Clinical and bronchial parameters
associated with the exacerbation
frequency of severe preschool
wheezers

<figure><img src="image_1.png" /></figure>

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Fabien Beaufils, MD, PhD<sup>a,b,c</sup>, Pauline Esteves, PhD<sup>a,c</sup>,
Raphael Enaud, MD, PhD<sup>a,b,c</sup>, Renaud Prevel, MD, PhD<sup>a,b,c</sup>,
Pauline Henrot, MD, PhD<sup>a,b,c</sup>, Marilyne Campagnac, BSc<sup>a,c</sup>,
Elise Maurat, BSc<sup>a,c</sup>, Marine Michelet, MD<sup>d,e</sup>,
Frederic Lavrand, MD<sup>b</sup>, Hugues Begueret, MD, PhD<sup>b</sup>,
Thomas Trian, PhD<sup>a,c</sup>, Michael Fayon, MD, PhD<sup>a,b,c</sup>, and
Patrick Berger, MD, PhD<sup>a,b,c</sup>, on behalf of the P'tit Asthme
Study Group*

Clinical Implications

To limit the risk of exacerbations in preschool wheezers, clinicians must aim to prevent and delay early-life wheezing episodes and target bronchial smooth muscle remodeling, as these are independent risk factors associated with the frequency of exacerbations.

Recurrent preschool wheezers represent approximately 10% of children under 5 years of age.¹ Among them, those who report frequent exacerbations (ie, 3 or more per year), mainly due to viral and/or bacterial infections, have an increased risk of persistent asthma and poor lung function throughout life.¹,² The risk of exacerbation has been previously associated with several clinical and/or biological parameters, including those of bronchial remodeling. The latter corresponds to a poorly reversible structural abnormality of the bronchial tissue (ie, altered epithelial integrity, increased mass of mucus gland and/or bronchial smooth muscle [BSM], increased density of blood vessels, and an increased collagen deposition leading to reticular basement membrane [RBM] thickening and increased submucosal fibrosis).²,³ However, it remains unclear whether these factors are independently associated with exacerbation frequency (no exacerbation), infrequent (1 or 2) exacerbations, or frequent (≥3) exacerbations. We aimed to identify the parameters independently associated with short-term subsequent exacerbation frequency (ie, within a year) in 80 severe preschool children (1-5 years old). These children have been pooled from 2 independent cohorts with the same inclusion criteria (NCT02806466 and NCT04558671), as described previously.³ All children had uncontrolled severe recurrent preschool wheeze despite receiving high doses of inhaled corticosteroids (ICS) and a second controller.⁴ Fiberoptic bronchoscopy with bronchial biopsies was performed during the stable period at least 4 weeks after an exacerbation. A detailed description of methods has been previously published elsewhere.³

Patients were divided into 3 groups according to the number
of exacerbations in the year after the fiberoptic bronchoscopy:
"No-Ex" (no exacerbation, 20/80 [25.0%]), "Low-Ex" (1 or 2
exacerbations, 27/80 [33.7%]), and "High-Ex" (3 exacerbations

or more, 33/80 [41.3%]). Clinical, biological, and histological parameters were compared between the groups using χ² tests or the Kruskal-Wallis test with Dunn's *post hoc* test using the SPSS software (version 29.0; IBM Corp, Armonk, NY). A *P* value of <.05 was considered significant.

Patients in the “High-Ex” group were younger at the first
episode of wheezing, had a lower RBM-BSM distance and
greater BSM area and RBM thickness, and required more
frequently an increase in ICS in the follow-up year than the other
2 groups, and had a higher prevalence of atopy than the “Low-
Ex” group. The “Low-Ex” group had the highest prevalence of
*Haemophilus* genus and *Streptococcus* genus bacteria in the
bronchoalveolar lavage fluid (BALF) and an increased BSM mass
compared with the “No-Ex” group (Table I). There were no
other significant differences between the 3 groups according to
clinical, biological, or histological parameters.

All clinical, biological, and bronchial remodeling parameters were included in an ordinal regression analysis adjusted for the patients' initial cohort membership to identify the parameters associated with the exacerbation frequency. Only the BSM area and the age at first episode of wheezing appeared as factors independently associated with the exacerbation frequency in severe preschool wheezers (Table II). The greater the BSM area and the earlier the first episode of wheezing, the higher the frequency of exacerbations in the year after the bronchoscopy (Table II).

In the present study, no association between exacerbation frequency and blood or bronchial inflammation has been identified. However, these results may have been impacted by a high dose of ICS treatment of the patient. By contrast, we highlighted an increased prevalence of bacteria in the BALF in both low and high subsequent exacerbation frequency groups, even though the bronchoscopies were performed in patients in a stable condition. However, the presence of bacteria in the BALF did not appear as an independent factor associated with the exacerbation frequency, which could suggest a beneficial effect of antibiotic treatment after bacterial identification of BALF.

These results also confirm an association between a high
exacerbation frequency and both very early-life first episode of
wheezing and increased BSM area. These 2 parameters have been
previously associated with exacerbation frequency, asthma
persistence, and/or low lung function later in life.²,³ Our results
can thus suggest an interplay between early-life infection and
BSM remodeling in the disease pathophysiology. Indeed, on one
hand, the first months of life appeared as a critical period in the
history of respiratory diseases²,³ characterized by a high suscep-
tibility to BSM growth and remodeling supported by a
mitochondria-dependent BSM cell proliferation⁴,⁵ in severe
preschool wheezers,⁶ and, on the other hand, viral infection can
promote BSM remodeling by inducing BSM cell migration⁷ and
the release of mediators that stimulate BSM cell proliferation.⁸ In
addition, BSM can increase the susceptibility to viral infection, as
demonstrated in asthmatic adults.⁹ However, the effect of early
viral infection on the BSM growth and remodeling remained
totally unknown.

Several limitations must be pointed out: (1) The 2 initial co-
harts of patients were pooled despite several differences between
them.³ However, inclusion criteria were the same in the 2 cohorts,
<table><caption>TABLE I. Baseline patients' characteristics according to the number of exacerbations during 1 year of follow-up</caption><thead><tr><th>Variables</th><th>No-Ex</th><th>Low-Ex</th><th>High-Ex</th><th>P value</th></tr></thead><tbody><tr><td>N</td><td>20</td><td>27</td><td>33</td><td></td></tr><tr><td>At inclusion</td><td></td><td></td><td></td><td></td></tr><tr><td>Male sex</td><td>12/20 (60.0)</td><td>18/27 (66.7)</td><td>24/33 (72.7)</td><td>.627</td></tr><tr><td>Age (y)</td><td>3.4 [2.0; 4.1]</td><td>2.4 [1.6; 3.6]</td><td>2.6 [2.0; 3.7]</td><td>.227</td></tr><tr><td>History or current atopic dermatitis</td><td>8/20 (40.0)</td><td>4/27 (14.8)</td><td>19/33 (57.6)</td><td><strong>.003*</strong></td></tr><tr><td>Aeroallergen allergy/sensitization</td><td>5/20 (25.0)</td><td>6/27 (22.2)</td><td>12/33 (36.4)</td><td>.442</td></tr><tr><td>Food allergy/sensitization</td><td>6/20 (30.0)</td><td>5/27 (18.5)</td><td>6/33 (18.2)</td><td>.543</td></tr><tr><td>Age at first wheezing episode (mo)</td><td>5.0 [4.0; 9.0]</td><td>4.0 [3.0; 9.5]</td><td>3.0 [1.0; 5.0]</td><td><strong>.007</strong>,†</td></tr><tr><td>Postnatal cigarette smoke exposure</td><td>10/20 (50.0)</td><td>16/27 (59.3)</td><td>19/33 (57.6)</td><td>.602</td></tr><tr><td>Gastroesophageal reflux</td><td>6/20 (30.0)</td><td>9/27 (33.3)</td><td>15/33 (45.5)</td><td>.456</td></tr><tr><td>Within a year before inclusion</td><td></td><td></td><td></td><td></td></tr><tr><td>No. of OCS bursts</td><td>5.0 [2.0; 7.0]</td><td>4.0 [3.0; 5.5]</td><td>5.0 [3.0; 8.0]</td><td>.475</td></tr><tr><td>No. of hospitalizations</td><td>1 [0; 1]</td><td>2 [0.5; 2.5]</td><td>2 [1; 3]</td><td>.163</td></tr><tr><td>Total IgE (kIU/L)</td><td>63.0 [10.0; 132.0]</td><td>22.0 [8.0; 106.5]</td><td>24.5 [9.0; 85.5]</td><td>.797</td></tr><tr><td>Blood eosinophils (/mm³)</td><td>200.0 [100.0; 300.0]</td><td>330.0 [170.0; 460.0]</td><td>220.0 [110.0; 470.0]</td><td>.374</td></tr><tr><td>Daily dose (µg, eq. beclomethasone)</td><td>1000 [500; 1700]</td><td>1600 [900; 2000]</td><td>1600 [500; 2000]</td><td>.279</td></tr><tr><td>Montelukast</td><td>16/20 (80.0)</td><td>23/27 (85.2)</td><td>29/33 (87.9)</td><td>.738</td></tr><tr><td>Long-acting β-agonists</td><td>11/20 (55.0)</td><td>6/27 (22.2)</td><td>14/33 (42.4)</td><td>.063</td></tr><tr><td>Cytology of BALF</td><td>17/20 (85.0)</td><td>23/27 (85.2)</td><td>28/33 (84.8)</td><td>1.000</td></tr><tr><td>Cells (×10⁴)/mL</td><td>16.5 [10.8; 30.0]</td><td>24.0 [19.0; 45.0]</td><td>16.0 [11.5; 28.3]</td><td>.051</td></tr><tr><td>Macrophages (%)</td><td>79.0 [66.5; 90.0]</td><td>69.0 [24.5; 82.0]</td><td>71.0 [66.5; 83.0]</td><td>.156</td></tr><tr><td>Neutrophils (%)</td><td>2.0 [1.5; 9.5]</td><td>9.0 [2.5; 69.0]</td><td>6.0 [2.5; 17.0]</td><td>.132</td></tr><tr><td>Lymphocytes (%)</td><td>20.0 [8.0; 23.0]</td><td>10.0 [6.5; 17.5]</td><td>14.0 [4.0; 18.5]</td><td>.225</td></tr><tr><td>Eosinophils (%)</td><td>0.0 [0.0; 0.0]</td><td>0.0 [0.0; 0.0]</td><td>0.0 [0.0; 1.0]</td><td>.128</td></tr><tr><td>Microbiology of BALF</td><td></td><td></td><td></td><td></td></tr><tr><td>Haemophilus genus</td><td>7/20 (35.0)</td><td>25/27 (92.6)</td><td>22/32 (68.8)</td><td><strong>&lt;.001</strong>,†‡</td></tr><tr><td>Streptococcus genus</td><td>9/20 (45.0)</td><td>22/27 (81.4)</td><td>23/32 (71.9)</td><td><strong>.025</strong>‡</td></tr><tr><td>Staphylococcus genus</td><td>0/20 (0.0)</td><td>2/27 (7.4)</td><td>1/32 (3.1)</td><td>.408</td></tr><tr><td>Neisseria genus</td><td>4/20 (20.0)</td><td>13/27 (48.1)</td><td>13/32 (40.6)</td><td>.134</td></tr><tr><td>Other bacteria genus</td><td></td><td></td><td></td><td></td></tr><tr><td>Viruses present</td><td>10/20 (50.0)</td><td>13/27 (48.1)</td><td>23/33 (69.7)</td><td>.178</td></tr><tr><td>Bronchial remodeling</td><td></td><td></td><td></td><td></td></tr><tr><td>Epithelial integrity (%)</td><td>18.4 [9.9; 30.9]</td><td>18.1 [6.0; 32.6]</td><td>14.1 [5.2; 26.2]</td><td>.488</td></tr><tr><td>RBM thickness (µm)</td><td>3.2 [3.1; 3.5]</td><td>3.3 [3.0; 3.5]</td><td>3.8 [3.4; 4.1]</td><td><strong>&lt;.001</strong>*†</td></tr><tr><td>RBM-BSM distance (µm)</td><td>64.5 [43.0; 84.3]</td><td>64.5 [41.6; 99.2]</td><td>36.8 [31.5; 50.0]</td><td><strong>.001</strong>*†</td></tr><tr><td>Normalized BSM area (%)</td><td>13.6 [11.1; 15.4]</td><td>19.6 [12.0; 24.0]</td><td>31.0 [24.3; 36.9]</td><td><strong>&lt;.001</strong>,†‡</td></tr><tr><td>Normalized submucosal fibrosis area (%)</td><td>31.9 [25.3; 50.3]</td><td>39.5 [34.3; 52.7]</td><td>31.4 [23.7; 40.2]</td><td>.065</td></tr><tr><td>Normalized mucus gland area (%)</td><td>14.7 [6.4; 20.0]</td><td>7.0 [2.0; 20.1]</td><td>8.0 [2.3; 12.8]</td><td>.154</td></tr><tr><td>Density of blood vessels (/µm²)</td><td>124.0 [79.1; 156.8]</td><td>161.0 [116.5; 212.5]</td><td>156.0 [117.0; 247.0]</td><td>.271</td></tr><tr><td>Within days after fiberoptic bronchoscopy</td><td></td><td></td><td></td><td></td></tr><tr><td>Pathogenic bacteria treated by ATB</td><td>9/11 (81.8)</td><td>21/26 (80.8)</td><td>23/26 (88.4)</td><td>.730</td></tr><tr><td>After 12 months of follow-up</td><td></td><td></td><td></td><td></td></tr><tr><td>Increased daily dose of ICS</td><td>0/20 (0.0)</td><td>2/27 (7.4)</td><td>16/33 (48.5)</td><td></td></tr><tr><td>Unchanged daily dose of ICS</td><td>9/20 (45.0)</td><td>15/27 (55.6)</td><td>14/33 (42.4)</td><td><strong>&lt;.001</strong>*†</td></tr><tr><td>Decreased daily dose of ICS</td><td>11/20 (55.0)</td><td>10/27 (37.0)</td><td>3/33 (9.0)</td><td></td></tr></tbody></table>

Patients were divided according to their number of exacerbations in the year after bronchoscopy into No-Ex (0 exacerbation), Low-Ex (1-2 exacerbations), and High-Ex (≥3 exacerbations).

Results are presented as absolute values and percentage: n/N (%); or as median with interquartile ranges: median [IQR₂₅; IQR₇₅].

Comparisons between the groups were performed using Kruskal-Wallis tests, with Dunn's post hoc tests for quantitative variables and χ² tests for categorical variables.

Bold P values indicate statistical significance: P < .05.

ATB, Antibiotics; BALF, bronchoalveolar lavage fluid; BSM, bronchial smooth muscle; ICS, inhaled corticosteroids; OCS, oral corticosteroids; RBM, reticular basement membrane.

*P < .05 for Low-Ex vs High-Ex.

†P < .05 for No-Ex vs High-Ex.

‡P < .05 for No-Ex vs Low-Ex.
<table><caption>TABLE II. Factors associated with increased exacerbation frequency in severe preschool wheezers</caption><thead><tr><th>Parameters</th><th>OR (95% CI)</th><th><i>P</i> value</th></tr></thead><tbody><tr><td>Normalized BSM area (%)</td><td>0.199 (0.112; 0.286)</td><td><i>&lt;.001</i></td></tr><tr><td>Age at first wheeze (mo)</td><td>-0.980 (-0.119; -0.004)</td><td><i>.046</i></td></tr><tr><td>Atopic dermatitis<br>(yes vs no)</td><td>-0.839 (-2.021; 0.342)</td><td>.164</td></tr><tr><td><i>Haemophilus</i> genus in the<br>BALF<br>(yes vs no)</td><td>-3.999 (-1.896; 1.098)</td><td>.602</td></tr><tr><td><i>Streptococcus</i> genus in the<br>BALF<br>(yes vs no)</td><td>-0.319 (-1.777; 1.131)</td><td>.666</td></tr><tr><td>RBM-BSM distance (μm)</td><td>0.003 (-0.012; 0.018)</td><td>.699</td></tr><tr><td>RBM thickness (μm)</td><td>0.516 (-0.330; 1.362)</td><td>.232</td></tr></tbody></table>

Patients were divided according to the number of exacerbations in the year after the fiberoptic bronchoscopy into the No-Ex (0 exacerbation, n = 20), Low-Ex (1 or 2 exacerbations, n = 27), and High-Ex (≥3 exacerbations, n = 33) groups.

Independent associations between factors and exacerbation frequency were determined using stepwise multiple multinomial regression with No-Ex as the reference group and using ordinal regression analysis.

Bold *P* values indicate statistical significance: *P* < .05.

and analyses were performed by using cohort membership as a covariable. (2) The number of patients remained limited, which has decreased the size of each group. Thus, the risk of type 2 error in the group comparisons and the 95% confidence intervals in the logistic regression analysis may have been increased. However, this pooled analysis represents the largest cohort describing both clinical and fiberoptic bronchoscopy parameters in severe preschool wheezers. (3) Our data did not include long-term follow-up (ie, more than 1 year), allowing the assessment of the stability of exacerbation frequency over time and its consequences on lung function and asthma persistence at school age.

Taken together, our results underline the interplay between early-life wheeze/viral infection and BSM remodeling in the pathogenesis of severe preschool wheezing and reinforce the need of further studies to better understand the underlying mechanisms leading to BSM remodeling and its role in exacerbation frequency, lung function, and asthma persistence.

## Acknowledgments

The authors thank the staff from the Clinical Investigation Center (CIC) and the pathology and microbiology departments of the University Hospital of Bordeaux (CHU de Bordeaux).

F. Beaufils, M. Fayon, and P. Berger contributed to conception and design of the study. F. Beaufils, P. Esteves, M. Campagnac, F. Lavrand, G. Simon, M. Michelet, H. Begueret, and M. Fayon acquired the data. F. Beaufils, R. Enaud, R. Prevel, P. Henrot, E. Maurat, H. Begueret, M. Fayon, and P. Berger analyzed the data. F. Beaufils, H. Begueret, T. Trian, M. Fayon, and P. Berger interpreted the data. F. Beaufils, M. Fayon, and P. Berger drafted the manuscript. All authors were involved in the revision and final approval of the version to be published. F. Auriol, S. Blanchon, A. M. Blondel, S. Marais, F. Nacka, F. Sgoifo, and T. Trian collaborated on general organization, regulatory aspects, and data acquisition. M.-L. Choukroun and H. Feghali conducted lung function testing. D. Carles, O. Ousova, and I. Rouquette were involved in lung tissue analysis, pathology, managing the tissue

bank, and conducting immunohistochemistry. V. Siao-Him-Fa, V. Boisserie-Lacroix, S. Blanchon, S. Debelleix, G. Labouret, A. M. Blondel, M. Mittaine, and F. Semjen performed bronchoscopy and anesthesia procedures.

## P'tit Asthme Study Group

Valerie Siao-Him-Fa, MD, PhD: INSERM U1045, Centre de Recherche Cardio-thoracique de Bordeaux, University of Bordeaux, Bordeaux, France; Département de Pédiatrie, CIC-P 1401, Service d'Anatomopathologie, Service d'Exploration Fonctionnelle Respiratoire, CHU Bordeaux, Bordeaux, France; INSERM U1045, Centre de Recherche Cardio-thoracique de Bordeaux, Centre d'Investigation Clinique (CIC-P 1401), Bordeaux, France

Françoise Auriol and Sylvain Blanchon: Service de pneumologie-allergologie pédiatrique, Service d'Anatomopathologie, CHU Toulouse, Hôpital des Enfants, Toulouse, France

Dominique Carles and Vincent Boisserie-Lacroix: Département de Pédiatrie, CIC-P 1401, Service d'Anatomopathologie, Service d'Exploration Fonctionnelle Respiratoire, CHU Bordeaux, Bordeaux, France

François Brémont: Service de pneumologie-allergologie pédiatrique, Service d'Anatomopathologie, CHU Toulouse, Hôpital des Enfants, Toulouse, France

Stéphanie Bui: INSERM U1045, Centre de Recherche Cardio-thoracique de Bordeaux, University of Bordeaux, France; Département de Pédiatrie, CIC-P 1401, Service d'Anatomopathologie, Service d'Exploration Fonctionnelle Respiratoire, CHU Bordeaux, Bordeaux, France; INSERM U1045, Centre de Recherche Cardio-Thoracique de Bordeaux, Centre d'Investigation Clinique (CIC-P 1401), Bordeaux, France

Guillaume Simon, BSc, and Marie-Luce Choukroun: Département de Pédiatrie, CIC-P 1401, Service d'Anatomopathologie, Service d'Exploration Fonctionnelle Respiratoire, CHU Bordeaux, Bordeaux, France

Stéphane Debelleix: INSERM U1045, Centre de Recherche Cardio-Thoracique de Bordeaux, University of Bordeaux, France; Département de Pédiatrie, CIC-P 1401, Service d'Anatomopathologie, Service d'Exploration Fonctionnelle Respiratoire, CHU Bordeaux, Bordeaux, France; INSERM U1045, Centre de Recherche Cardio-Thoracique de Bordeaux, Centre d'Investigation Clinique (CIC-P 1401), Bordeaux, France

Hala Feghali: Département de Pédiatrie, CIC-P 1401, Service d'Anatomopathologie, Service d'Exploration Fonctionnelle Respiratoire, CHU Bordeaux, Bordeaux, France

Géraldine Labouret and Audrey Martin Blondel: Service de Pneumologie-Allergologie pédiatrique, Service d'Anatomopathologie, CHU Toulouse, Hôpital des Enfants, Toulouse, France

Sébastien Marais: INSERM U1045, Centre de Recherche Cardio-Thoracique de Bordeaux, University of Bordeaux, Bordeaux, France

Marie Mittaine: Service de Pneumologie-Allergologie Pédiatrique, Service d'Anatomopathologie, CHU Toulouse, Hôpital des Enfants, Toulouse, France

Fabienne Nacka: INSERM U1045, Centre de Recherche Cardio-Thoracique de Bordeaux, Centre d'Investigation Clinique (CIC-P 1401), Bordeaux, France
Olga Ousova: INSERM U1045, Centre de Recherche Cardio-
Thoracique de Bordeaux, University of Bordeaux, Bordeaux,
France; INSERM U1045, Centre de Recherche Cardio-
Thoracique de Bordeaux, Centre d'Investigation Clinique
(CIC-P 1401), Bordeaux, France

Isabelle Rouquette: Service de Pneumologie-Allergologie
Pédiatrique, Service d'Anatomopathologie, CHU Toulouse,
Hôpital des Enfants, Toulouse, France

François Semjen and Frédérique Sgoifo: Département de
Pédiatrie, CIC-P 1401, Service d'Anatomopathologie, Service
d'Exploration Fonctionnelle Respiratoire, CHU Bordeaux,
Bordeaux, France

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2. Belgrave DCM, Granell R, Turner SW, Curtin JA, Buchan IE, Le Souëf PN, et al. Lung function trajectories from pre-school age to adulthood and their associations with early life factors: a retrospective analysis of three population-based birth cohort studies. Lancet Respir Med 2018;6:526-34.

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4. Wang KCW, Donovan GM, Saglani S, Mauad T, James AL, Elliot JG, et al. Growth of the airway smooth muscle layer from late gestation to childhood is mediated initially by hypertrophy and subsequently hyperplasia. Respirology 2022;27:493-500.

5. Fayon M, Andrieux A, Bara I, Rebola M, Labbé A, Marthan R, et al. An age-wise comparison of human airway smooth muscle proliferative capacity. PLoS One 2015;10:e0122446.

6. Beaufils F, Esteves P, Enaud R, Germande O, Celle A, Marthan R, et al. Mitochondria are involved in bronchial smooth muscle remodeling in severe pre-school wheezers. J Allergy Clin Immunol 2021;148:645-651.e11.

7. Celle A, Esteves P, Cardouat G, Beaufils F, Eyraud E, Dupin I, et al. Rhinovirus infection of bronchial epithelium induces specific bronchial smooth muscle cell migration of severe asthmatic patients. J Allergy Clin Immunol 2022;150:104-13.

8. Bara I, Ozier A, Tunon de Lara JM, Marthan R, Berger P. Pathophysiology of bronchial smooth muscle remodelling in asthma. Eur Respir J 2010;36:1174-84.

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<footnote>ªINSERM U1045, Centre de Recherche Cardio-thoracique de Bordeaux, University of Bordeaux, Bordeaux, France</footnote>

<footnote>ᵇDépartement de Pédiatrie, CIC-P 1401, Service d'Anatomopathologie, Service d'Exploration Fonctionnelle Respiratoire, CHU Bordeaux, Bordeaux, France</footnote>

<footnote>ᶜINSERM U1045, Centre de Recherche Cardio-thoracique de Bordeaux, Centre d'Investigation Clinique (CIC-P 1401), Bordeaux, France</footnote>

<footnote>ᵈService de pneumologie-allergologie pédiatrique, Service d'Anatomopathologie,
CHU Toulouse, Hôpital des Enfants, Toulouse, France</footnote>

<footnote>ᵉINSERM U1043 (CPTP), the University of Toulouse-Paul Sabatier, Toulouse,
France</footnote>

<footnote>*Members of the P'tit Asthme Study Group are listed below the Acknowledgments
section.</footnote>

<footnote>This study has received a research grant from the French Ministry of Health (grant numbers: B101222-30 and 2010-A01134-35) and the "Fondation Bordeaux Université (Fonds FGLMR/AVAD pour les Maladies Chroniques)."</footnote>

<footnote>Conflicts of interest: F. Beaufils has received a research grant from AstraZeneca and reports personal fees and nonfinancial support from Novartis, Chiesi, and AstraZeneca. R. Prevel has received support to attend conferences by Pfizer and GSK, and a research grant from CSL Behring. P. Henrot reports a research grant and nonfinancial support from FGLMR/Avad and nonfinancial support from Chiesi and GlaxoSmithKine. V. Siao-Him-Fa reports personal fees from Chiesi, Novartis, and ALK, and nonfinancial support from Novartis, Boehringer Ingelheim, and ALK. M. Michelet reports personal fees and nonfinancial support from Astra Zeneca, GSK, Novartis, and Sanofi. M. Fayon has received a research and educational grant from Novartis and reports personal fees as a speaker from GlaxoSmithKine. In addition, M. Fayon has 1 co-patent (number: FR 19/14751: ie, New in situ pulmonary treatment device in premature babies). P. Berger is the medical coordinator of the French national cohort (ie, COBRA), which received grants from AstraZeneca, GlaxoSmithKine, Roche, Chiesi, Novartis, and Legs Poix Foundation. He reports grants from Novartis and Boehringer Ingelheim; personal fees from Novartis, Chiesi, Boehringer Ingelheim, AstraZeneca, Sanofi, Menarini, and TEVA; and nonfinancial support from Chiesi, Boehringer</footnote>

<footnote>Ingelheim, AstraZeneca, and Sanofi, outside the submitted work. In addition, P. Berger has 3 patents: (1) (EP number: 15152886.6, ie, New compositions and methods of treating and/or preventing chronic obstructive pulmonary disease), pending; (2) (EP number: 3050574, ie, Use of plerixafor for treating and/or preventing acute exacerbations of chronic obstructive pulmonary disease), delivered; and (3) (EP number: 20173595.8, ie, New compositions and methods of treating COVID-19 disease), pending. The rest of the authors declare that they have no relevant conflicts of interest.</footnote>

<footnote>Received for publication September 26, 2023; revised November 30, 2023; accepted for publication December 8, 2023.</footnote>

<footnote>Available online December 19, 2023.</footnote>

<footnote>Corresponding author: Fabien Beaufils, MD, PhD, Département de Pédiatrie, Hôpital Pellegrin-Enfants, Place Amélie Raba-Léon, 33076 Bordeaux Cedex, France. E-mail: fabien.beaufils@u-bordeaux.fr.</footnote>

<footnote>2213-2198</footnote>

<footnote>© 2023 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).</footnote>

<footnote>https://doi.org/10.1016/j.jaip.2023.12.017</footnote>