American Journal of Respiratory and Critical Care Medicine

The tidal and raised volume rapid thoracoabdominal compression techniques are increasingly used to detect diminished airway function in infancy. The aim of this study was to assess the relative ability of parameters measured by these techniques to identify diminished airway function in infants newly diagnosed with cystic fibrosis (CF) with and without clinical evidence of prior lower respiratory illness. A cross-sectional, prospective study design was used in which maximal flow at functional residual capacity (VmaxFRC) from the tidal technique and FVC, FEV0.5, FEF75, and FEF25–75 from the raised volume technique were measured in 47 infants with CF and 187 healthy infants of similar body size, sex distribution, ethnic group, and exposure to maternal smoking. Multiple linear regression was used to assess group differences and to calculate SD scores for each parameter for the infants with CF. Airway function was also compared with clinical assessments of respiratory status made by pediatric pulmonologists. FEV0.5 was significantly diminished in 13 infants with CF, of whom 4 had been identified by clinicians as having normal respiratory status. Only one infant with CF had a VmaxFRC below the estimated normal range. Airway function is diminished in infants with CF irrespective of prior lower respiratory illness and in those whose respiratory status is considered normal by pediatric pulmonologists. In infants with CF, the raised volume technique identified diminished airway function more frequently than the tidal technique.

Respiratory morbidity secondary to chronic inflammation and infection is the leading cause of death among those with cystic fibrosis (CF). Recently, bronchial inflammation similar to that seen in older subjects has been identified in the lungs of affected infants (1), but the evolution of airway pathology in early infancy remains poorly understood. Previous reports of lung function in infants with CF have been difficult to interpret because of small numbers of subjects, inappropriate methods, and failure to recruit control groups (2).

The introduction of screening programs for CF and the development of new therapeutic interventions mean that novel and earlier treatments are possible. Objective outcome measures for the evaluation of early therapeutic interventions are required. In older subjects with CF, spirometric measurements of forced expiration, such as FEV1 and FEF at low lung volumes (e.g., FEF75), are used to assess airway function (3). Although several studies have used the tidal rapid thoracoabdominal compression (RTC) technique to investigate airway function in infants with CF (415), it remains unclear whether infants with CF with no evidence of prior lower respiratory illness (LRI) have diminished airway function (2). Methods to assess forced expiration over an extended volume range in infants have been described recently (16). This raised-volume RTC (RVRTC) technique uses a pump or manual inflations to increase the volume of inspiration before applying external pressure to the chest wall and abdomen using an inflatable jacket to generate FEF volume curves. From these curves, it is possible to derive parameters such as FEV in 0.4 or 0.5 seconds (FEV0.5) and FEF75, which are comparable to those obtained in older subjects. We have previously reported diminished airway function in those with or without clinically apparent prior LRI using this technique (17). However, the ability to identify diminished airway function at an individual rather than a group level would be of greater relevance to clinical practice.

It has been suggested that the identification of diminished airway function in infancy may be more readily detected by the RVRTC technique (11). In this study, we compare the extent to which parameters derived from the tidal RTC and the RVRTC techniques identify diminished airway function in this sample of subjects recently diagnosed clinically with CF, using reference data derived from healthy infants. We also compare clinical assessments of respiratory status made by pediatric pulmonologists with physiologically assessed airway function.

Subjects

Infants and young children newly diagnosed with CF by a sweat test and/or by a positive genotype for CF mutations (18) were recruited between January 1999 and May 2001 from five specialist centers in London (Royal Brompton, Great Ormond Street, King's College, Royal London and University Hospital Lewisham) where neonatal screening is not routinely undertaken. Subjects were eligible if they were less than 24 months of age at diagnosis and were free from additional congenital or acquired cardiorespiratory or neurologic abnormalities. The responsible pediatric pulmonologist was asked to make a clinical assessment on the basis of factors such as tachypnoea, retractions, auscultation, oxygen saturation, and the presence or absence of added sounds. This was performed at the time of recruitment, before the lung function test, and was scored using a four-point Likert scale to determine respiratory status (1 = normal, 2 = mild abnormality, 3 = moderate abnormality, and 4 = severe abnormality). The principal investigator performing the measurements remained blinded to the clinical assessments until the end of the study. Details of mode of presentation; prior hospital admission; current or prior treatment with intravenous, inhaled, or oral antibiotics; and prior episodes of bronchiolitis or other LRI were obtained by inspection of medical records and parental report. A cough swab was taken, and all past microbiologic assessments were reviewed at the time of the test. Infants without prior lower respiratory tract symptoms, with normal respiratory physical examination, not previously treated with oral, inhaled, or intravenous antibiotics and in whom all microbiologic assessments were negative, were classified as infants without clinically recognized prior LRI.

Healthy infants born at the Homerton or University College Hospitals in London were recruited by initial letter to the parents and a follow-up telephone call as part of an ongoing epidemiologic study (19). Subjects with a history of respiratory illness requiring hospitalization, congenital abnormalities, requirement for assisted ventilation in the neonatal period or gestational age of less than 36 weeks at birth were ineligible. Parents of both CF and healthy infants gave informed written consent. The study was approved by the North Thames Multicentre Research Ethics Committee and the Local Research Ethics Committees of the participating hospitals.

Measurement of Airway Function

Both CF and healthy infants were tested when well and clinically free from upper respiratory tract infections for at least 3 weeks. All lung function tests were performed in the infant respiratory physiology laboratories at the Institute of Child Health and Homerton Hospital by the same research team using identical methods and equipment. On the day of testing, infants were weighed, and crown–heel length was measured. Weight and length centiles were calculated using Child Growth Foundation Charts (20). Exposure to maternal smoking prenatally and postnatally was assessed from maternal report, and current smoking was confirmed by maternal salivary cotinine (21). All infants were studied in the supine position after sedation with an oral or rectal dose of 60–100 mg/kg of chloral hydrate or an equivalent dose of triclofos sodium.

The RTC technique was performed before the RVRTC using standardized methods (22). The RVRTC technique was performed using an adaptation of the technique described by Feher and colleagues (16). The technique and methods of analysis used in this study have been described in detail elsewhere (19, 23, 24). Expiration was forced from an inflation pressure of 3 kPa, and maneuvers were repeated until a minimum of two (usually three) acceptable and reproducible (sum of FVC and FEV0.5 within 10% of each other) flow-volume curves were obtained. Maximal flow at functional residual capacity (VmaxFRC) was calculated as the mean of the highest three values from technically acceptable flow–volume curves obtained using the RTC technique, whereas FVC, FEV0.5, FEF75, and FEF25–75 were reported from the “best” RVRTC flow-volume curve (defined as the technically acceptable maneuver with the highest sum of FVC and FEV0.5) (3, 19, 23).

Statistical Analysis

Associations between each parameter of airway function and CF with or without prior clinical evidence of LRI were examined after allowing for sex, age, body weight and length at test, and exposure to maternal smoking using multiple linear regression to confirm group changes that we had observed previously (17). Normality plots were used to verify that assumptions of normality were met. Prediction models from each of the parameters measured were created using only the values from healthy infants. Thus, airway function of infants with CF was compared with that predicted from measurements in healthy infants after taking into account differences in body size, age, sex, and exposure to maternal smoking. To identify diminished airway function in individual infants with CF, results were expressed as SD scores: SD score = (measured value − predicted value)/SD of prediction.

Power

The study was powered to identify group differences between those with and without CF. We assumed from previous data that body size, sex, and exposure to maternal smoking might account for 40 to 80% of the variability in FEV0.5 and FEF75. Were an additional 10% of this variability due to CF, a sample of 90 control subjects and 30 CF patients would be sufficient to detect this with at least 80% power at the 5% significance level (25).

Sixty-three subjects who were less than 24 months of age were diagnosed with CF over the 2-year study period. Sixteen infants were not studied. The reasons for this included parental refusal (n = 6), ventilation for respiratory failure (n = 2), adverse social circumstances (n = 1), distance from laboratory (n = 1), associated Arnold-Chiari malformation (n = 1), and Pierre-Robin syndrome (n = 1). Four infants were recruited but failed to attend for lung function tests on at least two occasions. Forty-seven infants with CF were therefore recruited and studied. The primary mode of presentation for these infants was recurrent chest infections (n = 21), failure to thrive (n = 7), meconium ileus (n = 11), meconium ileus with antenatal bowel pathology (n = 6), rectal prolapse (n = 1), and hypoproteinaemia (n = 1). They were diagnosed at a median (range) corrected age of 10 (0–88) weeks and were tested within a median (range) interval from diagnosis of 12 (0–38) weeks. There was no significant difference in the age at diagnosis, mode of presentation, and genotype between infants who were and were not recruited (data not shown).

Pseudomonas aeruginosa had been isolated in eight infants (17%) before the lung function assessment. Other organisms identified before the first assessment were Staphylococcus aureus (n = 4), methicillin-resistant S. aureus (2), Escherichia coli (6), klebsiella sp. (3), enterobacter sp. (2), Streptococcus pneumoniae (1), and aspergillus sp. (1). In 20 infants (43%), no organisms were isolated before the lung function test.

Twenty nine (62%) were homozygous for ΔF508; 14 (30%) were heterozygous for ΔF508. One infant was homozygous for the 621 + 1G→T mutation; no mutation was identified in three infants.

In addition to the 21 infants who presented with recurrent respiratory tract infections, 14 infants had positive bacteriologic cultures before the lung function test and/or had been prescribed intermittent courses of oral, inhaled, or intravenous antibiotics. These 35 infants were classified as having clinical evidence of prior LRI. Of the 12 infants with no prior LRI, 10 presented with meconium ileus and 2 with failure to thrive or malabsorption.

One hundred eighty-seven healthy infants were studied, 14 of which (7%) had been diagnosed with wheezing LRI by a physician before lung function testing; but none had been hospitalized because of respiratory illness, and all were well at the time of testing.

The background details of the infants with CF and healthy infants are shown in Table 1

TABLE 1. Details of the infants


Detail

Cystic Fibrosis

Healthy Infants

Difference (95% CI)
 CF: Healthy
Number47 187
Number (%) male19 (40.4)95 (50.8)−10.4% (−25.0, 5.5)
Number (%) white46 (97.9)186 (99.5)−1.6% (−10.6, 7.4)
Number (%) maternal smoking13 (27.7)75 (40.1)−12.4% (−25.3, 3.20)
Mean (SD) gestational age, wks39.0 (2.0)39.8 (1.5)−0.80 (−1.3, −0.3)
Mean (SD) birth weight, kg3.09 (0.56)3.33 (0.47)−0.24 (−0.39, −0.08)
Mean (SD) birth weight centile
42.6 (32.7)
43.4 (25.1)
−0.80 (−11.7, 9.5)

Definition of abbreviation: CF = cystic fibrosis; CI = confidence interval.

, and infant details at time of test are summarized in Table 2

TABLE 2. Details of the infants at test



Cystic Fibrosis


Prior Lower
 Respiratory Illness
 (n = 35)
No Prior Lower
 Respiratory Illness
 (n = 12)
Healthy Infants
 (n = 187)
Age, wks31 (7–93)15 (6–61)7 (1–100)
Weight, kg7.6 (4.5–11.4)4.7 (3.7–7.4)5.2 (2.5–14.8)
Weight centile12.6 (0–98.5)1.3 (0–48.5)45.9 (0.1–99.5)
Length, cm68.9 (54.0–86.8)59.2 (54.5–73.3)58.0 (49.9–90.1)
Length centile
44.4 (0.1–99.8)
20.8 (0–80.0)
64.6 (2.2–99.5)

* Data are shown as median (range).

.

Infants with CF and no clinical evidence of prior LRI were significantly younger when tested than those with prior LRI (p = 0.005) (Table 2), reflecting the younger age at diagnosis of nonpulmonary modes of presentation. They were also significantly lighter, and there was a trend for these infants to be shorter for age than those with prior LRI. Both groups of infants with CF were significantly lighter and shorter for age when compared with the healthy infants. Thus, although older, infants with CF were of similar length and weight to the healthy infants when tested (Table 2). Both groups were similar with respect to sex distribution, ethnic group, and the proportion of mothers who smoked in pregnancy.

Generally, there was good concordance between maternal reports of smoking and cotinine assay of maternal saliva; however, five infants (four healthy and one with CF) were reclassified into the smoking category, as maternal salivary cotinine concentrations ranged from 20.9 to 217.6 ng · ml−1 and were consistent with values from active smokers (more than 15 ng · ml−1) (26, 27). After reclassification of these five infants into the smoking category, median (interquartile range) maternal salivary cotinine was 0.2 (0.1–0.6) ng · ml−1 and 189 (59.2–316) ng · ml−1 in nonsmokers and smokers, respectively.

The tidal RTC technique was successful in 186 of 187 healthy infants. The RVRTC was attempted in 138 healthy infants and was successful in all of these. Two infants with CF failed to sleep at all. One woke up during the RTC technique, and two awoke before the completion of the RVRTC technique. Therefore, airway function was measured successfully using the RTC and RVRTC techniques in 45 and 42 of the 47 infants with CF, respectively. Early inspiration precluded measurement of FVC and hence FEF percentage in two infants in whom FEV0.5 could be measured.

The associations of airway function with length according to disease status are shown for FVC, FEV0.5, FEV0.5/FVC, FEF75, and VmaxFRC in Figure 1

. All parameters increased with body size, but FEFs were more widely scattered between subjects at any given length than volume parameters. Airway function was significantly lower in infants with CF both with and without clinical evidence of prior LRI using all parameters measured with the RVRTC except FEV0.5/FVC. Although VmaxFRC from the RTC was diminished in those with no clinical evidence of prior LRI, this was not the case for infants with prior LRI (p = 0.16) (Table 3)

TABLE 3. Mean (95% ci) reduction in airway function of infants with cystic fibrosis with and without clinical evidence of prior lower respiratory illness



Mean (95% CI) Reduction in Airway Function
Parameter
CF: Prior Lower
 Respiratory Illness
CF: No Prior Lower
 Respiratory Illness
FVC, ml50.8* (−67.8, −33.9)31.0* (−56.2, −5.74)
FEV0.5, ml42.5* (−56.8, −28.2)41.0* (−62.2, −19.9)
FEV0.5/FVC, %−2.5 (−5.2, 0.19)−3.0 (−7.0, 0.94)
FEF75, ml · s−162.1* (−97.1, −27.2)84.0* (−134, −33.8)
FEF25–75, ml · s−1113* (−165, −65.7)136* (−203, −59.6)
VmaxFRC, ml · s−1
20.6 (−49.3, 8.14)
49.2 (−92.6, −5.78)

*p ⩽ 0.001.

p < 0.05.

Definition of abbreviations: CF = cystic fibrosis; CI = confidence interval.

.

As a SD score of −1.96 equals the 2.5th centile, we defined diminished airway function in individual infants with CF using this cutoff. FEV0.5 was diminished in more infants with CF than any other parameter. Thirteen infants with CF had an FEV0.5 below the normal range, including 4 of 12 with no clinical evidence of prior LRI. FVC, FEV0.5/FVC, FEF75, FEF25–75, and VmaxFRC identified diminished airway function in 10, 8, 3, 5, and 1 infants with CF, respectively. SD scores for FEV0.5 and VmaxFRC and FEF75 and VmaxFRC are shown in Figure 2

where both measurements had been obtained. SD scores were not significantly different in those with or without clinical evidence of prior LRI, although there was a trend for diminished FVC in those with prior LRI. SD scores were not statistically different in those infants with CF who are homozygous for ΔF508 or those in whom P. aeruginosa had been isolated.

The SD scores for FEV0.5 in relationship to clinical assessment are shown in Figure 3

. Clinical assessments were made in 45 infants with CF at a median (interquartile range) interval of 5 weeks (4–6 weeks) before the lung function test. Measurements of airway function using the RVRTC technique were successful in 41 of these subjects, in whom clinical assessments were normal in 17. There was no significant difference in the mean SD score between those with normal and abnormal assessments (means of −1.1 and −1.4, respectively, p = 0.40). Four (24%) and nine (38%) infants with normal and abnormal respiratory assessments, respectively, had measurements of FEV0.5 of less than −1.96 SD (below 2.5th centile). Thus, approximately one-quarter of infants with CF who were asymptomatic when tested had diminished airway function shortly after diagnosis even though clinicians responsible for their care in specialist centers considered their respiratory status to be normal. Four infants had no clinical evidence of prior LRI but a SD score for FEV0.5 of less than −1.96. Two of these infants were considered normal by their pulmonologist. One was considered to have a mild abnormality, whereas no assessment was available for the fourth.

We have shown that airway function is reduced in infants with CF early in the course of the disease and that many individual infants with CF have airway function below the 2.5th centile defined by a healthy control group. Infants with no clinical evidence of prior LRI and infants assessed as having normal respiratory status by hospital specialists also had reduced airway function. Whereas the RTC technique was not useful for identifying diminished airway function in individual infants with CF in this study, FEV0.5 from the RVRTC technique identified diminished airway function in 31% of such infants.

In previous studies of healthy infants, male sex and exposure to maternal smoking in pregnancy have been associated with diminished airway function (2830), but these factors have rarely been taken into account when analyzing data in infants with CF (4, 6, 31). In this study, parameters of airway function from the RVRTC were significantly diminished in infants with CF even after allowing for these factors. Spirometric measurements of FEV1 are used in older subjects to assess the disease severity, progression, and response to interventions, but the first abnormality in older subjects with CF appears to be a reduction in mid and end FEFs (32). Although abnormalities in FEF75 and FEF25–75 were identified in our study, more infants with CF had diminished FEV0.5. Approximately 30% of infants with CF had an FEV0.5 below the 2.5th centile. This was not the case when VmaxFRC was used to compare airway function between infants with and without CF. This may in part explain the difficulty encountered when interpreting the results of previous studies that have applied the tidal RTC technique to infants with CF (2). Extending the volume range over which measurements of forced expiration are assessed appears to improve ability to detect diminished airway function. Because of a much shorter duration of forced expiration in infants, FEV0.5 is closer to FVC than FEV1 in adult subjects (23). FEV0.5 is therefore more likely to be reflecting properties of the airways at lower lung volumes than FEV1, which may partly explain why this parameter identified diminished airway function shortly after diagnosis. In adults and older children, airway obstruction is indicated by a reduction in the ratio of FEV1/FVC as FEV1 is reduced disproportionately compared with FVC. Although FEV0.5/FVC was not significantly reduced in the individual subgroups of infants with CF, the ratio was significantly lower when analyzed for the group as a whole (p = 0.02) but only by a mean of 2.7% (95% confidence interval, −5.0, −0.35). Eight infants were identified with an FEV0.5/FVC below the 2.5th centile; however, the interpretation of the ratio of FEV0.5/FVC in infants is difficult. In some infants, 0.5 seconds may be so close to the duration of forced expiration that FEV0.5 merely reflects FVC. In addition, interpretation of FEV0.5/FVC is complicated by the strong negative dependence on age and respiratory rate and its wide intersubject variability in infants (Figure 1), some of which may be due to dysanaptic lung growth (23).

Changes in lung function of infants with CF have been reported in several studies established to identify the evolution of pulmonary disease during the first year of life (4, 6, 3335), but their findings have not been conclusive. Tepper and colleagues (6) reported normal pulmonary function in 5 neonates presenting with meconium ileus, normal or diminished pulmonary function in 8 infants with failure to thrive but no respiratory symptoms, and severe airway obstruction in 12 infants with respiratory symptoms at diagnosis. Beardsmore and colleagues (4) reported that airway function, assessed using the RTC technique, was normal in 28 infants diagnosed by newborn screening and measured at an average of 19 weeks. In this study, we used a newer technique that is considered to be more sensitive in the detection of airway abnormalities (11). We have been able to recruit larger numbers of infants newly diagnosed with CF than previous studies through our London-wide collaboration and have, in addition, been able to compare findings with a large prospectively measured control group of infants of comparable sex, ethnic group, and exposure to maternal smoking.

There are several disadvantages of the RTC technique, including the lack of a reliable volume landmark for the measurement of VmaxFRC. FRC is known to be variable in this age group (36), as the end-expiratory lung volume is actively controlled rather than being passively determined. The extent to which FRC is dynamically elevated is influenced by age, maturity, and underlying respiratory mechanics, and it may also vary with dead space, disease state, and sleep state (37, 38). These add to the intrasubject and intersubject variability of VmaxFRC, which has been reported to have coefficients of variation of approximately 15% and 50%, respectively (39, 40). By using standardized methods, performing the measurements during quiet sleep and establishing a stable end-expiratory level, the within-subject variability of VmaxFRC was 5.3% and 6.7% in healthy infants and infants with CF, respectively, in this study, less than that for parameters of FEF from the RVRTC technique (within-subject variability of FEF75 was 9.3% and 8.8% for healthy infants and infants with CF, respectively); however, this did not increase the ability of the RTC technique to identify diminished airway function in this study. It is possible that small airway closure occurs in infants with CF at low volumes so that residual volume and FRC are elevated. As FEFs will be higher at larger lung volumes, the inability to demonstrate a difference in VmaxFRC in infants with CF and prior LRI when compared with healthy infants could be a result of small airway closure leading to elevated FRC in those with CF. The same process could explain the lower values for FVC, especially in those infants with prior LRI. An increased residual volume in these subjects would decrease FVC, elevate the lung volume at which FEFs are measured, and explain why such flows were somewhat larger in these subjects than those with no clinical evidence of prior LRI (Table 3). Another mechanism to explain diminished FVC in infants with CF is that because of airway obstruction, these infants inspired prematurely during forced expiration to defend lung volume. We tried to avoid this problem by carefully inspecting each flow-volume curve. Data for FVC and FEF75 from two infants were excluded because of early inspiration. It is possible that we may have failed to detect early inspiratory effort in some infants. Others have also noted this to be a problem during forced expiratory maneuvers in infants with airway obstruction (41).

It is important to stress that FEV0.5 and FEF75 measured by the RVRTC technique remain critically dependent on lung volume for the reasons discussed previously here. Measuring fractional lung volumes (42, 43) in addition to forced expiratory maneuvers may demonstrate the relationship between FEF and lung volumes more clearly in infants with CF. It is also possible that the finding of diminished FVC in the infants with CF is related to depressed lung growth in excess of poor somatic growth in these infants, that is, a restrictive or mixed pattern of disease rather than primarily airway obstruction. Such a mechanism could result in diminished parameters measured by the RVRTC, as the technique is performed over the full range of lung volume while having minimal effect on VmaxFRC measured from the RTC technique.

The plot of VmaxFRC versus length (Figure 1) shows that the measurements were widely scattered compared with parameters measured from the RVRTC. For a 70-cm male infant not exposed to maternal smoking, the predicted (2.5th to 97.5th) centiles for FEF75 and VmaxFRC were 316 (152 to 480) ml · s−1 and 176 (44 to 308) ml · s−1, respectively. Thus, a FEF75 value of less than 48% of the predicted mean would lie below the 2.5th centile (152 of 316), whereas the equivalent centile for VmaxFRC would be 26% of the predicted mean (44 of 176). The larger intersubject variability may also explain why VmaxFRC identified fewer CF subjects as having diminished airway function. The mean SD score for infants with CF was −0.82 and −0.27 for FEF75 and VmaxFRC, respectively. VmaxFRC was below the lower limits of normality in only one infant with CF.

One critical factor during forced expiratory maneuvers in infants is whether physiologically determined flow limitation is achieved. Although flow-limited isovolume pressure curves have been demonstrated during RTC maneuvers in infants with severe airway obstruction (44), flow limitation in healthy infants has not been documented consistently. When comparing healthy and disease groups, this could result in an underestimation of maximal flow in the healthy group, making discrimination between the groups more difficult. By adhering to a standardized protocol (22), we believe that we made every effort to achieve flow limitation in all infants in this study.

One limitation of this study was that clinical assessments were made before the lung function. Ideally, an assessment performed on the test day itself by a single independent physician who was blinded to both diagnosis and airway function would have allowed a more scientifically valid comparison of clinical status and airway function; however, such an approach would not have permitted the pulmonologist to use evidence gained on repeated occasions to inform his or her decision. It was not practical in this collaborative project for the pulmonologist responsible for the care of the child to attend the lung function laboratory to make the assessment on the day of the test itself, although the physical assessment and close questioning of the parents on the day of the study were able to ascertain any previously undocumented signs and symptoms up until the time of testing.

Little is known about the effects of augmented inflations during the RVRTC on the subject and whether these influence the measurements obtained. Because there could be an effect of repeated deep inflations on airway mechanics, the RTC was performed before the RVRTC technique in our subjects. It is possible that augmented inflations during the RVRTC increased the ability of the latter test to identify diminished airway function by differing effects on healthy infants and those with CF. The effects of deep inspiration in individuals with asthma differ from those observed in healthy subjects, in whom deep inspiration act both as a bronchoprotector (decreasing or ablating responsiveness to bronchoconstricting agents) and a bronchodilator (45). In asthma, bronchoprotection by deep inspiration appears to be lost and the bronchodilator ability of deep inspiration attenuated (46). Similar findings have been demonstrated in older subjects with CF (47). Investigators have attempted to assess the effect of deep inspiration on FEFs by comparing flow-volume curves from partial lung inflation, which are less affected by volume history, with flow-volume curves obtained from full inflation (48). We were unable to demonstrate a difference in response to inflations in our subjects, as there was no difference in the ratio of FEFs measured from the tidal and raised-volume technique (VmaxFRC versus FEF75) in those with or without CF, nor did successive RVRTC maneuvers exhibit a consistently increasing or decreasing series of values (data not shown). Further studies are required to assess the effects of augmented inflations and volume history on airway mechanics in infancy.

The repeated lung inflations required for the RVRTC could also cause gastric distension in some infants (49). Had this occurred to any measurable extent in this study, we would have expected a progressive reduction in FVC and FEV0.5 during successive maneuvers. To examine this possibility, we inspected consecutive RVRTC data from 15 healthy infants and 16 infants with CF from the study cohort and assigned a score depending on the chronologic order of the best maneuver (sum of FVC and FEV0.5). The percentage of best loops being the first, second, or third technically acceptable maneuvers was evenly distributed among both the healthy infants and the infants with CF, suggesting that errors caused by gastric distension were unlikely in this study. This may be related to the fact that we estimated “optimal” jacket inflation pressure to force expiration for the RVRTC during the RTC (50), thereby requiring relatively few RVRTC maneuvers in each child.

As yet, the RVRTC remains an unstandardized technique with respect to equipment, method (24, 50), or analysis (23), making comparisons of data collected in different centers extremely difficult (49). We have reported FEV0.4 previously from this cohort (17), as this parameter may be more appropriate in young infants due to the short duration of forced expiration (23). In this study, however, we have chosen to report FEV0.5 to facilitate interpretation of our results with respect to published prediction equations. We compared SD scores for FEV0.5 for the infants with CF in this study with those obtained using the prediction equations reported by Jones and colleagues (30). Eighteen (43%) of infants with CF were identified as having a SD score of less than −1.96 using these published prediction equations, but this included all 13 infants identified as having diminished airway function using prediction equations developed from the healthy infants reported in the current study. Recently, data for VmaxFRC in 459 healthy infants (226 boys) tested on 654 occasions during the first 20 months using standardized methods (22) have been collated from three centers (51). There was no significant difference between mean SD scores reported here and those calculated using the reference population of Hoo and colleagues. Six (14%) infants with CF had diminished airway function when measurements of VmaxFRC were compared with this reference population. Differences in method, analytical approach, and the reference populations studied could explain these findings.

Although in this study many healthy infants were less than 3 months of age as they were recruited as part of an ongoing epidemiologic project involving the assessment of airway function in the first few months of life (19), they were of similar body weight and length to the older infants with CF. Although using our reference population to predict RVRTC parameters may have underestimated the number of infants with CF with diminished airway function by comparison with published reference data, our approach has the advantage that measurements were obtained in both healthy infants and infants with CF by the same investigators using the same equipment and methods.

The lungs in CF are thought to be nearly normal at birth (52, 53). This implies that the process leading to impaired lung function probably occurs early in postnatal life, which is a period of rapid lung growth and development. Pulmonary inflammation has been identified in infants with CF, in some cases as young as 4 weeks of age (1, 54) and, therefore, is the most likely mechanism to explain damage to the lungs early in the course of disease. We did not perform bronchoalveolar lavage to identify pulmonary inflammation, as this procedure is rarely undertaken in asymptomatic infants with CF in London, and thus, we are unable to comment on the association between inflammation and diminished lung function in this cohort of infants. It is possible that bronchoalveolar lavage would have identified occult infection in some infants with no clinical evidence of prior LRI as infection has been detected using this procedure in asymptomatic infants (55, 56). In a recent study, an inverse correlation was demonstrated between either infection or inflammation and specific respiratory system compliance and a positive correlation demonstrated with hyperinflation in children with CF of mean age 25 months, suggesting that infection and inflammation impact lung function early in CF (57). The association between infection and inflammation and diminished airway function is yet to be demonstrated in infants with CF.

The longer term implications of early diminution in airway function in those with CF are unclear, as longitudinal studies in this population are lacking. There are few longitudinal epidemiologic studies of airway function in healthy infants, but those available suggest that infants with diminished airway function shortly after birth are at increased risk of diminished lung function and subsequent respiratory morbidity in later childhood (5860). Thus, early impairment of airway function may have long-term consequences in a disease in which the majority of patients die because of pulmonary involvement (61). Many new potential therapies are being developed (62), and the findings from this study may have implications for the timing of such therapeutic interventions in CF and the choice of outcome measures.

In conclusion, we have shown that the RVRTC technique is better at identifying diminished airway function than the RTC technique in infants newly diagnosed with CF. We have used this technique to demonstrate that lung function is diminished in those with no clinical evidence of prior LRI and in those considered to be free of respiratory problems by pediatric pulmonologists. Although longitudinal studies are needed to establish the significance of these findings, we have shown that the RVRTC is more sensitive than the RTC in the detection of early airway abnormalities in infants with CF.

The authors thank the families who participated in this study and Dr. Colin Feyerabend for his analysis of the cotinine samples. The London Collaborative Cystic Fibrosis Group is as follows: Beryl Adler, Ian Balfour Lynn, Andy Bush, Siobhán Carr, Rosie Castle, Kate Costeloe, Sarah Davies, Charlotte Daman-Willems, Jane Davies, Carol Dezateux, Robert Dinwiddie, Jackie Francis, Iris Goetz, Ah Fong Hoo, Jane Hawdon, Sooky Lum, Su Madge, John Price, Sarath Ranganathan, Mark Rosenthal, Gary Ruiz, Janet Stocks, John Stroobant, Angie Wade, Colin Wallis, and Hilary Wyatt.

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Correspondence and requests for reprints should be addressed to Dr. Sarath Ranganathan, Portex Unit, 6th Floor, Cardiac Wing, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. E-mail:

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