Pediatric Pulmonology 1452-57 (1992)
Response to Inhaled Bronchodilators and Nonspecific Airway Hyperreactivity in Children With Cystic Fibrosis lgnacio Sanchez,
MD,
Richard E. Powell, MD, and Victor Chernick, MD
Summary. We tested the hypothesis that children with CF who have a significant response to bronchodilator (ED) would respond positively to standard methacholine (Mch) challenge. Our objective was to correlate the response to BD with the concentration that produced a 20% fall (PC,) in forced expiratory volume in 1 second (FEV,). We studied 22 patients (12 males), aged 10.5 ? 0.7 years (mean ? SE), with a Shwachman-Kulczycki score 82 -t 2.6 and baseline FEV, of 80 ? 4.5% predicted. Baseline expiratory flows, static lung volumes, and airway resistance were measured before and 30 min after inhaled salbutamol. On a separate day, within 2 weeks, a Mch challenge was given, with doubling concentrations from 0.03 to 8.0 mg/mL. A positive challenge was defined as a PC, s 2.0 mg/mL, and a positive response to BD as a >6'/0of FEV, increase. Mch challenge yielded 17 responders (R) with a PC, of 0.5 0.1 mg/mL, and 5 nonresponders (NR) with a PC, of 8.8 ? 2.9 mg/mL. Baseline FEV, was 77 k 5.3% predicted in R compared to 89 ? 6.3% in NR (P = < 0.001). History of springtime rhinitis was positive in 9/17 Rand 2/5 NR. No significant correlation was found between baseline FEV, and PC,, or between change in FEV, post-BD and PC., A >6% increase in FEV, was seen in 14/17 R (83% sensitivity) and in none of the 5 NR (100% specificity). In R, 8/17 patients had baseline FEV, < 80% predicted, compared to 1/51in NR. We conclude that a change in FEV, > 6% from baseline after bronchodilator in children with CF suggests nonspecific airway hyperreactivity. Pediatr Pulmonol. 1992; 14:52-57. icj 1992Wiley-Liss, Inc. Key words: Methacholinechallenge; salbutamol; pulmonary function tests.
INTRODUCTION A significant proportion of patients with cystic fibrosis (CF) demonstrate increased airway hyperreactivity, a feature that has been well documented by several authors. I-" Furthermore, it has been shown that patients with a positive methacholine challenge test (Mch) have more severe and advanced lung disease, with more rapid pulmonary deterioration." The use of bronchodilators in CF still remains controversial and there is no consensus as to the efficacy of inhaled P-adrenergic medication in the treatment of the disease. Previous investigators have studied the airway response to P-adrenergic agents in children with CF and have reported various effects on expiratory airflows, ranging from positive, to negative, or even possible adverse effect^.^.'^ In spite of this controversy, airway responsiveness to P-adrenergic agents is tested regularly in patients with CF to assess the degree of reversibility to airflow obstruction. What is the relationship between the change in expiratory airflow following bronchodilator therapy and airway hyperresponsiveness in C F ? Eggleston et al.' found a mean of 7.3% increase in FEV, following isoproterenol in patients with a positive Mch. In those who were nonresponsive to Mch, the change in FEV, (AFEV,) was only 4.0%. not significantly different from the mean of 7.3%. 0 1992 Wiley-Liss, Inc.
However, they did not relate individual patients' bronchodilator response to the degree of airway responsiveness to Mch. As best we know, the relationship between airway hyperreactivity to methacholine and the changes in lung function measurements after inhaled P-adrenergic agents has not been defined for the individual patient with CF. We wished to test the hypothesis that a child with CF who has a significant bronchodilator response would also have nonspecific airway hyperreactivity as do children with asthma. l 5 Therefore, we performed a methacholine inhalation challenge, a complete assessment of pulmonary function test at baseline and again after inhaled From the Department of Pediatrics, University of Manitoba, Scction of Pediatric Respirology, Children's Hospital. Winnipeg, Manitoha. Received December 30; 199 I ; (revision) accepted for publication April 10, 1YY2.
I.S. and R.E.P. are Fellows of the Manitoba Lung Association Supported by the Children's Hospital of Winnipeg, Research Foundation, Inc. Address corrcspnndcncc and reprint requests to Dr V . Chernick, Department of Pediatrics, University of Manitoba, P216-770 Bannatyne Avenue, Winnipeg, Manitoba R3E OW3, Canada.
Response to Salbutamol and Airways Hyperreactivity in CF
salbutamol in a group of children with CF. The baselinerelated response to bronchodilator (BD) was compared to the degree of airway hyperreactivity (AH). MATERIALS AND METHODS
The study was approved by the Faculty of Medicine, Ethics Committee for the use of Human Subjects, University of Manitoba and informed consent was obtained from the patients and parent(s) prior to the study. Twenty-two children (12 males, 10 females) with CF, aged 6 1 8 years (mean, 10.5 ? 0.7 SE years) with mild to moderate lung disease [baseline FEV , 46-1 13% predicted (80 f 4.5%);Shwachman-Kulczyski (S-K) score, 60-95 (82 ? 2.6)] were studied. Subjects were excluded if FEV, < 40% predicted, or they had a history and clinical course consistent with asthma. Eleven children had a history of springtime rhinitis and two of these had one parent with asthma, but they were never diagnosed as asthmatic. The patients were free from upper respiratory tract infection or acute pulmonary exacerbation for at least 4 weeks and refrained from using inhaled salbutamol or caffeine-containing drinks for 8 hr immediately prior to the studies. Baseline pulmonary function tests included forced maximal expiratory flow volume curve, airway resistance (Raw)and static lung volume measurements by body plethysmography (Autobox 6200, Sensormedics Yorba Linda, CA) before and 30 min after inhaled bronchodilator (salbutamol, 200 pg). FEV, measurements were repeated 3 to 5 times until 3 values agreed within 3%, and the mid value was chosen. A positive response to inhaled bronchodilator was defined as an increase of >6% in FEV, .Is On a separate day, within a 2-week period, patients performed an Mch challenge test, according to Cockroft's method. Normal saline (0.9%)followed by serial inhalations of doubling concentrations of methacholine were administered for 2 min each, beginning with a methacholine concentration of 0.03 mg/mL and continuing every 5 min up to a maximum concentration of 8 mg/mL. All methacholine aerosols were generated by a Wright nebulizer with 2 mL of test solution, an oxygen flow of 10.9 L/min, and a rate of nebulization of 0.3 mL/min. The aerosol was delivered via a face mask and inhaled through the mouth and nose. After every inhalation, two forced expiratory maneuvers were performed and the highest FEV was recorded (Spirovit, SP-200 Schiller AG, Switzerland). The end point of the test was a 20% fall in FEV, from the best postsaline value, or when the final concentration of 8 mg/mL was reached. For each subject, FEV, was plotted against the log of the methacholine dose, and the concentration required for a 20% drop in FEV, (PC,,) was determined by interpolation. For children who had less than a 20% fall in FEV, at a concentration of 8 mg/mL, a PC,,, of 12 mg/mL was
,
'
,
53
arbitrarily assigned if the last fall in FEV, was between 1 I and 19% and a PC,,, of 16 mg/mL if the fall was less than 11%. This was done in order to calculate a mean PC,,, value for the group. A positive test was defined as PC,,, i2.0 rng/mL to clearly differentiate bronchial hyperresponsiveness from mild or borderline responses. Statistical Analysis
Geometric mean values of the PC,,, were calculated and used for statistical analysis. Unpaired two tailed t tests were used to compare pulmonary function tests. Correlation coefficients were calculated to compare lung function and methacholine challenge results. Chi-square analysis was applied to qualitative variables. A P value of 6% after BD occurred in 14/17 patients in Group I(83%sensitivity) and in none of the 5 children in Group I1 (100% specificity), P < 0.05 (Chi-square). The increase after BD in FEF,,, FEF2sp7s, and decrease in Raw correlated closely with changes in FEV, . There was no significant difference in static lung volumes between the two groups. Figure 1 shows the relationship between percent improvement in FEV after salbutamol and PC,, in mg/mL of methacholine. Patients in Group I (positive response to Mch) were divided into those with severe AH (PC,, < 0.25 mg/mL) in whom mean A FEV, after BD was 10.8 2 2.6% and those with moderate AH (PC,, = 0.25-2.0 mg/mL) with a AFEV, of 7.6 -+ 1.5%. Group I1 (PC,,, > 2.0 mg/mL) had
,
,
54
Sanchez et al.
TABLE 1-Baseline Subject No. 1
2 3
4
5 6 7 8 9 10
I1 12 13 14 IS
16 17 18 19 20 21 22
Characteristics of the Patients
Age (years) 6 7 7 7 7 7 8 8 9 9 9 10 I1 11 12
12 13 14 14
15 16 I8
,
SCX
SK-s"
M M M M M F F F F M F F F M M F M F F M M M
95 85 95 85 90 95 75 95 90 YO 85
,
FEV abs (L)
FEV (%pred.)
1.53 I .35 I .46 1.13
I I3
I .89 I .27
99
80 95 60 80 90 70 95 65
I02 87 99 78 91 100
90 73 48 68
85 57
1.23 3.56 I .33 2.65 I .49 I .95 3.04
65 65
Response to bronchodilator
100
0.97 I .37 I .56 1.52 1.64 0.88 1.49 2.20 I .09
I5
Seasonal rhinitis
55 108
53 84 46 47 80
.
"SK-s, Schwachman-Kulczycki scores: FEV, forced expiratory volume in I second.
TABLE 2-Baseline and Postbronchodilator Pulmonary Function Measurements of Children With a Positive Mch Challenge (Group I) Compared to Children With a Negative Mch Challenge (Group II) (Mean SE)
7
*
Group I ( n = 17) Age (years)
SK score PC,, rng/mL Baseline FEV, ('% pred.) FEF,,, (% pred.) FRC (% pred.) RV/TLC (%) R,, (cm H,O/L/s) Change after bronchodilator AFEV, (%) AFEF,, (%) AFRC (96) ARVITLC (%) AR..,
10.1 C _ 0.8 82 f 2.9 0.54 0.1
*
77
f 5.3
60 & 8.7 136 7.0
*
39 2 2.7 6.7 f 0.9
8.1 k 1.7 22.4 f 4.6 -5.3 f 0.1 2.5 f 0.5 -19.4 f 3.6
22
20
Group I1 ( n = 5)
*
5
*
U
1.9 85 f 5 . 4 8 . 8 2.0"*
11.6
6.3** 103 16.9"" 130 2 12.1 30 +- 3.6 3.8 f 0.5" 89
18-
5 2
3.3 f 0.4* 8.1 f 4.2 -3.1 f 1.1 1.0 2 0.1 -13.1 2 1.7
SK score, Shwachrnan-Kulczychi scores; FEV. forced expiratory V d ume in 1 second: FEFs,,, forced expiratory flow at 50% Vital capacity; FRC, functional residual capacity; RV/TLC, residual vohne/total capacity ratio; R,,, airway resistance. *P ’ 80well documented. I-’ It has been suggested that this bronkf cholability is more severe in those with more advanced .-t 70lung disease.6 Our definition of airway hyperreactivity 3 (PC,, Q 2.0 mg/mL) was arbitrarily chosen to avoid the 180overlap known to be present between mild and normal responsiveness to methacholine. This overlapping re50sponse has been shown bv several authors who studied patients with CF1’*I9and iealthy school children.20 We 40 I found 17/22 patients (77%) with airway hyperreactivity, s0.25 0.26 - 2.0 >2.0 which is a higher incidence than reported by others, from PCZO(mglml) as low as 25% to as high as 50%. This was so despite Fig. 2. Relationship between baseline FEV, ( O h predicted) and our more stringent definition of a positive Mch test. Most PC, divided into three groups as in Figure 1. Mean & SE per- previous studies have been done using histamine. At least centage FEV, (% predicted) is shown for each group. in asthmatic patients, there is a good correlation between histamine and methacholine challenge tests” but CF patients may be more sensitive to methacholine.” Eggleston and co-workers,6 in a group of children and adults line FEV, vs PC20 ( r = 0.143). History of allergy was with CF, found that 20 methacholine reactors had more present in 9/ 18 patients in Group I and in 3/5 in Group I1 severe lung disease, with a lower S-K score and more impairment of pulmonary function, than 16 nonreactive (n.s.). We compared the bronchodilator response to historic patients. However, we excluded patients with the most data from the hospital charts. We randomly selected two severe lung disease so that this does not explain the high pulmonary function tests in a 2-year period to evaluate incidence of airway hyperreactivity among our patients. the variability of this response. We found an inconsistent Since 1 1 of our patients (50%)had a history of hay fever, bronchodilator response in Group I patients: of 20 tests, this disorder might have influenced our findings; howonly 5 showed less than a 6% increase in FEV, following ever, two of five patients with a negative Mch also had a bronchodilator in the severe group (PC,, S 0.25 mg/ history of hay fever making this unlikely. Indeed, MitchmL), and 14 of 26 bronchodilator tests were negative in ell et a1.*’ have found no relationship between allergic the moderate group (PC,, 0.26-2.0 mg/mL). Group I1 rhinitis or positive skin tests and a positive Mch in pawas remarkably consistent with no AFEV, >6% in any of tients with CF. Thus, we are not able to explain the high incidence of airway hyperreactivity we have found, but the 14 tests. perhaps this is due to the relatively small sample size and not indicative of the true prevalence of airway hyperreacDISCUSSION tivity in CF. Riedel and von der HardtZ3found a mean increase in The efficacy of bronchodilator therapy in CF has been discussed by several authors in the Recently FEV, of 6.3%after salbutamol in 49 healthy school chilPattishall showed in a longitudinal and cross-sectional dren, but they did not exclude patients with a family study that 40% of patients presented a positive response history of asthma or atopy. In a more rigorously deto inhaled adrenergic agents, however, there was a lack signed, large epidemiological survey, Dales and co~ ~ that the average increase in FEV, in of consistent response. In our series, we found that 14/22 w o r k e r ~found subjects (64%) did have a positive response (>6%) to normal subjects (children and adults) was only 2.1%. salbutamol. However, when compared to historic data, These results are similar to the data presented by Ekwo methacholine responders showed a significant variability et al., who found a mean increase of 1.3 -+ 0.4% of in bronchodilator response. Twenty-five percent of tests FEV, after isoproterenol in 182 healthy Caucasian chilin patients with severe Mch responsiveness showed dren from 6 to 12 years of age.2s Recently, Bibi and AFEV, < 6%, whereas 54% of tests in patients with co-workers” showed in a group of children with susmoderate Mch sensitivity showed a AFEV, < 6%. Re- pected asthma, that a >6% change of FEV, from baseline 120
. . .
..
.
1: 1:
.
56
Sanchez et al.
after inhaled salbutamol was suggestive of nonspecific airway hyperreactivity with a specificity of 100% but a sensitivity of only 36%. In the present study of patients with CF we found that >6% increase in FEV I after bronchodilator therapy predicted nonspecific airway hyperreactivity with a sensitivity of 83%, and that this improvement in FEV, was not present in those with a negative Mch challenge (100% specificity). However, when all subjects were considered there was no correlation between A FEV, and PC2()( r = -0.256). This is not surprising because of the large variation in response to bronchodilator. Although the relationship between A FEW, and bronchial hyperreactivity in patients with CF has not been reported previously, it is possible to calculate from the data of Van Asperen et al.4 that 5 of their subjects with a >6% AFEV, after fenoterol, had a positive Mch after saline inhalation ( < I .6 mg/mL), but no subjects with a AFEV, > 6% had a negative Mch after saline (100% specificity). However, their test, in only 14 subjects, had a sensitivity of 50% compared to our result of 83%. We are confident of the accuracy of these tests. In our experience with another group of patients with CF, repeated Mch and baseline pulmonary function tests done within a 2-week period showed minimal variability: < I doubling concentration for PC,, and within 5 % for FEV, (unpublished data). The three patients with a positive Mch who did not show an increase in FEV, after bronchodilator are puzzling and we do not know why they failed to respond to bronchodilator. These subjects did not have a worsening of FEV, after bronchodilator so that increased collapsibility of airways was not a factor. Eggleston and co-workers' showed an increase in FEV, of 7 . 3 ? 1.3% in 20 mcthacholine reactors compared to 4.0 0.8% in 16 nonreactive subjects with CF. They used the Chai method2" and the equivalent cut off for airway hyperreactivity for the Cockroft method was 8 mg/mL, four times the concentration we used for separating our groups. Furthermore, they did not relate individual bronchodilator responsiveness to Mch sensitivity. In a more recent study Eggleston et al." have shown that among responders, daily peak expiratory tlow (PEF) improved significantly more during treatment with salbutamol (12 32 L/min) than in nonresponders (-9 -+ 30 Wmin). In addition, a clinically important level of irnprovement in PEF (15% increase) was reached significantly more frequently in the responders. Measurements of AFEV, or AFEF2s-7s were not significantly different between responders and nonresponders, but the bronchodilator tests in that study" were done at 2-week intervals for 2 months without repeating the Mch challenge, which may have given different results. We used a lower cut off for a positive Mch and only a single bronchodilator test within a two week period, which may account for the different results.
*
*
In conclusion, we have found that in children with CF a change of FEV, greater than 6% from baseline after inhaled salbutamol is suggestive of nonspecific airway hyperreactivity with a very high specificity, if tested with Mch within a 2-week period. In the present series only 17% of patients with CF who had airway hyperreactivity responded with less than 6% increase in FEV I to salbutamol (83% sensitivity). We speculate that patients who have a greater than 6% change in FEV, following a bronchodilator might benefit from therapy designed to reduce airway hyperreactivity . ACKNOWLEDGMENTS
We are grateful to Drs. Hans Pasterkamp and Paul Pianosi for their critical review of the manuscript, to Jessica Holbrow, R.R.T., and Danny Castillo, R.R.T., for their technical assistance, to Anne Rempel, R.N., for recruiting the patients, to Robert Tate for statistical analyses, and to Carol Funk and Barb Janz for their expert secretarial assistance. REFERENCES I . Mellis CM, Levison H. Bronchial reactivity in cystic fibrosis. Pediatrics 1978; 61:44&450. 2. Van Asperen 0, Mellis CM, South RT, Simpson SJ. Bronchial reactivity in cystic fibrosis with normal pulmonary function. AJDC 1981; 135:815-819. 3. Darga LL, Eason LA. Zach DMS, PolgarG. Cold air provocation of airway hyperreactivity in patients with cystic fibrosis. Pediatr Pulmonol 1986; 2232-88. 4. Van Asperen P, Manglick P, Allen H. Mechanisms of bronchial hyperreactivity in cystic fibrosis. Pediatr Pulmonol 1988; 5 : 139144.
5. Zach MS. Lung discasc in cystic fibrnsis. An updated conccpt. Pediatr Pulmonol 1990; 8: 188-202. 6 . Eggleston PA, Roscnstcin BJ, Stackhouse CM, Alexander MF. Airway hyperreactivity in cystic fibrosis. Clinical correlates and possible effects on the course of disease. Chest IYXX: 94:36&365. 7. Tohin MJ, Maguire 0, Reen D, Tempany E, Fitzgcrald MX. Atopy and bronchial reactivity in older patients with cystic Iibmsis. Thorax 1980; 35:807-813. 8. Kattan M, Mansell A, Levison H, Corey M, Krastins IRB. Response to aerosol salbutamol, SCH 1000 and placebo in cystic fibrosis. Thorax 1980; 35531-535. 9. Weintraub SJ, Eschenbacher WL. The inhaled bronchodilators ipratropium bromide and mctaprotercnol in adults with CF. Chest 1989; 95:861-864. 10. Sanchez I , Holbrow J . Chernick V. Acute bronchodilator response to a combination of beta-adrenergic and anticholinergic agcnts in patients with cystic fibrosis. J Pediatr 1992;120:486488. I I . Eggleston PA, Rosenstein BJ, Slackhouse CM, Mellits D, Baumgardner RA. A controlled trial of long-term bronchodilator therapy in cystic fibrosis. Chest 1991: 99:1088-1092. 12. Pattishall EN. Longitudinal response of pulmonary function to bronchodilators in cystic fibrosis. Pediatr Pulmonol 1990; 9:8& 85. 13. Landau LI, Phelan PD. The variable effect of a bronchodilating agent on pulnionary function in cystic fibrosis. J Pcdiatr 1973: 82:863-868.
Response to Salbutamol and Airways Hyperreactivity in CF 14. Zach MS, Oberwaldner B, Forche G, Polgar G. Bronchodilators increase airway instability in cystic fibrosis. Am Rev Respir Dis 1985; l31:537-543. 15. Bibi H, Montgomery M, Pasterkamp H, Chernick V. Relationship between response to inhaled salbutamol and methacholine bronchial provocation in children with suspected asthma. Pediatr Pulmonol 1991; 10:244-248. 16. Cockroft DW, Killian DN, Mellon JJA, Hargreave FE: Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy 1977; 7:235-243. 17. Konig P, Gayer D. Barber0 GJ, Shaffer J, Krentz C, Hines C. Home measurements of peak expiratory flow rate (PEFR); diurnal variation (DV) and response to bronchodilators (BD). Pediatr Pulmonol 1991; Suppl6:284 (abstract). 18. Holzer FJ, Olinsky A, Phelan PD. Variability of airways hyperreactivity and allergy in cystic fibrosis. Arch Dis Child 1981; 56:455459. 19. Godfrey S, Springer C, Noviski N, Maayan CH,Avital A. Exercise but not methacholine differentiates asthma from chronic lung disease in children. Thorax 1991; 46:488-492. 20. Clifford RD, Radford M, Howell JB, Holgate ST. Prevalence of
21. 22. 23. 24.
25. 26.
57
atopy and range of bronchial response to methacholine in 7 and I I year old school children. Arch Dis Child 1989; 64:I 126-1 132. Juniper EF, Frith PA, Dunett C , et al. Reproducibility and comparison of responses to inhaled histamine and methacholine. Thorax 1978; 33:705-710. Mitchell I, Corey M, Woenne R, Krastins IRB, Levison H. Bronchial hyperreactivity in cystic fibrosis and asthma. J Pediatr 1978; 93:74+748. Riedel F, von der Hardt H.Variable response to inhaled salbutamol of different lung function parameters in healthy children. Lung 1986; 164:335-338. Dales RE, Spitzer WO, Tousignant P, Schechtez M, Suissa S . Clinical interpretation of airway response to bronchodilator: Epidemiologic consideration. Am Rev Respir Dis 1988; 138:317320. Ekwo EE, Weinberger MM, Dusdieker LB, Huntley WH, Rodgers P, Maxwell GA. Airways responses to inhaled isoproterenol in normal children. Am Rev Respir Dis 1983; 127:108-109. Chai H, Farr RS, Froelich LA, Mathison DS, MacClean JA, et al. Standardization of bronchial inhalation challenge procedures. J Allerg Clin Immunol 1975; 56:323-328.
Response to Inhaled Bronchodilators and Nonspecific Airway Hyperreactivity in Children With Cystic Fibrosis lgnacio Sanchez,
MD,
Richard E. Powell, MD, and Victor Chernick, MD
Summary. We tested the hypothesis that children with CF who have a significant response to bronchodilator (ED) would respond positively to standard methacholine (Mch) challenge. Our objective was to correlate the response to BD with the concentration that produced a 20% fall (PC,) in forced expiratory volume in 1 second (FEV,). We studied 22 patients (12 males), aged 10.5 ? 0.7 years (mean ? SE), with a Shwachman-Kulczycki score 82 -t 2.6 and baseline FEV, of 80 ? 4.5% predicted. Baseline expiratory flows, static lung volumes, and airway resistance were measured before and 30 min after inhaled salbutamol. On a separate day, within 2 weeks, a Mch challenge was given, with doubling concentrations from 0.03 to 8.0 mg/mL. A positive challenge was defined as a PC, s 2.0 mg/mL, and a positive response to BD as a >6'/0of FEV, increase. Mch challenge yielded 17 responders (R) with a PC, of 0.5 0.1 mg/mL, and 5 nonresponders (NR) with a PC, of 8.8 ? 2.9 mg/mL. Baseline FEV, was 77 k 5.3% predicted in R compared to 89 ? 6.3% in NR (P = < 0.001). History of springtime rhinitis was positive in 9/17 Rand 2/5 NR. No significant correlation was found between baseline FEV, and PC,, or between change in FEV, post-BD and PC., A >6% increase in FEV, was seen in 14/17 R (83% sensitivity) and in none of the 5 NR (100% specificity). In R, 8/17 patients had baseline FEV, < 80% predicted, compared to 1/51in NR. We conclude that a change in FEV, > 6% from baseline after bronchodilator in children with CF suggests nonspecific airway hyperreactivity. Pediatr Pulmonol. 1992; 14:52-57. icj 1992Wiley-Liss, Inc. Key words: Methacholinechallenge; salbutamol; pulmonary function tests.
INTRODUCTION A significant proportion of patients with cystic fibrosis (CF) demonstrate increased airway hyperreactivity, a feature that has been well documented by several authors. I-" Furthermore, it has been shown that patients with a positive methacholine challenge test (Mch) have more severe and advanced lung disease, with more rapid pulmonary deterioration." The use of bronchodilators in CF still remains controversial and there is no consensus as to the efficacy of inhaled P-adrenergic medication in the treatment of the disease. Previous investigators have studied the airway response to P-adrenergic agents in children with CF and have reported various effects on expiratory airflows, ranging from positive, to negative, or even possible adverse effect^.^.'^ In spite of this controversy, airway responsiveness to P-adrenergic agents is tested regularly in patients with CF to assess the degree of reversibility to airflow obstruction. What is the relationship between the change in expiratory airflow following bronchodilator therapy and airway hyperresponsiveness in C F ? Eggleston et al.' found a mean of 7.3% increase in FEV, following isoproterenol in patients with a positive Mch. In those who were nonresponsive to Mch, the change in FEV, (AFEV,) was only 4.0%. not significantly different from the mean of 7.3%. 0 1992 Wiley-Liss, Inc.
However, they did not relate individual patients' bronchodilator response to the degree of airway responsiveness to Mch. As best we know, the relationship between airway hyperreactivity to methacholine and the changes in lung function measurements after inhaled P-adrenergic agents has not been defined for the individual patient with CF. We wished to test the hypothesis that a child with CF who has a significant bronchodilator response would also have nonspecific airway hyperreactivity as do children with asthma. l 5 Therefore, we performed a methacholine inhalation challenge, a complete assessment of pulmonary function test at baseline and again after inhaled From the Department of Pediatrics, University of Manitoba, Scction of Pediatric Respirology, Children's Hospital. Winnipeg, Manitoha. Received December 30; 199 I ; (revision) accepted for publication April 10, 1YY2.
I.S. and R.E.P. are Fellows of the Manitoba Lung Association Supported by the Children's Hospital of Winnipeg, Research Foundation, Inc. Address corrcspnndcncc and reprint requests to Dr V . Chernick, Department of Pediatrics, University of Manitoba, P216-770 Bannatyne Avenue, Winnipeg, Manitoba R3E OW3, Canada.
Response to Salbutamol and Airways Hyperreactivity in CF
salbutamol in a group of children with CF. The baselinerelated response to bronchodilator (BD) was compared to the degree of airway hyperreactivity (AH). MATERIALS AND METHODS
The study was approved by the Faculty of Medicine, Ethics Committee for the use of Human Subjects, University of Manitoba and informed consent was obtained from the patients and parent(s) prior to the study. Twenty-two children (12 males, 10 females) with CF, aged 6 1 8 years (mean, 10.5 ? 0.7 SE years) with mild to moderate lung disease [baseline FEV , 46-1 13% predicted (80 f 4.5%);Shwachman-Kulczyski (S-K) score, 60-95 (82 ? 2.6)] were studied. Subjects were excluded if FEV, < 40% predicted, or they had a history and clinical course consistent with asthma. Eleven children had a history of springtime rhinitis and two of these had one parent with asthma, but they were never diagnosed as asthmatic. The patients were free from upper respiratory tract infection or acute pulmonary exacerbation for at least 4 weeks and refrained from using inhaled salbutamol or caffeine-containing drinks for 8 hr immediately prior to the studies. Baseline pulmonary function tests included forced maximal expiratory flow volume curve, airway resistance (Raw)and static lung volume measurements by body plethysmography (Autobox 6200, Sensormedics Yorba Linda, CA) before and 30 min after inhaled bronchodilator (salbutamol, 200 pg). FEV, measurements were repeated 3 to 5 times until 3 values agreed within 3%, and the mid value was chosen. A positive response to inhaled bronchodilator was defined as an increase of >6% in FEV, .Is On a separate day, within a 2-week period, patients performed an Mch challenge test, according to Cockroft's method. Normal saline (0.9%)followed by serial inhalations of doubling concentrations of methacholine were administered for 2 min each, beginning with a methacholine concentration of 0.03 mg/mL and continuing every 5 min up to a maximum concentration of 8 mg/mL. All methacholine aerosols were generated by a Wright nebulizer with 2 mL of test solution, an oxygen flow of 10.9 L/min, and a rate of nebulization of 0.3 mL/min. The aerosol was delivered via a face mask and inhaled through the mouth and nose. After every inhalation, two forced expiratory maneuvers were performed and the highest FEV was recorded (Spirovit, SP-200 Schiller AG, Switzerland). The end point of the test was a 20% fall in FEV, from the best postsaline value, or when the final concentration of 8 mg/mL was reached. For each subject, FEV, was plotted against the log of the methacholine dose, and the concentration required for a 20% drop in FEV, (PC,,) was determined by interpolation. For children who had less than a 20% fall in FEV, at a concentration of 8 mg/mL, a PC,,, of 12 mg/mL was
,
'
,
53
arbitrarily assigned if the last fall in FEV, was between 1 I and 19% and a PC,,, of 16 mg/mL if the fall was less than 11%. This was done in order to calculate a mean PC,,, value for the group. A positive test was defined as PC,,, i2.0 rng/mL to clearly differentiate bronchial hyperresponsiveness from mild or borderline responses. Statistical Analysis
Geometric mean values of the PC,,, were calculated and used for statistical analysis. Unpaired two tailed t tests were used to compare pulmonary function tests. Correlation coefficients were calculated to compare lung function and methacholine challenge results. Chi-square analysis was applied to qualitative variables. A P value of 6% after BD occurred in 14/17 patients in Group I(83%sensitivity) and in none of the 5 children in Group I1 (100% specificity), P < 0.05 (Chi-square). The increase after BD in FEF,,, FEF2sp7s, and decrease in Raw correlated closely with changes in FEV, . There was no significant difference in static lung volumes between the two groups. Figure 1 shows the relationship between percent improvement in FEV after salbutamol and PC,, in mg/mL of methacholine. Patients in Group I (positive response to Mch) were divided into those with severe AH (PC,, < 0.25 mg/mL) in whom mean A FEV, after BD was 10.8 2 2.6% and those with moderate AH (PC,, = 0.25-2.0 mg/mL) with a AFEV, of 7.6 -+ 1.5%. Group I1 (PC,,, > 2.0 mg/mL) had
,
,
54
Sanchez et al.
TABLE 1-Baseline Subject No. 1
2 3
4
5 6 7 8 9 10
I1 12 13 14 IS
16 17 18 19 20 21 22
Characteristics of the Patients
Age (years) 6 7 7 7 7 7 8 8 9 9 9 10 I1 11 12
12 13 14 14
15 16 I8
,
SCX
SK-s"
M M M M M F F F F M F F F M M F M F F M M M
95 85 95 85 90 95 75 95 90 YO 85
,
FEV abs (L)
FEV (%pred.)
1.53 I .35 I .46 1.13
I I3
I .89 I .27
99
80 95 60 80 90 70 95 65
I02 87 99 78 91 100
90 73 48 68
85 57
1.23 3.56 I .33 2.65 I .49 I .95 3.04
65 65
Response to bronchodilator
100
0.97 I .37 I .56 1.52 1.64 0.88 1.49 2.20 I .09
I5
Seasonal rhinitis
55 108
53 84 46 47 80
.
"SK-s, Schwachman-Kulczycki scores: FEV, forced expiratory volume in I second.
TABLE 2-Baseline and Postbronchodilator Pulmonary Function Measurements of Children With a Positive Mch Challenge (Group I) Compared to Children With a Negative Mch Challenge (Group II) (Mean SE)
7
*
Group I ( n = 17) Age (years)
SK score PC,, rng/mL Baseline FEV, ('% pred.) FEF,,, (% pred.) FRC (% pred.) RV/TLC (%) R,, (cm H,O/L/s) Change after bronchodilator AFEV, (%) AFEF,, (%) AFRC (96) ARVITLC (%) AR..,
10.1 C _ 0.8 82 f 2.9 0.54 0.1
*
77
f 5.3
60 & 8.7 136 7.0
*
39 2 2.7 6.7 f 0.9
8.1 k 1.7 22.4 f 4.6 -5.3 f 0.1 2.5 f 0.5 -19.4 f 3.6
22
20
Group I1 ( n = 5)
*
5
*
U
1.9 85 f 5 . 4 8 . 8 2.0"*
11.6
6.3** 103 16.9"" 130 2 12.1 30 +- 3.6 3.8 f 0.5" 89
18-
5 2
3.3 f 0.4* 8.1 f 4.2 -3.1 f 1.1 1.0 2 0.1 -13.1 2 1.7
SK score, Shwachrnan-Kulczychi scores; FEV. forced expiratory V d ume in 1 second: FEFs,,, forced expiratory flow at 50% Vital capacity; FRC, functional residual capacity; RV/TLC, residual vohne/total capacity ratio; R,,, airway resistance. *P ’ 80well documented. I-’ It has been suggested that this bronkf cholability is more severe in those with more advanced .-t 70lung disease.6 Our definition of airway hyperreactivity 3 (PC,, Q 2.0 mg/mL) was arbitrarily chosen to avoid the 180overlap known to be present between mild and normal responsiveness to methacholine. This overlapping re50sponse has been shown bv several authors who studied patients with CF1’*I9and iealthy school children.20 We 40 I found 17/22 patients (77%) with airway hyperreactivity, s0.25 0.26 - 2.0 >2.0 which is a higher incidence than reported by others, from PCZO(mglml) as low as 25% to as high as 50%. This was so despite Fig. 2. Relationship between baseline FEV, ( O h predicted) and our more stringent definition of a positive Mch test. Most PC, divided into three groups as in Figure 1. Mean & SE per- previous studies have been done using histamine. At least centage FEV, (% predicted) is shown for each group. in asthmatic patients, there is a good correlation between histamine and methacholine challenge tests” but CF patients may be more sensitive to methacholine.” Eggleston and co-workers,6 in a group of children and adults line FEV, vs PC20 ( r = 0.143). History of allergy was with CF, found that 20 methacholine reactors had more present in 9/ 18 patients in Group I and in 3/5 in Group I1 severe lung disease, with a lower S-K score and more impairment of pulmonary function, than 16 nonreactive (n.s.). We compared the bronchodilator response to historic patients. However, we excluded patients with the most data from the hospital charts. We randomly selected two severe lung disease so that this does not explain the high pulmonary function tests in a 2-year period to evaluate incidence of airway hyperreactivity among our patients. the variability of this response. We found an inconsistent Since 1 1 of our patients (50%)had a history of hay fever, bronchodilator response in Group I patients: of 20 tests, this disorder might have influenced our findings; howonly 5 showed less than a 6% increase in FEV, following ever, two of five patients with a negative Mch also had a bronchodilator in the severe group (PC,, S 0.25 mg/ history of hay fever making this unlikely. Indeed, MitchmL), and 14 of 26 bronchodilator tests were negative in ell et a1.*’ have found no relationship between allergic the moderate group (PC,, 0.26-2.0 mg/mL). Group I1 rhinitis or positive skin tests and a positive Mch in pawas remarkably consistent with no AFEV, >6% in any of tients with CF. Thus, we are not able to explain the high incidence of airway hyperreactivity we have found, but the 14 tests. perhaps this is due to the relatively small sample size and not indicative of the true prevalence of airway hyperreacDISCUSSION tivity in CF. Riedel and von der HardtZ3found a mean increase in The efficacy of bronchodilator therapy in CF has been discussed by several authors in the Recently FEV, of 6.3%after salbutamol in 49 healthy school chilPattishall showed in a longitudinal and cross-sectional dren, but they did not exclude patients with a family study that 40% of patients presented a positive response history of asthma or atopy. In a more rigorously deto inhaled adrenergic agents, however, there was a lack signed, large epidemiological survey, Dales and co~ ~ that the average increase in FEV, in of consistent response. In our series, we found that 14/22 w o r k e r ~found subjects (64%) did have a positive response (>6%) to normal subjects (children and adults) was only 2.1%. salbutamol. However, when compared to historic data, These results are similar to the data presented by Ekwo methacholine responders showed a significant variability et al., who found a mean increase of 1.3 -+ 0.4% of in bronchodilator response. Twenty-five percent of tests FEV, after isoproterenol in 182 healthy Caucasian chilin patients with severe Mch responsiveness showed dren from 6 to 12 years of age.2s Recently, Bibi and AFEV, < 6%, whereas 54% of tests in patients with co-workers” showed in a group of children with susmoderate Mch sensitivity showed a AFEV, < 6%. Re- pected asthma, that a >6% change of FEV, from baseline 120
. . .
..
.
1: 1:
.
56
Sanchez et al.
after inhaled salbutamol was suggestive of nonspecific airway hyperreactivity with a specificity of 100% but a sensitivity of only 36%. In the present study of patients with CF we found that >6% increase in FEV I after bronchodilator therapy predicted nonspecific airway hyperreactivity with a sensitivity of 83%, and that this improvement in FEV, was not present in those with a negative Mch challenge (100% specificity). However, when all subjects were considered there was no correlation between A FEV, and PC2()( r = -0.256). This is not surprising because of the large variation in response to bronchodilator. Although the relationship between A FEW, and bronchial hyperreactivity in patients with CF has not been reported previously, it is possible to calculate from the data of Van Asperen et al.4 that 5 of their subjects with a >6% AFEV, after fenoterol, had a positive Mch after saline inhalation ( < I .6 mg/mL), but no subjects with a AFEV, > 6% had a negative Mch after saline (100% specificity). However, their test, in only 14 subjects, had a sensitivity of 50% compared to our result of 83%. We are confident of the accuracy of these tests. In our experience with another group of patients with CF, repeated Mch and baseline pulmonary function tests done within a 2-week period showed minimal variability: < I doubling concentration for PC,, and within 5 % for FEV, (unpublished data). The three patients with a positive Mch who did not show an increase in FEV, after bronchodilator are puzzling and we do not know why they failed to respond to bronchodilator. These subjects did not have a worsening of FEV, after bronchodilator so that increased collapsibility of airways was not a factor. Eggleston and co-workers' showed an increase in FEV, of 7 . 3 ? 1.3% in 20 mcthacholine reactors compared to 4.0 0.8% in 16 nonreactive subjects with CF. They used the Chai method2" and the equivalent cut off for airway hyperreactivity for the Cockroft method was 8 mg/mL, four times the concentration we used for separating our groups. Furthermore, they did not relate individual bronchodilator responsiveness to Mch sensitivity. In a more recent study Eggleston et al." have shown that among responders, daily peak expiratory tlow (PEF) improved significantly more during treatment with salbutamol (12 32 L/min) than in nonresponders (-9 -+ 30 Wmin). In addition, a clinically important level of irnprovement in PEF (15% increase) was reached significantly more frequently in the responders. Measurements of AFEV, or AFEF2s-7s were not significantly different between responders and nonresponders, but the bronchodilator tests in that study" were done at 2-week intervals for 2 months without repeating the Mch challenge, which may have given different results. We used a lower cut off for a positive Mch and only a single bronchodilator test within a two week period, which may account for the different results.
*
*
In conclusion, we have found that in children with CF a change of FEV, greater than 6% from baseline after inhaled salbutamol is suggestive of nonspecific airway hyperreactivity with a very high specificity, if tested with Mch within a 2-week period. In the present series only 17% of patients with CF who had airway hyperreactivity responded with less than 6% increase in FEV I to salbutamol (83% sensitivity). We speculate that patients who have a greater than 6% change in FEV, following a bronchodilator might benefit from therapy designed to reduce airway hyperreactivity . ACKNOWLEDGMENTS
We are grateful to Drs. Hans Pasterkamp and Paul Pianosi for their critical review of the manuscript, to Jessica Holbrow, R.R.T., and Danny Castillo, R.R.T., for their technical assistance, to Anne Rempel, R.N., for recruiting the patients, to Robert Tate for statistical analyses, and to Carol Funk and Barb Janz for their expert secretarial assistance. REFERENCES I . Mellis CM, Levison H. Bronchial reactivity in cystic fibrosis. Pediatrics 1978; 61:44&450. 2. Van Asperen 0, Mellis CM, South RT, Simpson SJ. Bronchial reactivity in cystic fibrosis with normal pulmonary function. AJDC 1981; 135:815-819. 3. Darga LL, Eason LA. Zach DMS, PolgarG. Cold air provocation of airway hyperreactivity in patients with cystic fibrosis. Pediatr Pulmonol 1986; 2232-88. 4. Van Asperen P, Manglick P, Allen H. Mechanisms of bronchial hyperreactivity in cystic fibrosis. Pediatr Pulmonol 1988; 5 : 139144.
5. Zach MS. Lung discasc in cystic fibrnsis. An updated conccpt. Pediatr Pulmonol 1990; 8: 188-202. 6 . Eggleston PA, Roscnstcin BJ, Stackhouse CM, Alexander MF. Airway hyperreactivity in cystic fibrosis. Clinical correlates and possible effects on the course of disease. Chest IYXX: 94:36&365. 7. Tohin MJ, Maguire 0, Reen D, Tempany E, Fitzgcrald MX. Atopy and bronchial reactivity in older patients with cystic Iibmsis. Thorax 1980; 35:807-813. 8. Kattan M, Mansell A, Levison H, Corey M, Krastins IRB. Response to aerosol salbutamol, SCH 1000 and placebo in cystic fibrosis. Thorax 1980; 35531-535. 9. Weintraub SJ, Eschenbacher WL. The inhaled bronchodilators ipratropium bromide and mctaprotercnol in adults with CF. Chest 1989; 95:861-864. 10. Sanchez I , Holbrow J . Chernick V. Acute bronchodilator response to a combination of beta-adrenergic and anticholinergic agcnts in patients with cystic fibrosis. J Pediatr 1992;120:486488. I I . Eggleston PA, Rosenstein BJ, Slackhouse CM, Mellits D, Baumgardner RA. A controlled trial of long-term bronchodilator therapy in cystic fibrosis. Chest 1991: 99:1088-1092. 12. Pattishall EN. Longitudinal response of pulmonary function to bronchodilators in cystic fibrosis. Pediatr Pulmonol 1990; 9:8& 85. 13. Landau LI, Phelan PD. The variable effect of a bronchodilating agent on pulnionary function in cystic fibrosis. J Pcdiatr 1973: 82:863-868.
Response to Salbutamol and Airways Hyperreactivity in CF 14. Zach MS, Oberwaldner B, Forche G, Polgar G. Bronchodilators increase airway instability in cystic fibrosis. Am Rev Respir Dis 1985; l31:537-543. 15. Bibi H, Montgomery M, Pasterkamp H, Chernick V. Relationship between response to inhaled salbutamol and methacholine bronchial provocation in children with suspected asthma. Pediatr Pulmonol 1991; 10:244-248. 16. Cockroft DW, Killian DN, Mellon JJA, Hargreave FE: Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy 1977; 7:235-243. 17. Konig P, Gayer D. Barber0 GJ, Shaffer J, Krentz C, Hines C. Home measurements of peak expiratory flow rate (PEFR); diurnal variation (DV) and response to bronchodilators (BD). Pediatr Pulmonol 1991; Suppl6:284 (abstract). 18. Holzer FJ, Olinsky A, Phelan PD. Variability of airways hyperreactivity and allergy in cystic fibrosis. Arch Dis Child 1981; 56:455459. 19. Godfrey S, Springer C, Noviski N, Maayan CH,Avital A. Exercise but not methacholine differentiates asthma from chronic lung disease in children. Thorax 1991; 46:488-492. 20. Clifford RD, Radford M, Howell JB, Holgate ST. Prevalence of
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