PEDIATRICS Vol. 107 No. 3 March 2001, pp. 512-518

Relation of Two Different Subtypes of Croup Before Age Three to Wheezing, Atopy, and Pulmonary Function During Childhood: A Prospective Study

José A. Castro-Rodríguez, MD, Catharine J. Holberg, PhD, Wayne J. Morgan, MD, Anne L. Wright, PhD, Marilyn Halonen, PhD, Lynn M. Taussig, MD, and Fernando D. Martinez, MD

From the Respiratory Sciences Center, University of Arizona, College of Medicine, Tucson, Arizona.

	ABSTRACT

Top Abstract Methods Results Discussion Conclusion References

Objective.  Some retrospective evidence suggests that children with a history of croup may be at increased risk of subsequently developing asthma, atopy, and diminished pulmonary function. The objective of this study was to determine the long-term outcome of croup (as diagnosed by a physician) in early life.

Methods.  Lower respiratory illnesses (LRIs) in the first 3 years of life were assessed in 884 children who were enrolled in a large longitudinal study of airway diseases at birth. Pulmonary function tests, markers of atopy, and wheezing episodes were studied at different ages between birth and 13 years.

Results.  Ten percent of children had croup with wheeze (Croup/Wheeze), 5% had croup without wheeze (Croup/No Wheeze), 36% had another LRI (Other LRI), and 48% had no LRI. Respiratory syncytial virus was more frequently isolated in children with Croup/Wheeze and Other LRI than in those with Croup/No Wheeze. There was no association between croup in early life and markers of atopy measured during the school years. Only children with Croup/Wheeze and with Other LRI had a significant risk of subsequent persistent wheeze later in life. Significantly lower levels of indices of intrapulmonary airway function were observed at ages <1 (before any LRI), 6, and 11 years in children with Croup/Wheeze and Other LRI compared with children with No LRI. Conversely, inspiratory resistance before any LRI episode was significantly higher in infants who later developed Croup/No Wheeze than in the other 3 groups.

Conclusions.  We distinguish 2 manifestations of croup with and without wheezing. Children who present with croup may or may not be at increased risk of subsequent recurrent lower airway obstruction, depending on the initial lower airway involvement, and preillness and postillness abnormalities in lung function associated with this condition.  Key words:  croup, wheezing, atopy, pulmonary function, children.

Viral croup (acute laryngotracheobronchitis) is a frequent childhood respiratory infection that is characterized by inspiratory stridor, hoarse voice, and barking cough.^1-4 Data from the United States indicate that croup is a common cause of medical consultation in infants, with a peak incidence of nearly 60 cases/1000 child-years in children between the ages of 1 and 2 years.⁵ Although croup is usually a self-limited disease, there is some evidence to suggest that children with a history of severe or recurrent croup may be at increased risk of developing asthma when compared with those with mild or no croup.^1,3,4,6 In support of this contention, studies in older children show that those with a history of hospital admissions for croup have a higher prevalence of bronchial hyperresponsiveness, allergy skin test response, and increased total serum immunoglobulin E (IgE) levels than do children without such a history.^1,3,4,7,8 Diminished pulmonary function has also been reported in schoolchildren with a history of croup in infancy.^9,10

Most of these studies, however, were retrospective and were based on selected populations of children with great variability in croup severity and recurrence. Only one published study is based on a general population sample of unselected schoolchildren,¹¹ but ascertainment of croup was retrospective and based on parental questionnaires.

In this study we assessed the long-term outcome of croup in early life using data from a large longitudinal study of airway diseases in >1000 children who were enrolled at birth. Assessment of croup (and the concurrent presence or absence of wheeze) was made directly by a physician during early childhood.

	METHODS

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The children who were included in this study were part of a birth cohort enrolled from 1980 to 1984 in the Tucson Children's Respiratory Study,¹² a large longitudinal study of respiratory illnesses during childhood. Detailed information about the study design has been published elsewhere.¹² A total of 1246 healthy newborns originally were enrolled in the study. Birth weight, level of maternal education, maternal smoking, and data on parental history of physician diagnosis of asthma and allergic rhinitis were obtained from questionnaires administered to parents shortly after their child's birth. This study was approved by the Human Subjects Committee at the University of Arizona, and informed consent was obtained from parents.

Lower Respiratory Illnesses (LRIs)

During the first 3 years of life, participating children were taken by their parents to consult with their pediatricians whenever they had signs or symptoms of lower respiratory illnesses (LRIs; ie, deep or wet chest cough, wheezing, hoarseness, stridor, barking cough, or shortness of breath). The pediatricians obtained a detailed history at the time of such illnesses and recorded on a study form all relevant signs and symptoms (including audible stridor and wheezing on auscultation). Nasopharyngeal swabs and throat specimens were collected at the time of the LRIs for agent isolation, including respiratory viruses (respiratory syncytial virus [RSV], parainfluenza, adenovirus, influenza, and others), and mycoplasma and chlamydia. Culture techniques have been described in detail elsewhere.¹³ Of the original 1246 children who were enrolled in the study, 888 were followed for LRIs by the original study pediatricians for the entire first 3 years of life. A comparison between children who were followed for LRIs and those who dropped from follow-up has been reported elsewhere.¹⁴ Briefly, children who were not followed were of lower socioeconomic status and had a higher prevalence of maternal smoking.

Data collected in standardized form during the first 3 years of life for each episode of LRI were used to categorize the type of LRI. Croup was defined as a syndrome characterized by stridor (by history or physical examination) plus hoarseness (by history or physical examination) or barking cough (by history). The presence of wheezing was defined by history and physical examination. Children were classified into 4 hierarchical mutually exclusive groups: croup with wheezing (Croup/Wheeze), croup without wheezing (Croup/No Wheeze), LRI other than croup (Other LRI), and no LRI (No LRI). Children who had >1 LRI during the first 3 years of life and had at least 1 episode of croup with wheezing were included in the Croup/Wheeze group. Children who had at least 1 episode of croup without wheeze but also had at least 1 wheezing LRI were included in the Croup/Wheeze group. Four of the 888 eligible children had incomplete information for their LRI episode and were considered as missing. To describe age of onset and cause of the LRI categories, only the first episode for each LRI group was considered for each child.

School-Age Wheezing

Questionnaires were completed by the parent at the Yr6 Survey (age: 6.3 ± 0.9 years), Yr8 Survey (age: 8.6 ± 0.7 years), Yr11 Survey (age: 10.9 ± 0.6 years), and the Yr13 Survey (age: 13.5 ± 0.6 years). In each questionnaire, parents were asked whether the child's chest had sounded wheezy or whistling during the past year and how often this had occurred. Children were considered to have any current wheezing if they had 1 or more episodes of wheezing during the previous year. Children were considered to have current frequent wheezing if the child had >3 episodes of wheezing during the previous year.

Allergic Rhinitis

Parents were asked whether the child ever had hay fever or any other condition that made his or her nose stuffy, itchy, or runny apart from colds. Current MD allergic rhinitis was defined as a physician diagnosis of allergic rhinitis for which the child had taken medicine for that condition more than once during the year before the Yr6 or the Yr11 survey.

Markers of Atopy

Skin prick tests were performed using extracts of common allergens in the Tucson area. At the time of the Yr6 survey, house dust, Bermuda grass, olive, careless weed, Alternaria alternata, mesquite, and mulberry were used, and at the time of the Yr11 survey, Dermatophagoides farinae and cat dander were added (allergens provided by Holister-Stier Laboratories, Everett, WA). Two perpendicular diameters of all wheals were measured at 20 minutes. A positive skin test was defined as positive reaction (wheal size measuring 3 mm or more after subtraction of the control value) to 1 or more skin tests.

Blood for serum IgE analysis was obtained at a median age of 9.3 months (the 9 month sample) and again at the Yr6 and Yr11 surveys. Total serum IgE levels were measured with paper radioimmunosorbent test (Pharmacia Diagnostics, Piscataway, NJ). All samples were assayed in duplicate, and results were expressed as international units per milliliter.

Pulmonary Function Tests

Pulmonary function tests (PFTs) were obtained for 176 children during infancy (mean age: 2.4 ± 2.0 months). Of these 176, 131 had complete follow-up to 3 years of age, including complete data about croup-related symptoms for all LRIs, and were tested before any LRI. A detailed description of the selection criteria and the medical and demographic characteristics of these infants, as compared with those who were not tested, has been reported¹⁵; prevalence of a family history of asthma or allergies did not differ significantly between the infants who underwent pulmonary function testing and those who were not tested. Partial expiratory flow-volume curves were obtained by the chest compression technique.^14,16 Total respiratory resistance was measured during quiet expiration by use of the forced-oscillation technique with frequencies of 6 Hz and 10 Hz; only the findings at 6 Hz are reported here because a larger number of children were tested at this frequency.

At the time of the Yr6 survey (mean age: 6.4 ± 0.5 years), total respiratory resistance was again measured by the forced-oscillation technique with frequencies of 6 Hz and 10 Hz; to make results comparable, only the findings at 6 Hz are reported here. Partial expiratory flow-volume curves were also obtained with voluntary maneuvers as described originally by Taussig.¹⁷ Maximal expiratory flow at functional residual capacity (V'_max FRC) was calculated as described previously¹⁴ both for tests performed during infancy and for those obtained at the time of the Yr6 survey.

At the time of the Yr11 survey (mean age: 10.8 ± 0.5 years), forced vital capacity (FVC), forced expiratory volume in 1 second (FEV₁), and forced expiratory flow at 25%-75% of the FVC (FEF_25-75) were measured using standard spirometry. The best curve was chosen using predefined criteria.^18,19

Also, at the time of Yr11 survey, children who had been trained to measure peak expiratory flow (PEF) took home peak flow meters to measure PEF 3 times daily for 1 week. Only children who recorded PEF measurements at least twice per day for at least 4 days were included in the analysis. Positive PEF was considered to be present in participants with amplitude percent mean values above the 90th percentile for a healthy reference subgroup; more detailed information about this technique has already been published.²⁰

Statistical Analysis

Total serum IgE values were log-normally distributed, and results were expressed as geometric mean and geometric standard error of the mean (SEM). Values for total pulmonary resistance and for logarithmically transformed V'_max FRC were adjusted for length or height; results were standardized to the children's average length at infancy (58.42 cm) or height at the time of the Yr6 survey (115.48 cm). Values for FVC, FEV₁, and FEF_25-75 obtained at the Yr11 survey were also logarithmically transformed and adjusted for height (143.2 cm for boys and 144.9 cm for girls). Results of total pulmonary resistance are expressed as mean ± SD, and results for V'_max FRC, FVC, FEV₁, and FEF_25-75 were expressed as geometric means and 95% confidence intervals.

Analysis of variance and Duncan's multiple-comparison test were used to compare means, and ² test was used to compare proportions.²¹ The 95% confidence intervals for odds ratios were calculated using standard algorithms. Multiple regression models were used to determine whether Croup/Wheeze, Croup/No Wheeze, and Other LRI remained associated with the dependent variables (any current wheezing and current frequent wheezing) after controlling for gender, parental history of asthma, parental history of allergic rhinitis, parental ethnicity, maternal smoking, and maternal education level. Statistical significance was defined by a 2-sided  level of 0.05.

	RESULTS

Top Abstract Methods Results Discussion Conclusion References

Of the 884 children who were included in this study and who were followed for LRIs during the first 3 years of life, 90 (10.2%) children had Croup/Wheeze, 20 (22%) of whom had at least 1 episode of croup without wheeze but also at least 1 wheezing LRI; 46 (5.2%) had Croup/No Wheeze; 322 (36.4%) had Other LRI; and 426 (48.2%) had No LRI. More than 80% of the episodes that were classified as Other LRI were wheezing LRIs. There were more males in the Croup/Wheeze group (60%) than in the No LRI (48.1%; P = .02) and Other LRI (48.1%; P = .046) groups. The mean (±SD) age at the time of the first episode of LRI was significantly lower in children in the Other LRI group than in the Croup/Wheeze or Croup/No Wheeze group (0.5 ± 0.2 years vs 1.3 ± 0.8 years vs 1.4 ± 0.7 years, respectively; P < .0001). RSV was isolated more frequently in children in the Croup/Wheeze group (32.2%) and Other LRI group (45.2%) than in the Croup/No Wheeze group (14.0%); P = .03 and P = .0001, respectively. Conversely, parainfluenza was significantly more prevalent in the Croup/No Wheeze group than in the Other LRI group (24.0% vs 11.4%, P = .03). There were only 8 cases of recurrent croup with wheezing (6 with 2 episodes, 2 with 3 episodes) and 7 cases of recurrent croup without wheezing (6 with 2 episodes, 1 with 4 episodes). These illnesses were experienced predominantly by an outpatient population of infants; only 2 children with croup (both in the Croup/Wheeze group) required hospitalization.

Subsequent Prevalence of Wheezing

There were marked differences in the outcome of children with a history of croup with wheezing as compared with those with a history of croup without wheezing (Tables 1 and 2). Within the Croup/Wheeze group, children who had at least 1 episode of croup without wheezing but also at least 1 wheezing LRI were not significantly different in wheezing outcomes from those who presented with croup with wheezing; they were, however, in general, significantly higher in wheezing prevalence when compared with those in the Croup/No Wheeze group. Children with croup with wheezing had prevalence rates of wheezing at all surveys that were consistently and significantly higher than those of children with no LRIs. In addition, there was no significant difference in the prevalence of wheezing outcomes at any survey comparing croup with wheezing with and without RSV. On the contrary, the risk of subsequent wheezing was consistently and significantly lower in children with a history of croup without wheezing than in children with croup with wheezing and was consistently lower (albeit not significantly) in the former than even in children with no LRIs. Consistent with other reports from this same cohort,²² children with a history of other LRIs (mainly wheezing LRIs) were at increased risk of subsequent wheezing. For both children with croup with wheezing and for those with other LRIs, the risk of subsequent wheezing decreased significantly with age, also previously reported.²²

A logistic regression analysis confirmed that croup with wheezing was independently and significantly associated with any current wheezing and current frequent wheezing at the Yr6, Yr8, Yr11, and Yr13 surveys after controlling for potential confounders (gender, parental history of asthma, parental history of allergic rhinitis, parental ethnicity, maternal smoking, and maternal education level). Conversely, children with a history of croup without wheezing were no more likely to wheeze at any age compared with children with no LRIs (data not shown).

Skin Prick Test, Allergic Rhinitis, and Total Serum IgE

There were no significant differences in prevalence of at least 1 positive skin test to local allergens between children with croup with wheezing, croup without wheezing, other LRIs, and controls (48.4% vs 33.3% vs 38.7% vs 40.9%, respectively; numbers of tested participants: 64, 30, 230, and 303, respectively). Similarly, no significant differences were found in the prevalence of positive skin test at the Yr11 survey among the 4 study groups (69.4%, 44.8%, 59.9%, and 62.8%, respectively; number of tested participants: 62, 29, 237, and 304, respectively). The prevalence of current MD allergic rhinitis at the Yr6 and Yr11 surveys was not significantly different between any of the LRI groups and the control group (data not shown).

Geometric mean for total serum IgE levels at 9 months and the Yr11 survey were not statistically different between groups, although children in the Croup/No Wheeze group had the lowest values (Fig 1). At the Yr6 survey, children in the Croup/No Wheeze group had significantly lower total serum IgE levels than the Croup/Wheeze group and than the No LRI group (Fig 1).

View larger version (62K): [in this window] [in a new window]   Fig. 1.   Geometric means (±SEM) for total serum IgE levels at 9 months, Yr6, and Yr11 of survey, by types of LRI. Duncan's multiple comparison: *P <.05 compared with Croup/Wheeze and with No LRI groups.

Pulmonary Function Testing

Results of PFTs performed during the first year of life (Table 3) showed that both children in the Croup/Wheeze group and those in the Other LRI group had significant lower levels of lung function than did children in the No LRI group. Children in the Croup/No Wheeze group had levels of lung function that were similar to those of the No LRI group.

There were no differences in expiratory resistance measured during the first year of life and before any LRI between any of the 2 croup groups and children with No LRIs (data not shown). However, mean inspiratory resistance was significantly higher in infants who later developed Croup/No Wheeze than in children in the other 3 groups (Table 4).

At the time of the Yr6 survey, significantly lower V'_max FRC values were observed in children with a history of croup with wheezing and in children with other LRIs before age 3 when compared with controls (Table 3). Conversely, children with a history of croup without wheezing had significantly higher values of V'_max FRC than did children in the Other LRI group and also had higher values than did children in the Croup/Wheeze group (Table 3). Inspiratory and expiratory resistance was not significantly different between groups (Table 4).

At the time of the Yr11 survey, children with a history of croup without wheezing in the first 3 years of life had significant lower values of basal FVC than did children in the Other LRI group and controls (Table 3). Children with a history of croup with wheezing and other LRIs in the first 3 years of life had a significant lower basal FEV₁ and FEF_25-75 than did controls.

Children with a history of having either croup with wheezing or other LRIs in the first 3 years of life were significantly more likely to have increased PEF variability than were controls. Conversely, children with a history of croup without wheezing had a prevalence of increased PEF variability that was not significantly different from that of controls (Table 5).

	DISCUSSION

Top Abstract Methods Results Discussion Conclusion References

In this longitudinal study, we were able to distinguish 2 groups of children with croup in early life. One group, approximately two thirds of all children with croup, also had physician-ascertained wheezing during the episode of croup or during a different episode of LRI. These participants subsequently behaved in a manner similar to that of children who were included in the Other LRI group, 80% of whom had wheezing LRIs: they had a significant risk of persistence of wheeze during the school years. On the contrary, the second group (pure croup), which consisted of those without physician-ascertained wheezing (one third of all cases of croup), showed no increased risk of subsequent wheezing. Moreover, much like children with LRIs other than croup, children with croup with wheezing had significantly lower mean levels of small airway function shortly after birth and both at age 6 and at age 11, whereas children with pure croup had mean levels of small airway function that were within the normal range at all ages. A similar pattern was observed for peak flow variability measured at age 11, which was increased both in children with a history of croup with wheezing and in those who were classified here as Other LRI, but not in those with a history of croup without wheezing.

The conclusion that there are 2 different forms of croup in early life is supported by the differences in the most frequently isolated viruses for each of these 2 forms. Whereas RSV was the most frequent cause of episodes of croup with wheezing, parainfluenza was the most frequent virus isolated in children with pure croup. Therefore, it is likely that in the former, the upper airway symptoms are the manifestation of an extension of a disease process that affects mainly the lower airways. Which part of the upper/central airway is responsible for the croup-like symptoms in these children is a matter of speculation. However, croup-like symptoms also can be caused by involvement of the main bronchi and trachea,²³ and it is tempting to speculate that in children with croup with wheezing, RSV and other viruses that affect the lower airways may affect the central airways as well. Conversely, in children with pure croup, the disease process is likely to affect mainly the laryngeal mucosa, for which parainfluenza viruses seem to have particular tropism.²⁴

We found that children with croup with wheezing and those with LRIs other than croup had lower mean values for several indices derived from expiratory flow-volume loops obtained both before and years after the development of their lower respiratory symptoms. We know of no other studies in which premorbid lung function was measured in children who would subsequently develop croup. Our results support our previously stated hypothesis that in children with croup and wheezing, the upper/central respiratory symptoms may be an extension of a process that usually affects the lower airways. The finding that lung function is still diminished in children with croup with wheezing years after their acute illness is in agreement with the findings of several^1,9 but not all^4,10,23 studies of lung function in children with a history of croup. Interestingly, we observed normal values for expiratory flow-volume loops but significantly increased inspiratory resistance of the respiratory system during the first months of life in infants who would go on to have croup without wheezing when compared with infants who would have no LRIs (Table 4). By age 6, however, children with croup without wheezing had inspiratory resistance values that were within normal ranges. It is important to stress that these results were based on a small subgroup of children and thus require independent confirmation. However, they suggest the possibility that the size and the structure of the larynx, main determinants of upper airway resistance²⁵ and thus of inspiratory resistance, may play important roles in determining which children who are infected by parainfluenza will develop croup. Results should be interpreted cautiously because extrathoracic airway instability in early life may also influence measurement of airway resistance. In addition, it seems that whatever the abnormality that determines an increase in inspiratory resistance in these children in early life may be, it may be outgrown by age 6, a time when the incidence of croup has become almost nonexistent. The differences in abnormalities in lung function observed between children with croup with wheezing as compared with those with croup without wheezing may explain the contradictory results of lung function tests reported in previous studies in which children with croup were not classified according to their lower airway symptoms.

Both children with croup with wheezing and those classified as having LRIs other than croup were at increased risk of subsequent development of persistent wheezing. As reported previously in this cohort for children who had RSV LRIs independent of their specific symptoms,²² the association between LRI in early life and subsequent wheezing tended to decrease with age, and for children classified here as having LRIs other than croup, the association was not significant by age 13. However, children with a history of croup with wheezing were at higher risk of subsequent wheezing at all ages when compared with those classified as having LRIs other than croup (Tables 1 and 2). Furthermore, all wheezing outcomes remained higher in prevalence for those in the Croup/Wheeze group compared with those in the Other LRI group who also wheezed; for any current wheezing at all surveys and current frequent wheezing in the Yr11 survey, P values ranged from .02 to 0.05 (data not shown). Moreover, the risk of wheezing was still significantly higher at age 13 among children with a history of croup with wheezing than among children who had no LRIs in early life. These data suggest that, much like we recently observed for pneumonia,²⁶ croup-like symptoms, when associated with wheezing in early life, may be a marker for airway or lung abnormalities that predispose those who carry them to more persistent subsequent wheezing, even in the absence of subsequent croup-like symptoms.

We have no clear explanation for this intriguing finding. It has been suggested that a predisposition to allergies may be a risk factor for croup.^1,9,23 However, we found that children with a history of croup, regardless of its association with wheezing, were not more likely to have either subsequent skin test reactivity to local aeroallergens or increased total serum IgE levels as compared with children without croup. This is in apparent contradiction with data reported by Zach et al,¹ who found that children who were hospitalized as infants for croup and who had a history of recurrent episodes of croup were more likely to have positive allergy skin test than were controls. However, children who are hospitalized with LRIs seem to be more likely to be atopic than those who are not,²⁷ and very few participants from our cohort were hospitalized for their LRIs. Our data are similar to those of Gurwitz et al⁹ and of Nicolai and Mutius,¹⁰ who found no increased risk of allergic sensitization in school-aged children with a history of croup in early life.

Both children with a history of LRIs other than croup and those with a history of croup with wheezing had higher variability of peak flow at age 11 than did children who had no LRIs in early life. This is in agreement with previous studies that showed that school-aged children with a history of croup have increased exercise-induced bronchospasm when compared with children without such a history.²³ Interestingly, Zach et al¹ reported that children with a history of recurrent croup showed peculiar responses to histamine challenge as compared with children with asthma and no croup. Whereas the latter showed only decreases in maximal expiratory flows, children with croup showed falls in both inspiratory and expiratory flows.⁸ The authors speculated that both extrathoracic and intrathoracic airways may be involved in the hyperresponsiveness observed in croup. Therefore, it is possible that this specific, dual type of airway hyperresponsiveness may predispose both to croup with wheezing in early life and to more persistent wheezing later in life. Our measurement of peak flow variability was probably not sensitive enough to detect these differences in airway responses between children with croup with wheezing and those with LRIs other than croup.

	CONCLUSION

Top Abstract Methods Results Discussion Conclusion References

Croup is a heterogeneous disease, and young children who present with croup may or may not be at increased risk of subsequent, recurrent lower airway obstruction, depending on the initial lower airway involvement, and preillness and postillness abnormalities in lung function associated with this frequent condition.

	ACKNOWLEDGMENTS

This work was supported by grants from the National Heart, Lung and Blood Institute (HL 14136, HL 56177, and HL 03154).

We are indebted to the members of the Group Health Medical Associates: John Bean, MD, Henry Bianchi, MD, John Curtiss, MD, John Ey, MD, Alejandro Sanguineti, MD, Barbara Smith, MD, Terry Vondrak, MD, Neil West, MD, and Maureen McLellan, RN, PNP; to Marilyn Smith, RN, and Lydia De La Ossa, RN, the study nurses; and to Debra A. Stern, MS, and Bruce Saul, MS, for technical assistance.

	FOOTNOTES

Dr Taussig is now at the National Jewish Medical and Research Center, Denver, Colorado.

Received for publication Sep 15, 1999; accepted Jun 13, 2000.

Reprint requests to (F.D.M.) 1501 N Campbell Ave, Suite 2349, Box 245030, Tucson, AZ 85724. E-mail: fernando{at}resp-sci.arizona.edu

	ABBREVIATIONS

IgE, immunoglobulin E; LRI, lower respiratory illness; RSV, respiratory syncytial virus; PFT, pulmonary function test; V'_max FRC, maximal expiratory flow at functional residual capacity; FVC, forced vital capacity; FEV₁, forced expiratory volume in 1 second; FEF_25-75, forced expiratory flow at 25%-75% of the forced vital capacity; PEF, peak expiratory flow; SEM, standard error of the mean.

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Top Abstract Methods Results Discussion Conclusion References

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