly physician examinations for a period of 10 weeks. Radioallergosorbent (RAST) titres for the major weeds in the Denver area (ragweed, Russian thistle, and sage) were determined before the weed pollen season, and one and three months after the weed pollen season. There was no significant difference in symptom scores between the 4% cromolyn sodium- and placebo-treated groups, nor objective evidence on bi-weekly examinations by a physician to suggest differences in the two groups. Significant differences in favor of the 4% cromolyn-treaicd group were noted in the amount of antihistamines taken for symptomatic relief during the weed pollenating season, suggesting some protective effect ofthe drug. The clinical significance of this finding is not clear. Selecting patients with high baseline RAST titres for one or more of the major weeds did not alter the results of the study. In a second double-blind study twenty-two patients reporting to the allergy clinic with symptomatic seasonal allergic rhinitis due to weeds were randomly assigned to receive 4% cromolyn sodium or placebo nasal spray and followed through the weed pollen season. There was no difference between the two groups in either symptom scores or use of antihistamines for asymptomatic relief. Introduction Cromolyn sodium has been used extensively in the treatment of bronchial asthma since its introduction in England by Altounyan in 1967. Because of its action of blocking immunological release of mediators from mast cells, and its proven cffecliveness in blocking nasal and bronchial challenges as well as in treating reagin-mcdiutcd asthma, it was natural to try cromolyn for the treatment of allergic rhinitis. *The opinions or assertions herein are those of the author and are not to be construed as official or as reflecting the view of Ihe Department of the Air Fore: or Army. Correspondence: Lt Col William C. Posey, Allergy-Clinical Immunology Service (SGH/MAC), Wilford Hall USAF Medical Ccnicr. San Antonio, Texas 78236. U.S.A.
485
486
W. C. Posey and H. S. Nelson
In I%9 Orie and associates reported that the oral inhalation of 1°;', cromolyn sodium solution hlocked the nasal etTects of bronchial antigen challenge. These same authors (Pelikan ei ai., 1970) later reporled that i% cromolyn sodium applied directly to the nasal mucosa blocked nasal antigen challenge. The ability of cromolyn sodium to block nasal antigen challenge was confirmed by Taylor & Shivalkar (1971) using I and 10 mg cromolyn sodium powder. Connell (1972) reported that 4% cromolyn sodium was more elTective than 2",', solution in preventing the expected increase in nasal airways resistance after ragweed nasal challenge in ragweed-sensitive individuals. Clinical trials with cromolyn sodium in seasonal allergic rhinitis have yielded conflicting results. Knight & Underdown (1975) and Leiferman et al. (1975) have reported significant reduction in symptoms of ragweed pollenosis in patients treated with cromolyn sodium powder compared with placebo-treated groups. Because administration of cromolyn powder by nasal insulHator is inconvenient and because there is a question as to how etfectively the drug is distributed over the entire nasal mucosa, several clinical trials have been undertaken to test the effectiveness of 1%. 2% and 4% cromolyn sodium solutions. Blair & Herbert (1973) noted a decided patient and physician preference for 2% cromolyn sodium solution in a double-blind controlled study in forty patients with seasonal allergic rhinitis. Manners & Ezeoke (1973). however, in a similar study involving forty-six patients with seasonal allergic rhinitis could not demonstrate theelfectivenessof 2",, cromolyn sodium nasal solution. This study reports the results of clinical trials with 4" „ cromolyn sodium in patients with summer weed pollenosis., and further compares the results of using the drug prophylactically before the weed pollen season with its use in patients already symptomatic during the weed pollen season. Malerials and methods Selection and testing of patients The study was designed as a double-blind group comparative trial carried out during the ragweed pollen season of 1974. Thirty-four patients participated in the preseasonal study, eighteen males and sixteen females, ranging in age from 12 to 54 years. The patients were selected on the basis of a clear-cut history of acute late summer hay fever symptoms presumably due to weed pollen; all had had symptoms for at least 2 years, with the duration of symptoms ranging from 2 to 40 years. Weed sensitivity was confirmed by titrated skin tests and nasal challenges. The presence of perennial rhinitis, nasal polyps, significant nasal septal deviation or sinusitis was reason for exclusion from the study. Adniinistration of systemic corticosteroids within the preceding 3 months or topical steroids within the preceding month was also reason for exclusion. Previous hyposensitization was not a reason for exclusion but the dose of extract was not altered during the course of the study. Titrated skin tests were performed using glycerinated aqueous extracts of ragweed mix (25% giant ragweed, 25% short ragweed. 25% western ragweed. 25"o burweed marshelder), chenopod mix (50% Russian thistle. 50% kochia) and sage mix (40% common sage, 40";^ white sage, 20";, pasture sage), beginning with an intradernial injection of 0 02 ml of 1:100,000 w/v concentration of each antigen and progressing up to 0-02 ml of I; 100 w/v concentration. A positive reaction consisted of a weal at least 10 mm in diameter within 15 min after injection of the antigen.
Four per cent nasal cromolyn in allergic rhinitis
487
The nasal challenges consisted of spraying 010 ml of serial dilutions of mixed weed extract beginning with 100 PNU/ml and progressing up to a maximum concentration of 10.000 PNU/ml after first obtaining a negative challenge with glycerine -saline diluent control, A positive nasal challenge consisted of the appearance of nasal symptoms within 15 min of the challenge. Patients were carefully paired and assigned to 4% cromolyn sodium solution or placebo solution treatment group on the basis of (a) age; (b) sex; (c) the results of titrated skin tests; (d) the degree of anticipated exposure to weed pollen; and (e) hyposensitization therapy. The pairing of patients was performed by a third party who was also responsible for the packaging and distribution ofthe medication or placebo solutions. Treatment Patients in the active drug group received a solution containing 4% w/v cromolyn sodium with 0 01% disodium edetate and OOI"f, benzylkonium chloride diluted in sterile water in 12 ml glass bottles, for use in a special metered-dose nebulizer delivering approximately 0-13 ml/spray, equivalent to approximately 5 mg cromolyn sodium per spray. The patients in the control group received a placebo solution containing only the preservatives in the same concentration as the active drug solution. The patients were asked to spray each nostril every 3 hr six times a day. Both groups of patients were provided with an antihistamine (4 mg chlorplieniramine maleate tablets) to be taken only as needed for severe hay fever symptoms, and not to exceed six tablets per day Met hoc/ of study Symptom diary cards were provided for each week of the study with patients requested to record separately the severity of eye, throat, and nasal symptoms twice daily, utilizing a scale from 0 to 4, ranging from no symptoms to incapacitating symptoms. Patients were also requested to record the number of times the spray was used each day and the number of antihistamines taken. After a 1 week baseline period the patients began using the spray every 3 hr. Treatment began during the week of July 13, 1974 and concluded 8 weeks later on September 14. Patients were examined and diary cards collected at the end of the baseline and every 2 weeks thereafter. Unused spray and antihistamines were collected and a new supply of each was issued to each patient, and the amount of spray and antihistamines remaining was then measured to check for patient compliance and accuracy of recording of antihistamines in the diary. Pollen counts Semi-quantitative weed pollen counts were obtained daily throughout the study with a Rotoslide sampler, and expressed as the number of weed pollen grains per square centimeter slide surface area. Analysis of serum for specific IgE antibodies Serum samples were obtained from each patient at the start of the study (July 6), at the end of the treatment period (September 14) and 4 weeks after the end of the study (October 11). [gE antibody titres specific for short ragweed (Ambrosia elator), Russian thistle (Salsola pestifer) and sage (Artemesia vulgaris) were measured by the
488
IV. C. Posey and H. S. Nelson
radioallergosorbent (RAST) test. Ragweed-speciTcIgEantibody titres were performed by Dr Gerald Gleich at the Mayo Clinic. Rochester. Minnesota. Russian thistle and sage IgE antibody titres were performed in our own laboratory employing commercially available reagents (Pharmacia Corporation). Serum samples were stored at — 70"C and all three samples were analysed at the same time. Baseline RAST titres to the three weeds were therefore not available for the purpose of pairing patients at the start of the study. The levels of IgE antibody were expressed as the percentage of total added counts bound. A level greater than 5% counts bound was considered indicativeof sensitivity for ragweed. A value that was "clearly positive', i.e. greater than the ' C standards provided by Pharmacia Corporation was considered indicative of sensitivity to Russian thistle and sage. Statistical analysis The effects of treatment for each week of the study with 4% cromolyn sodium vs placebo was compared using two-tailed tests of significance (conlidence limits). Average symptoms scores and the amount of antihistamines used were analysed separately. Differences between the active drug group and the placebo group existing at baseline were corrected by the method of covariate analysis. Patients' and physicians' overall assessment for each group were analysed by the x^ test for frequency data. Coseasona! study A second study was carried out the same summer to evaluate the effectiveness of 4% cromolyn sodium treatment begun following the onset of symptoms of seasonal allergic rhinitis. Twenty-two patients reporting to the allergy clinic with symptomatic hay fever due to weeds were randomly assigned to a 4% cromolyn sodium or placebo treatment group. This was also a double-blind study, and the patients were evaluated and followed in a manner similar to that described for the preseasonal study. However, no attempt was made to produce matched pairs. The patients began using the 4% cromolyn sodium or placebo spray during the week of August 16, 1974. 5 weeks after the patients in the preseasonal study, and at the peak of the weed pollen season. Results Preseasonal study Table I shows the results of the titrated skin tests and nasal challenges. Skin test threshold and nasal challenge threshold are recorded as the reciprocal of the log,o Table 1. Results of tilratcd skin tests and nasal challenges of palienis in preseasonal study Skin test threshold* Treated group 4% cromolyn Placebo soluliun
Documented grass sensitivity 14/17 14'17
Ragweed
Chenopod
Sage
49
45
50
Nasal challenge threshold*
* Skin test threshold and nasal challenge threshold are given as the reciprocal of the dilution giving a positive reaction.
3-6 17
Four per cent nasal cromolyn in allergic rhinitis
489
dilution giving a positive test. It should be noted that about 80% of the patients in each group were sensitive to grass as well as weeds. Most of the patients were sensitive to two or all three of the weeds. Al! the patients were sensitive to ragweed, but patients with pure ragweed sensitivity are uncommon in the Denver area. The clinical data on the patients in each group is shown in Table 2. Thirty-two ofthe thirty-four patients completed the preseasonal study. One patient was dropped during the baseline week because of severe symptoms which could not be controlled with antihistamines and required the use of steroids. Another patient in the placebo group was dropped because ofthe development of severe chemical rhinitis. Table 2. Details of patients in the preseasonal study Details No. of patients Age (years) Ratige Mean Sex (Male/Female) Duration of hayfever symptoms Range Mean No. on hyposensitization
Placebo
4% Cromolyn
17
t7
13-54 32 9/8
12-44
1-M 15
3^0 13
5
6
29 9/8
The results of the analysis of the symptom diary cards for eacb week of the study are shown in Fig. I. The asnount of antihistamines was not included in this symptom score, but instead was analysed separately. Average weekly weed pollen counts are sbown in the lower part of Fig. I and correlate well with the rise in symptoms, peaking during weeks 7 and 8 of the study. Analysis of the average daily symptom scores for all symptoms for each group reveals a trend towards fewer symptoms at the peak of the weed pollen season for patients on tbe 4% cromolyn sodium solution, but this difference is not statistically significant. Although the nasal spray was begun before tbe weed pollen season, tbe baseline period was not an asymptomatic period. This may be explained by the fact that more than 80% ofthe patients in each group were also sensitive to grass and were just recovering from the effects of the MayJune grass pollen season in Denver. In as much as tbe baseline was not an asymptomatic period, and particularly since there was substantially greater symptomatology in tbe placebo group than the 4% cromolyn sodium group during the baseline, each individual symptom was analysed separately and adjusted by covariate analysis to correct the differences existing at baseline. Again, there was no statistical difference between any of the symptoms reported by the two groups: wherever a difference between the two groups was found during the study, tbat difference appears to have existed prior to initiation of treatment. Fig. 2 shows the amount of antihistamines taken for symptomatic relief by the two groups. A striking and statistically significant difl'erence in favor of the 4% cromoiyn sodium is noted throughout most of the weed pollen season, and is most pronounced (P
