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(Chest. 2002;122:791-797.)
© 2002 American College of Chest Physicians

Bronchoalveolar Cells in Children < 3 Years Old With Severe Recurrent Wheezing*

Muriel Le Bourgeois, MD; Maria Goncalves, MD; Laurence Le Clainche, MD; Marie-Rose Benoist, MD; Jean-Christophe Fournet, MD; Pierre Scheinmann, MD and Jacques de Blic, MD

* From the Service de Pneumologie et d’Allergologie Pédiatriques (Drs. Le Bourgeois, Goncalves, Le Clainche, Benoist, Scheinmann, and de Blic) and Laboratoire d’Anatomopathologie (Dr. Fournet), Hôpital Necker-Enfants Malades, Paris, France.

Correspondence to: Muriel Le Bourgeois, MD, Service de Pneumologie et d’Allergologie Pédiatriques, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75743 Paris Cedex 15, France; e-mail: muriel.lebourgeois{at}nck.ap-hop-paris.fr


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Study objective: To determine the cell profile of BAL from infants with severe recurrent wheezing who were not acutely ill at the time of investigation, suggesting an ongoing inflammation.

Design and patients: In a retrospective study, we determined BAL cell profiles for 83 children with wheezing aged 4 to 32 months (mean ± SD, 11.3 ± 5.5 months). Fiberoptic bronchoscopy was performed in children with severe recurrent wheezy bronchitis unresponsive to inhaled steroids. These children were compared with 17 children aged 6 to 36 months (mean, 15.1 ± 7.5 months) with various nonwheezing pulmonary diseases. Children were included as control subjects if they had no endobronchial inflammation and no atopy.

Results: The BAL cell profile of young children with wheezing typically includes a significantly higher cell count (mean, 644.4 ± 956.8 x 103/mL vs 313 ± 203.2 x 103/mL, p = 0.008), a significantly higher percentage of neutrophils (mean, 9 ± 12.1% vs 2.1 ± 2.2%, p = 0.003), and a higher neutrophil count (mean, 43.2 ± 81.6 x 103/mL vs 7.9 ± 11.8 x 103/mL, p = 0.003), as compared with control subjects. The larger number of neutrophils in children with wheezing was not correlated with bacterial or viral infection, or with age, sex, or atopic status. In contrast to the situation in asthmatic adults, eosinophil levels were not higher in children with wheezing than in control subjects (mean, 0.09 ± 0.27% vs 0.08 ± 0.25%).

Conclusion: Neutrophil-mediated inflammation in the airways appears to better characterize severe recurrent wheezing in children < 3 years old.

Key Words: asthma • BAL • flexible bronchoscopy • infants • wheezing


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Recurrent episodes of wheezing are highly heterogeneous and a major cause of morbidity in young children. The clinical manifestations of recurrent wheezing in infants resemble those of asthma. Progression is variable in these infants: some will have only transient wheezing associated with recurrent respiratory viral infections, whereas others will have persistent asthma. Maternal asthma, atopy, and male gender seem to predispose the infant to late-onset persistent wheezing.1 The physiopathology of recurrent episodes of wheezing in young children is unclear, but persistent bronchial inflammation may play an essential role. Consistent with this, inhaled corticosteroids have been shown to be effective, improving symptoms and decreasing the need for oral corticosteroids.2 3 4 5 In these very young children, bronchial inflammation seems to be characterized by a high level of neutrophils in BAL.6 7 Azevedo et al8 9 demonstrated the involvement of macrophage activation in the BAL of infants with wheezing. This activation results in the excessive production of proinflammatory metabolites, such as tumor necrosis factor-{alpha},8 and eicosanoids, such as thromboxane B2 and leukotriene B4,9 which are involved in the chemoattraction of neutrophils.10 The aim of this study was to determine the cell profile of BAL from infants with severe recurrent wheezing far from an acute exacerbation, to confirm an increase in neutrophil levels in the BAL suggesting an ongoing inflammation, and to evaluate its relationship to various factors: infection, atopy, and age.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Demographic and clinical data were obtained by retrospective review of the patients’ medical records.

Children With Wheezing
All of the children < 36 months of age who underwent flexible bronchoscopy (FB) with BAL for severe recurrent wheezing (at least three moderate-to-severe episodes) were retrospectively identified from a bronchoscopy database between January 1993 and December 1999. Severe recurrent wheezing attested by frequent exacerbations requiring oral corticosteroids more than once a month, persistent chronic symptoms in between with poor response to inhaled bronchodilators, and a trial of at least 6 weeks of inhaled corticosteroids led to an investigation of airway abnormalities by FB. Eighty-three children with wheezing were retrospectively included (age range, 4 to 32 months; mean ± SD, 11.3 ± 5.5 months), 58 of whom were male (70%). Some of these children have been included in previous studies.8 9 11 FB was performed at least 15 days after an acute exacerbation and at least 15 days after an eventual short course of oral steroids. None of the children were receiving antibiotics at the time of FB.

Children with wheezing were classified as atopic if they had at least one of the following: a family history of atopy, atopic dermatitis diagnosed by a doctor, or positive skin test findings for common allergens. Children were considered to have a family history of atopy if one or both parents or any siblings had atopic diseases (allergic rhinitis, asthma, or atopic dermatitis). Allergy tests were performed and interpreted as previously described.12 13 Atopic predisposition was investigated in 66 of the 83 children with wheezing, of whom 47 children (71%) were considered to have atopy.

Control Group
The 17 children in the control group were similar in age and sex ratio to the children with recurrent wheezing (age range, 6 to 36 months; mean, 15.1 ± 7.5 months), including 13 male children (77%). As it is ethically difficult to design a study to investigate BAL fluid cell analysis in healthy children, we chose to utilize control subjects with disease. These control subjects underwent FB for the investigation of various pulmonary diseases during the same time period (recurrent bronchitis without wheezing [seven children], persistent pulmonary infiltrate [four children], suspicion of foreign body aspiration [three children], persistent cough [two children], stridor [one child]). Children of the control group were excluded if they had the following: (1) endoscopic bronchial inflammation, (2) wheezing at the time of the examination, (3) a history of wheezing, and/or (4) a personal or familial history of atopy.

FB and BAL
Informed consent for clinically indicated FB was obtained from the parents at the time of the assessment of their children. According to French bioethic law, this informed consent is sufficient to carry out a retrospective analysis of medical and biological results.

Children received sublingual atropine sulfate, 0.01 mg/kg, and IV midazolam, 150 µg/kg, as premedication. Upper and lower airway anesthesia was achieved with 2% and 0.5% lidocaine, respectively. The flexible bronchoscope (Olympus BF3C20 and BF3C30; Olympus Winter IBE Gmbh; Hamburg, Germany) was wedged into the right lower or middle lobe. The airways were washed conventionally three times with 1 mL/kg of prewarmed sterile 0.9% saline solution, which was then gently aspirated into sterile polypropylene vials (Falcon 50 mL; Becton-Dickinson; Rutherford, NJ). The first aliquot was kept separate and sent for viral analysis. The second and third aliquots were pooled and sent for cell count analysis and, if the volume was sufficiently large, for microbiological analysis (aerobic bacteria, mycobacteria, and fungi).

Cell Counts
Total cell counts were determined with a hemocytometer (Malassez; Preciss; Strasbourg, France). Differential cell counts were obtained using a modified version of Wright-Giemsa staining (Diff-Quick; Baxter Dade AG; Duedingen, Switzerland) and cytocentrifuged smears of BAL cell suspensions. At least 300 cells were examined by the same observer for each specimen.

Data were expressed as a percentage of total cell counts and as an absolute number. Results are presented as means ± SD and as medians (25th to 75th percentile range).

Microbiological Analysis
The first aliquot was used for viral analysis by immunofluorescence. The pooled sample was used for nonquantitative cultures to detect bacteria and fungi.

Statistical Analysis
Control subjects were compared with children with wheezing, and groups of children with wheezing were compared with each other using the nonparametric Mann-Whitney two-sample U test for unpaired data. A p value < 0.05 was considered significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
FB Findings
FB and BAL were well tolerated by children with wheezing and control subjects, and no major complications were observed. For the 83 children with wheezing, bronchoscopy results were normal in 36 children and mild airway inflammation (erythema) was detected in 43 children. Airway morphology was abnormal in the four remaining children with wheezing: slight laryngomalacia (n = 2) and moderate anterior compression of the trachea (n = 2). These four children were retained in the analysis because their respiratory symptoms were not considered to be due to these anatomic findings, and all four had personal and family histories of atopy. Consistent with the exclusion criteria, none of the 17 control children had airway abnormalities and no inflammation was observed in these children.

Viral Analysis
Viral analysis was performed for 56 of the children with wheezing (67%) and 10 of the control subjects (58%). Viruses were detected by immunofluorescence tests in nine of the children with wheezing (16%): cytomegalovirus (n = 6), respiratory syncytial virus (RSV) [n = 3], and in two of the control subjects (cytomegalovirus) [20%].

Microbiological Culture
Microbiological tests were carried out using samples from 30 of the children with wheezing (36%) and 8 control subjects (47%). The small number of children tested was partly due to the small volume of BAL collected, which was preferentially kept for cell count analysis and partly due to the retrospective design of the study. Culture findings were positive in 18 of the 30 children with wheezing (60%): Haemophilus influenzae (n = 9), Streptococcus pneumoniae (n = 4), Staphylococcus aureus (n = 3), Moraxella (n = 3), Neisseria (n = 1), Escherichia coli (n = 1). Culture findings were positive in five of the eight control subjects (62%): H influenzae (n = 3), Morganella (n = 1), Moraxella (n = 1), Pseudomonas (n = 1). Four children with wheezing and two control subjects had positive culture findings for two or more pathogens. In no patients were both a virus and a bacterial pathogen isolated.

Total and Differential Cell Counts in BAL Samples
The mean fluid recovery rate was 65% (range, 40 to 80%) and was similar for wheezy children and control subjects. The total and differential cell counts for the pooled sample are presented in Table 1 . The number of cells recovered varied widely in both groups. The results of the control group were within the normal range for BAL cell analysis in healthy young children compared with available published data.14


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  		Table 1. Cellular Content of BAL*

 
Comparison Between Children With Wheezing and Control Subjects
Cell counts were significantly higher in children with wheezing than in control subjects (644.4 ± 956.8 x 103/mL vs 313 ± 203.2 x 103/mL, p = 0.008; Table 1 ). Absolute counts and percentages of neutrophils were significantly higher in BAL from infants with wheezing than in control subjects (43.2 ± 81.6 x 103/mL vs 7.9 ± 11.8 x 103/mL [p = 0.003] and 9 ± 12.1% vs 2.1 ± 2.2% [p = 0.003], respectively). The percentage of lymphocytes was slightly lower in children with wheezing than in control subjects (6.4 ± 5.6% vs 10.1 ± 7.3%, p = 0.03), but absolute numbers were similar. The number and percentage of eosinophils (< 1%) were low, with no significant difference between children with wheezing and control subjects.

Comparisons Between Groups of Children With Wheezing
Atopy:
Atopy status was known for 66 of the children with wheezing. No significant difference in absolute and differential counts of macrophages, lymphocytes, neutrophils, and eosinophils was observed between the 47 atopic and the 19 nonatopic children with wheezing.

Age and Sex:
We compared the results obtained for children < 12 months old (n = 54) and > 12 months old (n = 29). We observed no significant difference in absolute and differential counts of macrophages, lymphocytes, neutrophils, and eosinophils. There was also no significant difference between boys and girls.

Microbiological Results:
The number of cells was higher for children with wheezing having positive bacteriological test results than for children with wheezing having negative bacteriological test results (1,636.6 ± 1,903.2 x 103/mL vs 469 ± 274.4 x 103/mL, p = 0.02). The absolute number of lymphocytes was higher in children with wheezing having positive bacteriological test results (55.4 ± 31.7 x 103/mL vs 24.6 ± 33.7 x 103/mL p = 0.02) but the percentage of lymphocytes was not. The absolute and differential counts of macrophages, neutrophils, and eosinophils showed no significant differences between children with wheezing having positive and negative bacteriological test results.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
Little is known about cell profile in normal young children and in infants with recurrent wheezing (Table 2 ). This series of 83 infants with wheezing constitutes the largest reported. Our indications for bronchoscopy were very restrictive. In each case, bronchoscopy was used in search of airways abnormalities in children with severe recurrent wheezing, as recommended by other authors.15 16 BAL was carried out according to the recommendations of the European Respiratory Society.14 One possible limitation of this study is the choice of control group, as normal healthy children were not used. However, it is considered ethically unacceptable in France to perform endoscopy in healthy children. All of the children in the control group had respiratory diseases that did not involve wheezing, had no history of familial or personal atopy, and had normal bronchoscopy findings. The results for our control population are similar to those obtained for BAL in healthy children.14 17 18 19 20 Only one study21 reported an increase in neutrophils in control children.


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  		Table 2. Cellular Contents of BAL From Young Children With Wheezing*

 
The total BAL cells per milliliter is significantly increased in children with wheezing compared with children without wheezing. This increase has been reported in other studies,7 20 suggesting that inflammation is present in lower airways of young children with recurrent wheezing.

The main finding of this study was the higher number and percentage of neutrophils in children with wheezing than in the control subjects. An increase in the number of neutrophils in BAL has already been reported in infants with wheezing.6 7 Schellhase et al6 studied BAL in 27 infants with recurrent wheezing that responded poorly to ß2-adrenergic drugs and also reported a high number of neutrophils. Marguet et al,7 comparing 14 asthmatic children aged > 4 years, 26 infants with wheezing, 12 children with chronic cough, and 10 control subjects, noted a significantly higher level of neutrophils in the infants with wheezing.

The high number of neutrophils may have different explanations: infection, age, and severity of symptoms. In our study, 60% of the infants with wheezing for whom bacteriological analysis of BAL was performed had positive culture results. The microorganisms detected were those usually found in children of this age, the most frequent being H influenzae. As the microbiological analysis were not quantitative, it was difficult to distinguish oropharyngeal contamination or lower airway colonization from a bacterial infection of the lower airways. Among the children with wheezing, no significant correlation was found between the number or percentage of neutrophils and positive microbiological culture results. The frequency of bacteriological-positive BAL was identical in children with wheezing and control subjects, although the BAL of control subjects did not show an increase in neutrophils. This suggests that the infection is not solely responsible for the increase in neutrophil levels, although it is always very difficult to formally exclude the possibility of bacterial infection. Other studies7 22 have also shown that this increase in neutrophil levels in the BAL of wheezy infants is not correlated with bacteriological results, suggesting that at this age, the observed neutrophil-mediated inflammation is independent of bacterial infection. Neutrophil levels may also increase during viral infection. The release of interleukin-8 and leukotriene B4 during the initial phase of a viral infection favors the preferential recruitment of neutrophils in the airways.23 In two studies,24 25 analysis of BAL during acute episodes of RSV infection revealed a significant increase in neutrophil levels. In our population of children with wheezing, BAL was not carried out during acute exacerbation. However, positive results were obtained for 16% of the children with wheezing whose BAL was tested for viruses. The viruses detected were RSV and cytomegalovirus (we did not test for rhinoviruses). There was no significant difference in the number or percentage of neutrophils in the BAL between children with wheezing who had positive test results for viruses and those who had negative test results. This result contrasts with those of Schellhase et al,6 who observed a tendency for the number and percentage of neutrophils to increase in cases of viral infection.

Another possible reason for the higher number of neutrophils in young children is that endoscopic exploration may be less distal, due to the small diameter of the airways, resulting in the collection of BAL from the more proximal regions. We would have found more neutrophils in the youngest children who have the narrowest airways and possibly in boys. This does not seem to be borne out by our results, which show that the number of neutrophils did not differ in children < 12 months old and > 12 months old, and was not correlated with sex.

The presence of neutrophils may be related to the severity of symptoms, as it is shown in severe asthmatic adults.26 27 Marguet et al7 observed a correlation between the increase in neutrophil levels and the severity of symptoms in children with asthma, chronic cough, or infantile wheeze. In our study, all of the infants with wheezing had severe respiratory symptoms that justified endoscopic investigation in search of airway abnormalities. Our population of wheezy children was therefore relatively homogeneous in severity, rendering it impossible to establish a correlation between severity and the extent of the increase in neutrophil levels in the BAL. This may account for the high numbers of neutrophils. The persistence outside an acute episode of an abundance of neutrophils in the BAL suggests a different inflammatory mechanism in young children with wheezing than in older asthmatic children and adults.

In asthmatic adults and school-age children, eosinophil levels are high in the BAL.28 29 Stevenson et al30 showed that BAL contained more eosinophils and mastocytes in a group of atopic asthmatic children with a mean age of 8 years (and even in a subgroup of children < 5 years old) than in a group of children with a mean age of 3 years having recurrent episodes of wheezing due to viral infection. In our population of young children with wheezing, as in the study by Marguet et al,7 normal numbers and percentages of eosinophils were observed. Eosinophils were not correlated with age, in contrast to the findings of Schellhase et al,6 who observed higher eosinophil levels in children aged 13 to 18 months than in children aged 0 to 6 months, nor with atopic status. It is clear that having a normal number of eosinophils does not exclude the possibility that eosinophils are involved in the physiopathology of asthma in infants. Activated and degranulated eosinophils may not be detected if a counting method dependent on staining is used.31 Eosinophil cationic protein levels are high in the BAL of infants but may at least partly reflect the presence of neutrophils,32 33 suggesting that eosinophils, and also probably neutrophils, are involved in wheezing in infants.10 The analysis of specific markers of neutrophil activity would clearly make it possible to characterize in more detail these features of the infant with wheezing.34 35 36 The low percentage and number of eosinophils in BAL of children with wheezing does not exclude the presence of eosinophils in bronchial biopsies, as this investigation cannot be routinely performed in young children.37


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
This study was carried out with a large series of children with severe recurrent wheezing. The high level of neutrophils and the normal number of eosinophils in the BAL seem to be specific in children of this age group with severe respiratory symptoms. These features confirm the presence of inflammation outside an acute episode. This high level of neutrophils does not seem to be associated with the quality of collection or the presence of a bacterial or viral infection. Our results suggest that mechanisms other than an increase in eosinophil levels in the lower airways are involved in the pathophysiology of persistent wheezing in young children. Large longitudinal studies with prospective follow-up of wheezy infants are necessary to precise specific inflammatory markers involved in the development of asthma.


   Footnotes
 
Abbreviations: FB = flexible bronchoscopy; RSV = respiratory syncytial virus

Received for publication August 13, 2001. Accepted for publication February 28, 2002.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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Role of the chemokines RANTES, monocyte chemotactic proteins-3 and -4, and eotaxins-1 and -2 in childhood asthma
Eur. Respir. J., August 1, 2003; 22(2): 310 - 316.
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