Assessment of Airway Responsiveness in Infants with Cystic Flbrosls'"
ACKERMAN,3 G. MONTGOMERY,4 H. EIGEN, and R. S. TEPPER5
Bronchial challenge testing of older children and adults with cystic fibrosis (CF) has demonstrated a high incidence of airway hyperresponsiveness (1-5). It has generally been assumed that the hyperresponsiveness in these patients results from recurrent respiratory infections and persistent inflammation of their airways. However, evaluation of heterozygotes with cystic fibrosis has demonstrated increased responsiveness of the airways and the autonomic nervous system, suggesting that airway hyperresponsiveness in CF may be related genetically to the basic defect (6, 7). Because bronchial challenge testing has previously been performed only in older patients with cystic fibrosis, it has not been possible to determine whether airway hyperresponsiveness in cystic fibrosis was inherent or acquired. The purpose of this study was to assess whether infants with cystic fibrosis have heightened airway responsiveness compared with normal infants. Methods Subjects Fourteen stable infants with cystic fibrosis (4 males; 10 females) were recruited from the CysticFibrosis Center at the James Whitcomb Riley Hospital for Children, Indiana University Medical Center. The mean age at testing was 16.0months (3.3to 29.5). The mean Brasfield chest radiographic score was 21 (range 23 to 17). Ten of the infants had not been hospitalized since diagnosis, although four of the 10 had been treated as outpatients for symptoms of mild lower respiratory tract illnesses. The other four infants had required hospitalization for acute pulmonary exacerbations. Only one CF infant had a history of asthma in a first-degree relative. Fourteen normal control infants (7 males; 7 females) with a mean age of 17.6 months (11.0 to 28.0)wererecruited by advertisement in the Medical Center newsletter. The control infants were full term and had no congenital anomalies. The respiratory history of the normal control infants was negative for wheezing, lower respiratory illness, and familyasthma. 344
SUMMARY Wecompared the responses of cystic fibrosis (CF) (N 14)and normal (N 14) Infants with Inhaled methacholine. Airway function was assessed by forced expiratory flows at functional residual capacity (Vmax FRC) generated by the rapid compression technique, and methacholine responsiveness was quantitated as (1) TC: the threshold concentration to decrease Vmax FRC by 2 SO from baseline; (2) PC30 : the provocative concentration to decrease Vmax FRC by 30%; and (3) SPC30 : the slope of the dose-response curve between TC and PC30 • There were no significant differences In age between CF and normal Infants (16 ± 8 versus 17 ± 5 months, p > 0.3); however, the CF Infants were shorter (74 ± 10 versus 81 ± 5 em, p < 0.05), had lower absolute Vmax FRC (241 ± 103 versus 374 ± 113 mils, p < 0.001), and tended to have lower percentage of predicted flow values (87 ± 13 versus 111 ± 34%, P < 0.10). Comparison of the Indices of airway responsiveness revealed no difference In 10gTC; however, the CF Infants had smaller, more negative values for logPC 3o ( - 0.76 ± 0.52 versus - 0.22 ± 0.53, P < 0.02) and steeper slopes to their dose-response curves (logSPC 3Ot 2.42 ± 0.45 versus 1.88 ± 0.74, P < 0.025). Indices of airway responsiveness correlated significantly with baseline Vmax FRC (% of predicted). After the Influence of baseline flow upon airway responsiveness was accounted for by multiple linear regression analysis, there was a tendency for CF Infants to be more responsive than control Infants. We concluded that our Infants with CF had heightened methacholine responsiveness compared with normal age-matched control Infants; however, the difference In responsiveness was primarily related to CF Infants having AM REV RESPIR DIS 1991; 144:344-346 lower baseline flows.
At the time of pulmonary function testing, all infants, cystic fibrosis and control, were stable outpatients and had exhibited no upper respiratory symptoms for at least 3 wk. Before testing, infants with cystic fibrosis were not administered theophylline products for 24 h, sympathomimetics for 12 h, and sodium cromoglycate for 48 h. Informed consent was obtained from the parents of CF and control infants, and the study was approved by the Committee for the Protection of Human Subjects.
Methods All infants received 50 to 75 mg/kg of chloral hydrate orally before pulmonary function testing, which was performed while the infant was sleeping in the supine position. Airway function was assessed from maximal expiratory flows generated by the rapid chest compression technique as previously described (8). The partial expiratory flow volume (PEFV) curves were quantitated by the maximal expiratory flow at functional residual capacity (Vmax FRC). Criteria for an acceptable PEFV curve included (1) peak flow attained before forced expiration of 50070 of the tidal volume; (2) a smooth curve without transients in the region of FRC; (3) forced expiration past FRC; and (4) Vmax FRC reproducible within 10070. Methacholine bronchial challenge testing was then performed as previously described (9). After baseline flows were obtained, in-
fants inhaled for 2 min by tidal breathing an aerosol of normal saline generated by a smallvolume nebulizer (Model #00220, Inspiron) powered by 10 L/min airflow. PEFV curves were repeated in triplicate 1 min following completion of the aerosol. Beginning with a methacholine concentration of 0.075 mg/ml, infants inhaled doubling concentrations of methacholine until Vmax FRC decreased by at least 30070 or the methacholine concentration of 2.4 mg/ml was nebulized. At the completion of the bronchial challenge, each infant inhaled the bronchodilator metaproterenol (5070 solution; 0.025mI/kg diluted in 2 mI normal saline). During the pulmonary function testing, heart rate and oxygen saturation were continuously monitored by pulse oxim(Received in original form October 23, 1990 and in revised form January 17, 1991) 1 From the Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana. 1 Correspondence and requests for reprints should be addressed to Robert S. Tepper, M.D., Ph.D., James Whitcomb Riley Hospital for Children, Section of Pulmonology, Room 293, 702 Barnhill Drive, Indianapolis, IN 46223. 3 Supported by a Cystic Fibrosis Research Fellowship Award. 4 Supported by a CysticFibrosis Clinical Fellowship Award. S Supported by Clinical Investigator Award No. HL-01322from the National Institutes of Health.
AIRWAY RESPONSIVENESS IN INFANTS WITH CYSTIC FIBROSIS
etry (Nelcor" 200, Hayward, CA). A physician was present during the testing and performed regular auscultation of the chest.
Analysis The control value of Vmax FRC for the methacholine dose-response curve was calculated as the mean of six flow measurements, three done before and three after inhalation of an aerosol of normal saline. The percentage change in Vmax FRC from the control value was calculated with the highest value of Vmax FRC recorded after each inhaled concentration of methacholine. The coefficient of variation (CV) for the control value of Vmax FRC was employed as a measurement of the individual's variability. The threshold concentration (TC) was defined as that required to decrease Vmax FRC by 2 SD standard deviations from control. The PC 30 was defined as the provocative concentration of methacholine required to decrease Vmax FRC by 30070 from control. The values for TC and PC 30 were obtained by linear interpolation between methacholine concentrations on the dose-response curve. The slope of the dose-response curve between TC and PC 30 was defined as SPC 30 • If Vmax FRC did not decrease by 30070 with the maximum methacholine concentration administered (2.5 mg/ml), then 5.0mg/ml was entered for PC 30 , and a value of 1.0 for SPC 30 • The logarithmic transformations of TC, PC30 , and SPC 30 were employed for statistical analysis. The baseline maximal expiratory flow was expressedas both the absolute flow (milliliters per second) and as the percentage of predicted (070 predicted). The predicted values were obtained from the linear regression equations based upon body length and gender, derived from the results of 109normal infants evaluated in our laboratory. The results from the CF and control groups were compared with an unpaired t test. In addition, with the CF and control infants combined, stepwise multiple linear regression analysis was employed to evaluate the relationships among the indicesof airwayresponsiveness(logTC, log PC 30 , and log SPC 30 ) and the infants' age, gender, baseline flow, and respiratory history. Results
The individual values, means and standard deviations for the anthropometric data, baseline pulmonary function, and indices of methacholine responsiveness are summarized in tables 1 and 2. When the CF and control infants were compared, there were no significant differences in age, gender, or history of asthma in the immediate family. Infants with CF were significantly shorter in body length and weighed less than the control infants. The percentage predicted values for baseline maximal expiratory flows tended to be lower for the CF than the control infants, and the absolute flows were significantly lower for the CF than
TABLE 1 CYSTIC FIBROSIS INFANTS
1 2 3 4
5 6 7 8 9 10 11 12 13 14 Mean ± SO
3.25 4.0 7.5 11.0 13.75 14.5 14.5 16.0 20.25 20.75 22.25 23.0 23.75 29.5 16.0 7.8
53 60 66 71 67 72 75 73 80 76 84 85 85 87 74t 10
Log PC ao
Log SPC ao
134 28 118 133 132 79 86 35 67 82 49 116 78 75 87§ 13
-2.00 -2.00 -0.52 -1.05 0.24 -1.30 -0.92 -0.74 -0.74 -1.70 -1.70 0.28 -0.70 -0.66 -0.97 0.72
-1.05 -1.15 -0.74 -0.92 0.34 -1.05 -0.85 -0.70 -0.68 -1.30 -1.40 0.35 -0.68 -0.74 -0.7611 0.52
-2.54 2.62 2.50 2.87 1.33 2.60 2.85 2.54 2.31 2.76 2.83 1.75 2.41 2.03 2.4211 0.45
235 346 301 214 255 87 231 252 186 459 305 280 24ft: 103
Definition of abbreviations: TC = threshold concentration, the methacholine concentration required to decrease Vmax FRC 2 SO from the control value; PCso .. methacholine concentration required to decrease flow (Vmax FRC) 30% from the control value; SPC so = slope of the dose-response curve between threshold concentration and PCso and an index of airway reactivity. • Based on 109 normal infants tested in our laboratory. Values indicated are significantly different from control values (table 2). t p < 0.05. :1= p < 0.001. §p