Abstract
Spirometry is routinely used to assess pulmonary function of older children and adults with cystic fibrosis (CF); however, few data exist concerning the preschool age group. We have reported normative spirometric data for 3- to 6-year-old children. The current study was designed to assess a similarly aged group of clinically stable patients with CF. Thirty-three of 38 children with CF were able to perform 2 or 3 technically acceptable maneuvers. These patients had significantly decreased FVC, FEV1, FEV1/FVC, and FEF25–75 when expressed as z scores (number of SD from predicted): −0.75 ± 1.63, −1.23 ± 1.97, −0.87 ± 1.33, and −0.74 ± 1.63, respectively. There were significant positive correlations of the Brasfield radiological score with FVC and FEV1 z scores (r2 = 0.26, p < 0.01 and r2 = 0.24, p < 0.01). In addition, homozygous patients for the ΔF508 mutation had lower z scores for FVC (−1.21 versus 0.47, p < 0.01) and FEV1 (−1.38 versus 0.21, p < 0.05) than heterozygous patients. Of the 14 patients who had full flow–volume spirometric measurements during infancy, 10 had FEF25–75 z scores greater than −2 at both evaluations. Our findings suggest that spirometry can successfully be used to assess lung function in preschool children with CF and has the potential for longitudinal assessment from infancy through adulthood.
As patients with cystic fibrosis (CF) age, there is a progressive decline in lung function that eventually leads to respiratory insufficiency. Pathologic studies have shown that infants with CF have normal lungs at birth, with no evidence of airway obstruction (1), but we know that ∼ 50% of infants newly diagnosed with cystic fibrosis will have respiratory symptoms and these infants demonstrate airway obstruction on pulmonary function testing (2–5). By the time children reach school age, many have already developed measurable reductions in lung function (6). The spirometric parameter with the earliest decline is the mean forced expiratory flow between 25 and 75% expired volume (FEF25–75). In patients with CF who are between 6 and 12 years of age, FEF25–75 is 70% of predicted, and by ages 18 to 24 years it has declined to 30% of predicted (7). The FEV1, which correlates best with risk of mortality (2), is much lower in children with CF compared with nonaffected children (7). The mean FEV1 declines from 90% of predicted at age 6–12 years to 59% of predicted by age 18 years (8–10). Although the spectrum of pulmonary disease has been defined in older children and adults and increasing information is available about infants with CF (3–5), few pulmonary function data exist for children with CF who are 3–6 years of age.
It is important to understand the point at which lung function can be shown to deviate from normal, using techniques that are clinically applicable. Early quantitative assessment may allow for intervention before irreversible lung damage has occurred and may decrease morbidity and early mortality. The preschool years represent a critical time span during which disease may progress unnoticed, because we do not obtain lung function measurements during this period. We have reported that with good coaching a high success rate for spirometric measurements can be obtained in normal healthy children between the ages of 3 and 6 years (11). The purpose of our current study is to quantify the spectrum of airway disease in clinically stable children with CF who are between 3 and 6 years of age. A subgroup of these patients had spirometric measurements of lung function obtained during infancy, which enabled us to evaluate whether there was a relationship between measurements obtained during infancy and preschool.
Children with cystic fibrosis who were between 3 and 6 years old were recruited from the Cystic Fibrosis Center at James Whitcomb Riley Hospital for Children (Indianapolis, IN). Patients had a clinical history consistent with CF and the diagnosis was confirmed by pilocarpine iontophoresis quantitative sweat test done in duplicate. Children were included only if they were at their baseline condition, as judged by the attending physician, with no acute exacerbation of respiratory symptoms for at least the previous 3 weeks. Patients were excluded if they were born at a gestational age of less than 35 weeks.
This study was approved by the Institutional Review Board of the James Whitcomb Riley Hospital for Children and written informed consent was obtained.
Subjects were measured and weighed on the day of testing and z scores for weight for age, weight for height, and height for age were calculated in relation to data from the World Health Organization (12, 13). A z score is the number of standard deviations that a value deviates from the expected mean; −2 to +2 corresponds to the 95% confidence interval.
At the pulmonary function laboratory, measurements were obtained with a Vmax-22 spirometer (SensorMedics Corporation, Yorba Linda, CA) by skilled pediatric pulmonary function technicians, who regularly work with children of this age. Calibration was performed daily and according to the manufacturer's instructions. After appropriate coaching, as we have previously described, forced expiratory maneuvers were obtained with the children standing upright (11). Curves were accepted only when the difference between FEV1 curves and between FVC curves was 5% or less and excluded if a peak expiratory flow (PEF) could not be clearly determined by inspection of the curve, if there was a sharp drop or cessation of flow when flow was still greater than 10% of PEF, or if the child did not inhale above tidal volume breathing. Total training and testing time was limited to 20 minutes. Subjects who were unable to perform at least two reproducible, technically acceptable maneuvers were considered to be unsuccessful and their data were not used in the calculation of the results. Expiratory flows were corrected to btps.
Records were reviewed to determine genotype, history of Pseudomonas aeruginosa colonization obtained through oropharyngeal swabs or sputum collection, and full flow–volume spirometric measurements of lung function performed during infancy (14, 15). In addition, the most recent chest radiograph (CXR) was reviewed and assigned a Brasfield score between 0 and 25 (normal) by two of the investigators and the two scores were averaged (16).
Parameters used for statistical analysis were derived from the best curve, which was the flow–volume maneuver with the greatest sum of FEV1 and FVC. From the best forced expiratory flow–volume curve, the following parameters were obtained: FVC, FEV1, the ratio between FVC and FEV1, and FEF25–75. For each individual a coefficient of variation (standard deviation/mean) was calculated from the technically acceptable maneuvers; in addition, the intraclass coefficient of correlation was computed. We calculated z scores for these parameters using our previously published normative data for children in this age group, based on 184 normal white children (11). The change in spirometric data between infancy and preschool evaluation was compared by paired t test, as well as with a Pearson correlation comparing the former and the later values. Spirometric parameters between genetic groups and patients according to Pseudomonas status were compared by unpaired t test. A Pearson correlation was used to compare Brasfield radiological scores and spirometric parameters. A p value less than 0.05 was considered statistically significant.
Thirty-eight subjects with CF were enrolled. Thirty-three of 38 children were able to perform technically acceptable spirometry. Four of 6 3-year-olds, 9 of 11 4-year-olds, 10 of 10 5-year-olds, and 10 of 11 6-year-olds were able to perform at least two reproducible maneuvers. The 3-year-old children had a greater percentage of subjects who were not successful when compared with the 5-year-old children (p = 0.05).
The anthropometric characteristics and respiratory history of the subjects who successfully performed spirometry are summarized in Table 1
Characteristic | Value |
|---|---|
| Number of subjects | 33 |
| Age, yr | 5.3 ± 1.0 |
| Weight, kg | 17.9 ± 2.2 |
| Height, cm | 107 ± 6 |
| Weight-to-age z score | −0.49 ± 0.64* |
| Height-to-age z score | −0.84 ± 0.77† |
| Weight-to-height z score | 0.11 ± 0.71 |
| Sex, no. of males (%) | 20 (61%) |
| Race, no. of white subjects (%) | 32 (97%) |
| Positive family history of asthma | 4 (12%) |
| Positive tobacco home exposure | 14 (42%) |
Twenty-one of 33 subjects were able to perform three reproducible maneuvers; the remaining 12 were able to perform only two reproducible maneuvers. Four children, who were able to perform at least two reproducible flow–volume maneuvers, did not exhale completely to zero flow. In these four subjects FEV1 was the only parameter used, as FVC and FEF25–75 would be inaccurate.
The coefficients of variation (CVs) for FVC, FEV1, FEV1/FVC, and FEF25–75 were 2.2, 2.4, 2.0, and 7.7%, respectively. The CV was greater for FEF25–75 (p < 0.001) as compared with the other parameters, and there were no differences in variability related to age. Intraclass coefficients of correlation for FVC, FEV1, FEV1/FVC, and FEF25–75 were 0.996, 0.995, 0.929, and 0.959, respectively; all correlations had p < 0.0001.
The group mean z scores and mean absolute values for the spirometric parameters are summarized in Table 2
Parameter | z Score | Absolute Value |
|---|---|---|
| FVC, L | −0.75 ± 1.63* | 1.08 ± 0.30 |
| FEV1, L | −1.23 ± 1.97† | 0.93 ± 0.26 |
| FEV1/FVC | −0.87 ± 1.33† | 0.88 ± 0.07 |
| FEF25–75, L/s | −0.74 ± 1.63* | 1.24 ± 0.43 |
Twenty-five of 26 (96%) patients with known genotypes had either two ΔF508 mutations (homozygous) or one ΔF508 mutation (heterozygous). When genotype was used for comparison, subjects homozygous for the ΔF508 mutation had lower z scores for FVC (−1.21 versus 0.47, p < 0.01) and FEV1 (−1.38 versus 0.21, p < 0.05) than heterozygous patients. Sex, age, weight-for-age, weight-for-height, or height-for-age z scores were not different between the two genetic groups. Only 27% of the subjects with CF had positive P. aeruginosa cultures. Among the subjects with CF, spirometric parameters were not related to age at diagnosis, positive culture for P. aeruginosa, family history of asthma, or tobacco exposure in the household.
The mean Brasfield radiological scores ranged from 11.5 to 24. There were significant positive correlations of the Brasfield score with FVC and FEV1 z scores (r2 = 0.26, p < 0.01 and r2 = 0.24, p < 0.01, respectively); better spirometric parameters correlated with better radiological scores.
Fourteen of our subjects underwent spirometric measurements of lung function during infancy, when not acutely ill. The z score values of FEF25–75 obtained during infancy and in the current study are shown in Figure 5A
Figure 5. (A) Longitudinal values of FEF25–75 (z score) between infant and preschool assessments. (B) Longitudinal values for timed forced expiratory volumes: FEV0.5 (z score) measured during infancy and FEV1 (z score) measured during preschool years.
[More] [Minimize]Our study has demonstrated that most subjects with CF who are between 3 and 6 years of age can successfully perform spirometry. Our group of subjects with CF had lower pulmonary function compared with a previously studied healthy population. We also found that among the preschool children with CF who had full flow–volume spirometric measurements during infancy, most had normal airway function at both evaluations. Our findings suggest that spirometry can be used successfully to assess lung function in preschool children with CF and that measurement of the flow–volume curve has the potential to be used in the longitudinal assessment of lung function for patients with CF from infancy through adulthood.
Unlike our previously reported healthy control subjects, who were naive to spirometry, most of our patients with CF had previously attempted spirometry, which is introduced to our patients at a young age. The variability of the spirometric measurements that we observed in this study of preschool children with cystic fibrosis is similar to the variability that we previously reported in a larger group of healthy preschool children (11, 17). However, a smaller percentage of our preschool children with CF, compared with healthy control children, were able to perform three reproducible maneuvers. We would anticipate that during periods of an acute pulmonary exacerbation, the variability would increase. The variability of FEF25–75 was greater than the variability for FVC or FEV1, a finding consistent with spirometry performed in older subjects (18). This measure of variability, the coefficient of variation, is similar to the measure frequently employed in other studies. The coefficient of variation offers a degree of quality control; however, it is biased in favor of FEV1 and FVC, which are used in the criteria for accepting the forced expiratory maneuver.
As a group, our patients with CF had mild airway obstruction, although there was wide variability in the degree of airway obstruction among the patients with CF. Our findings of airway obstruction in these preschool children with CF assessed with full flow–volume maneuvers is consistent with the lower forced expiratory flows at functional residual capacity (V·maxfrc) previously reported in preschool children with CF who were assessed with partial flow–volume maneuvers (19). We also found that among subjects with CF, lower z scores for FEV1 and FVC correlated with lower Brasfield scores, a finding also consistent with previous studies of older children and adults with CF (20, 21).
Our group of preschool patients with CF had decreased values for FVC based on our reference population of healthy white subjects of the same age. As the reference population evaluated in our laboratory under the same conditions had similar rates of technically successful measurements and similar variability of the measurements, we do not believe group differences in FVC resulted from technical differences in performing the forced expiratory maneuvers. For the reference population the z scores are based on body length as an indirect index of lung size. Although we also use body length as the predictor for pulmonary function in our patients with CF, these patients have abnormal growth with decreased weight and height for age (Table 2). The preschool patients with CF may have decreased lung growth relative to their somatic growth, thus accounting for their decreased FVC. The CF group still has evidence of airway obstruction because the FEV1/FVC was lower in the CF group. The lower FEV1/FVC ratio also suggests that the decreased FVC was not secondary to an underestimate of FVC, as we would then expect a normal FEV1/FVC. Therefore, the decreased FVC may reflect an increase in residual volume secondary to airway obstruction, as well as potentially a smaller lung volume.
The z score for FEV1/FVC was significantly decreased in the group of patients with CF. However, the group mean for the absolute value for FEV1/FVC was 0.88, with 19 of 29 patients with CF having a value greater than 0.85. As very young children have faster rate constants for lung emptying during forced expiration, with FEV1/FVC approaching 1.0 (14, 22), the use of FEV1/FVC, particularly if reference values for older children are employed, may underestimate the degree of airway obstruction in preschool children with CF.
Our findings of lower FVC and FEV1 (z scores) for ΔF508 homozygous compared with heterozygous preschool subjects with CF suggest a more severe pulmonary disease in the homozygous subjects. Our finding is consistent with other studies that showed an obstructive pattern in homozygous infants (23) and an earlier age of diagnosis in the same group (24–26). Because 7 of 11 heterozygous subjects in our study did not have the second mutation identified, it is possible that these subjects could have milder mutations with less pulmonary involvement.
The 27% prevalence for P. aeruginosa colonization in our preschool children is within the wide range reported for children with CF (2–72%), which may relate to the methodology for obtaining cultures, the frequency of collection, colony count criteria, and age (8, 27–32). In our study, positive cultures for P. aeruginosa, which were obtained by sputum or throat swab, did not correlate with pulmonary function. In contrast, studies of older subjects with CF have reported lower lung function in subjects colonized with P. aeruginosa (33–35). The absence of a relationship may have resulted from the younger age of our patients with CF, lower colonization rate, and the shorter time period for the appearance of its adverse effects.
We have reported that during infancy, those subjects with CF who had lower V·maxfrc values at diagnosis had lower values at 1-year follow-up (36). Most previous studies of infants with CF used partial flow–volume maneuvers; however, in this current study our measurements in infants with CF were obtained with full flow–volume maneuvers, which yield spirometric parameters similar to maneuvers performed in older, cooperative children and adults. Our current data suggest that spirometric measurements obtained during infancy track airway function into the preschool years.
In summary, spirometric measurements in preschool children with CF can quantify lung function in this age group and detect the presence of airway obstruction. As spirometric measurements can also be obtained in infants and toddlers, spirometry has the potential for the longitudinal assessment of lung function in patients with CF from infancy through adulthood.
Supported by grants from the Cystic Fibrosis Foundation and CAPES (Brasília, Brazil).
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