# Sensitivity of FEV1 and Clinical Parameters in Children With a Suspected Asthma Diagnosis

Anouchka Fillard, Amelia Licari, Nicolas Molinari, Gianluigi Marseglia, Pascal Demoly, Davide Caimmi

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## To cite this version:

Anouchka Fillard, Amelia Licari, Nicolas Molinari, Gianluigi Marseglia, Pascal Demoly, et al.. Sensitivity of FEV1 and Clinical Parameters in Children With a Suspected Asthma Diagnosis. Journal of Allergy and Clinical Immunology: In Practice, 2023, 11 (1), pp.238-247. 10.1016/j.jaip.2022.10.011. hal-03930657

HAL Id: hal-03930657

https://hal.umontpellier.fr/hal-03930657

Submitted on 5 Apr 2024

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Distributed under a Creative Commons Attribution 4.0 International License
# Sensitivity of FEV1 and Clinical Parameters in Children With a Suspected Asthma Diagnosis

Anouchka Fillard, Amelia Licari, Nicolas Molinari, Gianluigi Marseglia, Pascal Demoly, Davide Caimmi

► To cite this version:

Anouchka Fillard, Amelia Licari, Nicolas Molinari, Gianluigi Marseglia, Pascal Demoly, et al. Sensitivity of FEV1 and Clinical Parameters in Children With a Suspected Asthma Diagnosis. Journal of Allergy and Clinical Immunology: In Practice, 2023, 11 (1), pp.238-247. 10.1016/j.jaip.2022.10.011. hal-03930657

HAL Id: hal-03930657

https://hal.umontpellier.fr/hal-03930657v1

Submitted on 5 Apr 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

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

Distributed under a Creative Commons Attribution 4.0 International License
1 Sensitivity of FEV₁ and clinical parameters in children with a suspected asthma

2 diagnosis

3

4 Authors

5 Anouchka FILLARD¹, MD a-fillard@chu-montpellier.fr

6 Amelia LICARI², MD amelia.licari@unipv.it

7 Nicolas MOLINARI³,⁴, PhD nicolas.molinari@inserm.fr

8 GianLuigi MARSEGLIA², MD gl.marseglia@smatteo.pv.it

9 Pascal DEMOLY¹,⁴, MD, PhD pascal.demoly@inserm.fr

10 Davide CAIMMI¹,⁴, MD, PhD davide.caimmi@gmail.com

11

12 Affiliations

13 1. Allergy Unit, Département de Pneumologie et Addictologie, Hôpital Arnaud de Villeneuve,
14 CHU de Montpellier, Univ Montpellier, France.

15 2. Pediatric Unit, University of Pavia, San Matteo Hospital, Pavia, Italy

16 3. Département de Statistiques, IMAG UMR5149 S, CHRU de Montpellier, Montpellier,
17 France

18 4. IDESP, UMR UA11 Université de Montpellier - INSERM, Montpellier, France

19

20 Corresponding Author

21 Davide CAIMMI

22 Unité d'allergologie, CHU de Montpellier

23 371, Avenue du Doyen Gaston Giraud – 34090 Montpellier (France)

24 Phone : +33630061134

25 Mail : davide.caimmi@gmail.com

26

27 Word count: 3519

28 4 Tables

29 3 Figures

30

31 The Authors declare no conflict of interest for the present work.

32 No funding source for the present work.
1 Sensitivity of FEV₁ and clinical parameters in children with a suspected asthma

2 diagnosis

3

4 Authors

5 Anouchka FILLARD¹, MD a-fillard@chu-montpellier.fr

6 Amelia LICARI², MD amelia.licari@unipv.it

7 Nicolas MOLINARI³,⁴, PhD nicolas.molinari@inserm.fr

8 GianLuigi MARSEGLIA², MD gl.marseglia@smatteo.pv.it

9 Pascal DEMOLY¹,⁴, MD, PhD pascal.demoly@inserm.fr

10 Davide CAIMMI¹,⁴, MD, PhD davide.caimmi@gmail.com

11

12 Affiliations

13 1. Allergy Unit, Département de Pneumologie et Addictologie, Hôpital Arnaud de Villeneuve,
14 CHU de Montpellier, Univ Montpellier, France.

15 2. Pediatric Unit, University of Pavia, San Matteo Hospital, Pavia, Italy

16 3. Département de Statistiques, IMAG UMR5149 S, CHRU de Montpellier, Montpellier,
17 France

18 4. IDESP, UMR UA11 Université de Montpellier - INSERM, Montpellier, France

19

20 Corresponding Author

21 Davide CAIMMI

22 Unité d'allergologie, CHU de Montpellier

23 371, Avenue du Doyen Gaston Giraud – 34090 Montpellier (France)

24 Phone : +33630061134

25 Mail : davide.caimmi@gmail.com

26

27 Word count: 3519

28 4 Tables

29 3 Figures

30

31 The Authors declare no conflict of interest for the present work.

32 No funding source for the present work.
33

**ABSTRACT (282 words)**

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**Background:** Asthma is the most common chronic disease in children and a robust diagnosis is crucial to optimize patient care and reduce its burden. To diagnose asthma in children, GINA recommendations propose a 12% improvement in FEV₁ after a bronchodilation test. Nevertheless, such criterion is rarely confirmed in these patients in clinical practice.

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**Objective:** The objective of this study was to evaluate the sensitivity of spirometric and clinical parameters in identifying children with possible asthma.

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**Methods:** The VERI-VEMS Study is a multicenter international retrospective cohort study. Data were collected, from January 2008 until January 2019, for all consecutive children (aged 5 to 18 years), with a diagnosis of asthma, who performed a spirometry at the time of the diagnosis. We compared the sensitivity of the reversibility criterion proposed by GINA guidelines, with other spirometric and clinical variables, using physician diagnosed asthma and response to treatment as the standard.

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**Results:** 871 children were included in the study. The reversibility criterion of 12% of FEV₁ showed a sensitivity of 30.4%. The three best spirometric or clinical criteria were the presence of "dry cough, or wheezing or atopy" and "dry cough, or wheezing or exercise induced dyspnea", with a sensitivity reaching 99.5%, with no added value of the spirometric parameters in the calculation of the cumulated sensitivity for the diagnosis of pediatric asthma.

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**Conclusion:** Post bronchodilator reversibility of 12%, although essential for patients' follow-up, has an insufficient low sensitivity in reaching a diagnosis of asthma in pediatric patients, compared to a combination of clinical symptoms, that show, on the other hand, a better sensitivity. Further studies on specificity will help clarify the role of this change in diagnostic paradigm in formally diagnosing children with asthma.

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**Trial Registration** The study was registered on ClinicalTrials.gov (ID: NCT03814018).
33

**ABSTRACT (282 words)**

34

35

36

37

**Background:** Asthma is the most common chronic disease in children and a robust diagnosis is crucial to optimize patient care and reduce its burden. To diagnose asthma in children, GINA recommendations propose a 12% improvement in FEV₁ after a bronchodilation test. Nevertheless, such criterion is rarely confirmed in these patients in clinical practice.

38

39

**Objective:** The objective of this study was to evaluate the sensitivity of spirometric and clinical parameters in identifying children with possible asthma.

40

41

42

43

44

45

**Methods:** The VERI-VEMS Study is a multicenter international retrospective cohort study. Data were collected, from January 2008 until January 2019, for all consecutive children (aged 5 to 18 years), with a diagnosis of asthma, who performed a spirometry at the time of the diagnosis. We compared the sensitivity of the reversibility criterion proposed by GINA guidelines, with other spirometric and clinical variables, using physician diagnosed asthma and response to treatment as the standard.

46

47

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49

50

**Results:** 871 children were included in the study. The reversibility criterion of 12% of FEV₁ showed a sensitivity of 30.4%. The three best spirometric or clinical criteria were the presence of "dry cough, or wheezing or atopy" and "dry cough, or wheezing or exercise induced dyspnea", with a sensitivity reaching 99.5%, with no added value of the spirometric parameters in the calculation of the cumulated sensitivity for the diagnosis of pediatric asthma.

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55

**Conclusion:** Post bronchodilator reversibility of 12%, although essential for patients' follow-up, has an insufficient low sensitivity in reaching a diagnosis of asthma in pediatric patients, compared to a combination of clinical symptoms, that show, on the other hand, a better sensitivity. Further studies on specificity will help clarify the role of this change in diagnostic paradigm in formally diagnosing children with asthma.

56

57

**Trial Registration** The study was registered on ClinicalTrials.gov (ID: NCT03814018).
58

**Keywords:** asthma; children; Pulmonary Function Tests; FEV₁; clinical symptoms; GINA;

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sensitivity.

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58

**Keywords:** asthma; children; Pulmonary Function Tests; FEV₁; clinical symptoms; GINA;

59

sensitivity.

60
## 61 Highlights box

62 1. What is already known about this topic?

63 • GINA international guidelines advise to perform pulmonary function tests to
64 diagnose asthma, both in children and adults. Diagnostic criteria in children require a
65 FEV₁/FVC ratio lower than 90% and an increase of 12% of their FEV₁ after
66 bronchodilation test, based on what was observed in adults.

67 2. What does this article add to our knowledge?

68 • In this multicenter international retrospective cohort study, we evaluated pulmonary
69 function tests results of children with a physician-made diagnosis of asthma, and
70 collected clinical data, to assess the sensitivity of the FEV₁ reversibility criterion.
71 While reversibility criteria showed a sensitivity of 30.4%, the sensitivitty of the
72 association of three clinical parameters was 99.5%.

73 3. How does this study impact current management guidelines?

74 • The results of the present work bring an important contribution to current knowledge
75 on asthma diagnosis in children, showing that spirometric values have a very
76 unsatisfying low sensitivity, especially if compared with clinical symptoms.

77

## 78 Abbreviations

79 AIT – Allergen Immunotherapy

80 FEF₂₅₋₇₅ – Forced expiratory flow at 25-75% of the pulmonary volume

81 FENO – Fractional exhaled nitric oxide

82 FEV₁ – Forced Expiratory Volume in 1 second

83 FVC – Forced vital capacity

84 GINA – Global Initiative for Asthma

85 PFTs – Pulmonary Function Tests

86 SD – Standard Deviation

87 Se – Sensitivity
## 61 Highlights box

62 1. What is already known about this topic?

63 • GINA international guidelines advise to perform pulmonary function tests to
64 diagnose asthma, both in children and adults. Diagnostic criteria in children require a
65 FEV₁/FVC ratio lower than 90% and an increase of 12% of their FEV₁ after
66 bronchodilation test, based on what was observed in adults.

67 2. What does this article add to our knowledge?

68 • In this multicenter international retrospective cohort study, we evaluated pulmonary
69 function tests results of children with a physician-made diagnosis of asthma, and
70 collected clinical data, to assess the sensitivity of the FEV₁ reversibility criterion.
71 While reversibility criteria showed a sensitivity of 30.4%, the sensitivitty of the
72 association of three clinical parameters was 99.5%.

73 3. How does this study impact current management guidelines?

74 • The results of the present work bring an important contribution to current knowledge
75 on asthma diagnosis in children, showing that spirometric values have a very
76 unsatisfying low sensitivity, especially if compared with clinical symptoms.

77

## 78 Abbreviations

79 AIT – Allergen Immunotherapy

80 FEF₂₅-₇₅ – Forced expiratory flow at 25-75% of the pulmonary volume

81 FENO – Fractional exhaled nitric oxide

82 FEV₁ – Forced Expiratory Volume in 1 second

83 FVC – Forced vital capacity

84 GINA – Global Initiative for Asthma

85 PFTs – Pulmonary Function Tests

86 SD – Standard Deviation

87 Se – Sensitivity
88

**Introduction**

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Asthma is a chronic inflammatory disorder of the bronchi, associated to airflow hyperreactivity, and possibly leading to acute symptoms, that are reversible either spontaneously or after appropriate bronchodilator treatment¹,². With both prevalence and incidence increasing over the last decades, asthma is a major public health problem³⁻⁵. Considering the pediatric population, asthma is the most frequent chronic non-communicable disease, and the leading cause of childhood morbidity, mainly caused by acute exacerbations characterized by breathlessness, wheezing, chest tightness, and/or cough⁶,⁷. It is also associated to a high rate of emergency room visits, hospitalizations, absence from school and presenteism, and still contributes to many deaths amongst young people even in developed countries²,⁸. This condition, also frequent in adulthood, often begins in early childhood, with an earlier onset in males, and initially with intermittent symptoms, especially occurring during viral respiratory tract infections. Other possible triggers include allergies, physical exercise, cold air, extreme emotional arousal, and even some drugs (aspirin, non-steroid anti-inflammatory drugs, or beta-blockers)³,⁹,¹⁰. In pediatrics, known predisposition factors include a family history of asthma, atopy, allergic rhinitis, low birth weight or a history of multiple wheezing episodes during the first two years of life¹¹⁻¹⁵. In general, asthma is known to be a chronic disease, tending to present as a lifetime condition¹⁶,¹⁷. For such reason, an appropriate management with a correct and prompt diagnosis is crucial to control symptoms and therefore reduce asthma burden and increase patients' quality of life. The Global Initiative for Asthma (GINA) international guidelines advise to perform pulmonary function tests (PFTs) to diagnose asthma, both in children and adults. Diagnostic criteria in children require a FEV₁/FVC ratio lower than 90% and an increase of 12% of their FEV₁ after bronchodilation test, based on what was observed in adults⁴,¹⁸⁻²⁰. Nevertheless, the bronchodilation test following GINA recommendations, is sometimes difficult to perform in children younger than 5 years, due to age-related difficulties in achieving test-satisfying controlled expirations⁴,¹²,²¹,²². The increase of the FEF₂₅-₇₅ after bronchodilation has also been proposed in children to corroborate the diagnosis, but studies seem not to be conclusive²³,²⁴. Also,
88

**Introduction**

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Asthma is a chronic inflammatory disorder of the bronchi, associated to airflow hyper-reactivity, and possibly leading to acute symptoms, that are reversible either spontaneously or after appropriate bronchodilator treatment¹,². With both prevalence and incidence increasing over the last decades, asthma is a major public health problem³⁻⁵. Considering the pediatric population, asthma is the most frequent chronic non-communicable disease, and the leading cause of childhood morbidity, mainly caused by acute exacerbations characterized by breathlessness, wheezing, chest tightness, and/or cough⁶,⁷. It is also associated to a high rate of emergency room visits, hospitalizations, absenteism from school and presenteism, and still contributes to many deaths amongst young people even in developed countries²,⁸. This condition, also frequent in adulthood, often begins in early childhood, with an earlier onset in males, and initially with intermittent symptoms, especially occurring during viral respiratory tract infections. Other possible triggers include allergies, physical exercise, cold air, extreme emotional arousal, and even some drugs (aspirin, non-steroid anti-inflammatory drugs, or beta-blockers)³,⁹,¹⁰. In pediatrics, known predisposition factors include a family history of asthma, atopy, allergic rhinitis, low birth weight or a history of multiple wheezing episodes during the first two years of life¹¹⁻¹⁵. In general, asthma is known to be a chronic disease, tending to present as a lifetime condition¹⁶,¹⁷. For such reason, an appropriate management with a correct and prompt diagnosis is crucial to control symptoms and therefore reduce asthma burden and increase patients' quality of life. The Global Initiative for Asthma (GINA) international guidelines advise to perform pulmonary function tests (PFTs) to diagnose asthma, both in children and adults. Diagnostic criteria in children require a FEV₁/FVC ratio lower than 90% and an increase of 12% of their FEV₁ after bronchodilation test, based on what was observed in adults⁴,¹⁸⁻²⁰. Nevertheless, the bronchodilation test following GINA recommendations, is sometimes difficult to perform in children younger than 5 years, due to age-related difficulties in achieving test-satisfying controlled expirations⁴,¹²,²¹,²². The increase of the FEF₂₅-₇₅ after bronchodilation has also been proposed in children to corroborate the diagnosis, but studies seem not to be conclusive²³,²⁴. Also,
114 the accuracy of these criteria is debated in children and other possible diagnostic methods have been
115 investigated<sup>25,26</sup>. Indeed, in clinical practice, clinical signs and response to inhaled therapy are
116 currently considered by pediatricians as the most useful tools to suspect and then diagnose asthma
117 in children<sup>27,28</sup>.

118 The aim of the present study was to measure, in real-life settings, the sensitivity of the
119 reversibility criterion proposed by GINA recommendations (i.e., the increase of 12% of the FEV₁),
120 and to look for other spirometric and clinical parameters with a high sensitivity to identify children
121 that respond to asthma treatment, and that may be appropriate to clinical management, without
122 further testing, for a diagnosis of asthma in children.
114 the accuracy of these criteria is debated in children and other possible diagnostic methods have been
115 investigated<sup>25,26</sup>. Indeed, in clinical practice, clinical signs and response to inhaled therapy are
116 currently considered by pediatricians as the most useful tools to suspect and then diagnose asthma
117 in children<sup>27,28</sup>.

118 The aim of the present study was to measure, in real-life settings, the sensitivity of the
119 reversibility criterion proposed by GINA recommendations (i.e., the increase of 12% of the FEV₁),
120 and to look for other spirometric and clinical parameters with a high sensitivity to identify children
121 that respond to asthma treatment, and that may be appropriate to clinical management, without
122 further testing, for a diagnosis of asthma in children.
123 Methods

124 1. Study Design and included population

125 We conducted a multicenter retrospective cohort study that included data from January 2008
126 to January 2019. Data were collected at the Pediatric and at the Allergy Unit of the University
127 Hospital of Montpellier, France, and at the Immunology and Allergy Pediatric Unit of the
128 University Hospital of Pavia, Italy. The study was approved by a local ethical committee, in
129 Montpellier (2019_IRB-MTP_01-06) and validated by the Ethical Committee of the University
130 Hospital of Pavia. The study was registered on ClinicalTrials.gov (ID: NCT03814018).

131 We included all consecutive children, followed by each center, with a diagnosis of asthma,
132 and who performed a PFT at the time of the diagnosis. In each center, patients were considered as
133 asthmatic if, after the first consultation, the pediatrician, specialized in childhood respiratory and
134 allergic diseases, concluded the visit by declaring the child affected by asthma, and if they
135 responded to prescribed treatment at least within 2 follow-up visits. This was clearly based on their
136 long clinical experience, including PFT results and response to anti-asthma treatments. Diagnosis of
137 asthma had to be reached between their 5th and their 18th anniversary. Children were excluded if
138 suffering from other chronic and obstructive respiratory diseases, acute infectious diseases, and
139 genetic disorders possible affecting the respiratory system. They were also excluded if, at the time
140 of the first visit, they had already been prescribed with anti-asthmatic drugs, including short-acting
141 beta agonists, inhaled corticosteroids, and leukotriene receptor antagonists. They were also
142 excluded if PFTs results didn't meet acceptability criteria.

143 For each patient, we collected demographic information (height, weight, age at diagnosis,
144 sex), country of provenance (either France or Italy), PFT results at the time of the diagnosis, asthma
145 severity (based on prescribed treatment and GINA guidelines), clinical information (presented
146 symptoms, physician-evaluated treatment efficacy after the first consultation, personal history of
147 bronchiolitis/recurrent wheezing during the first two years of life). Presence of atopic comorbidities
148 was evaluated as well, including atopy, defined as sensitization to at least one common respiratory
123 Methods

124 1. Study Design and included population

125 We conducted a multicenter retrospective cohort study that included data from January 2008
126 to January 2019. Data were collected at the Pediatric and at the Allergy Unit of the University
127 Hospital of Montpellier, France, and at the Immunology and Allergy Pediatric Unit of the
128 University Hospital of Pavia, Italy. The study was approved by a local ethical committee, in
129 Montpellier (2019_IRB-MTP_01-06) and validated by the Ethical Committee of the University
130 Hospital of Pavia. The study was registered on ClinicalTrials.gov (ID: NCT03814018).

131 We included all consecutive children, followed by each center, with a diagnosis of asthma,
132 and who performed a PFT at the time of the diagnosis. In each center, patients were considered as
133 asthmatic if, after the first consultation, the pediatrician, specialized in childhood respiratory and
134 allergic diseases, concluded the visit by declaring the child affected by asthma, and if they
135 responded to prescribed treatment at least within 2 follow-up visits. This was clearly based on their
136 long clinical experience, including PFT results and response to anti-asthma treatments. Diagnosis of
137 asthma had to be reached between their 5th and their 18th anniversary. Children were excluded if
138 suffering from other chronic and obstructive respiratory diseases, acute infectious diseases, and
139 genetic disorders possible affecting the respiratory system. They were also excluded if, at the time
140 of the first visit, they had already been prescribed with anti-asthmatic drugs, including short-acting
141 beta agonists, inhaled corticosteroids, and leukotriene receptor antagonists. They were also
142 excluded if PFTs results didn't meet acceptability criteria.

143 For each patient, we collected demographic information (height, weight, age at diagnosis,
144 sex), country of provenance (either France or Italy), PFT results at the time of the diagnosis, asthma
145 severity (based on prescribed treatment and GINA guidelines), clinical information (presented
146 symptoms, physician-evaluated treatment efficacy after the first consultation, personal history of
147 bronchiolitis/recurrent wheezing during the first two years of life). Presence of atopic comorbidities
148 was evaluated as well, including atopy, defined as sensitization to at least one common respiratory
149 allergen (including Dermatophagoides pteronissinus, Dermatophagoides farinae, grass, cypress,
150 birch, cat, dog, *Alternaria alternata*); allergic rhinitis, defined as the presence of typical disease
151 symptoms due to exposure to an airborne allergen to which the patients are sensitized; food allergy,
152 defined as the appearance of hypersensitivity symptoms related to consumption of a food allergen to
153 which the patients are sensitized, or a positive food challenge to the culprit food; atopic dermatitis,
154 defined by the presence of an inflammatory, pruritic, chronic or chronically relapsing skin disease,
155 and on the recognition of characteristic signs and symptoms by a pediatric allergist²⁹.
156

157 **2. Outcomes of the study**

158 The primary outcome of this study was to assess the sensitivity of the reversibility criterion
159 proposed by GINA guidelines of an increase of 12% of FEV₁ after bronchodilation test, compared
160 to clinical symptoms that respond to therapy to diagnose presumed pediatric asthma.

161 The secondary endpoints were: (i) to assess the sensitivity of other spirometric parameters –
162 such as the presence of obstructive syndrome in children, as proposed by GINA guidelines
163 (FEV₁/FVC < 90%), and the reversibility of small airways (FEF₂₅-₇₅), defined as an increase greater
164 than 30% after bronchodilation test from basal values; and (ii) to evaluate, in a subgroups analysis,
165 possible correlations between asthma severity and comorbidities.
166

167 **3. Statistical analysis**

168 Continuous variables were summarized with descriptive statistics (number, mean, SD), while
169 frequency counts and percentages were provided for categorical data. Statistics were computed for
170 patients with available (i.e., non-missing) data. Comparison of patient characteristics was assessed
171 after grouping patients as for asthma severity (persistent severe, persistent moderate, persistent
172 mild, and intermittent asthma). We used the Student's t-test for data in case of continuous variables
173 and the chi-square test for categorical variables. Differences between groups were considered
174 statistically significant if p-values were <0.05.
149 allergen (including *Dermatophagoides pteronissinus*, *Dermatophagoides farinae*, grass, cypress,
150 birch, cat, dog, *Alternaria alternata*); allergic rhinitis, defined as the presence of typical disease
151 symptoms due to exposure to an airborne allergen to which the patients are sensitized; food allergy,
152 defined as the appearance of hypersensitivity symptoms related to consumption of a food allergen to
153 which the patients are sensitized, or a positive food challenge to the culprit food; atopic dermatitis,
154 defined by the presence of an inflammatory, pruritic, chronic or chronically relapsing skin disease,
155 and on the recognition of characteristic signs and symptoms by a pediatric allergist²⁹.
156

157 **2. Outcomes of the study**

158 The primary outcome of this study was to assess the sensitivity of the reversibility criterion
159 proposed by GINA guidelines of an increase of 12% of FEV₁ after bronchodilation test, compared
160 to clinical symptoms that respond to therapy to diagnose presumed pediatric asthma.

161 The secondary endpoints were: (i) to assess the sensitivity of other spirometric parameters –
162 such as the presence of obstructive syndrome in children, as proposed by GINA guidelines
163 (FEV₁/FVC < 90%), and the reversibility of small airways (FEF₂₅-₇₅), defined as an increase greater
164 than 30% after bronchodilation test from basal values; and (ii) to evaluate, in a subgroups analysis,
165 possible correlations between asthma severity and comorbidities.
166

167 **3. Statistical analysis**

168 Continuous variables were summarized with descriptive statistics (number, mean, SD), while
169 frequency counts and percentages were provided for categorical data. Statistics were computed for
170 patients with available (i.e., non-missing) data. Comparison of patient characteristics was assessed
171 after grouping patients as for asthma severity (persistent severe, persistent moderate, persistent
172 mild, and intermittent asthma). We used the Student's t-test for data in case of continuous variables
173 and the chi-square test for categorical variables. Differences between groups were considered
174 statistically significant if p-values were <0.05.
175

All analyses were performed using SAS version 9.4 (SAS Institute Inc, Cary, NC, USA).
176

# Results

177

## 1. Included population

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We included a total of 888 children with a diagnosis of asthma reached between January 2008 and January 2019. 17 of them were excluded from the analysis because of missing data (Figure 1). 342 patients were included from the Montpellier University Hospital: 219 of them (64.0%) were males; their mean age at diagnosis was 9.2 years (SD 3.4). 529 patients were included from the Pavia University Hospital: 329 of them (62.2%) were males; their mean age at diagnosis was 9.3 years (SD 3.2). The two populations were not statistically different, when considering their sex and their age (p-value: 0.5825 and 0.6605, respectively). Moreover, basal FEV₁ values did not differ between the French and Italian population (1800 mL and 1900 mL, respectively; p-value: 0.0728). For all the above reasons, statistical analysis was performed considering the two groups as a single cohort. On the other hand, since there was a significant difference between mean basal values of FEV₁/FVC in the two populations and the presence of atopy, allergic rhinitis, and food allergy, we also assessed the sensitivity of spirometric criteria in the two countries, separately (vide infra).

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An interesting difference between the two populations concerned the prescription of Allergen Immunotherapy (AIT): patients received significantly more AIT treatments in the French population, compared with the Italian one (17.0% vs. 8.1%; p-value < 0.0001). Another difference concerned sensitization to cypress and birch pollen: in fact, cypress pollen allergy is very common in the Montpellier area, but not in the Pavia area. The opposite consideration is true for birch pollen allergy. We considered these differences very unlikely to influence our objectives.

Characteristics of the children included in the study are shown in Table 1.

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199

## 2. Primary outcome

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201

The reversibility criterion of an increase of at least 12% of the FEV₁ after bronchodilation test was confirmed in 266 out of 871 children (Figure 2), with a sensitivity (Se) of 30.4% (Table 2).
176

# Results

177

## 1. Included population

178

179

180

181

182

183

184

185

186

187

188

189

190

We included a total of 888 children with a diagnosis of asthma reached between January 2008 and January 2019. 17 of them were excluded from the analysis because of missing data (Figure 1). 342 patients were included from the Montpellier University Hospital: 219 of them (64.0%) were males; their mean age at diagnosis was 9.2 years (SD 3.4). 529 patients were included from the Pavia University Hospital: 329 of them (62.2%) were males; their mean age at diagnosis was 9.3 years (SD 3.2). The two populations were not statistically different, when considering their sex and their age (p-value: 0.5825 and 0.6605, respectively). Moreover, basal FEV₁ values did not differ between the French and Italian population (1800 mL and 1900 mL, respectively; p-value: 0.0728). For all the above reasons, statistical analysis was performed considering the two groups as a single cohort. On the other hand, since there was a significant difference between mean basal values of FEV₁/FVC in the two populations and the presence of atopy, allergic rhinitis, and food allergy, we also assessed the sensitivity of spirometric criteria in the two countries, separately (vide infra).

191

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194

195

196

197

An interesting difference between the two populations concerned the prescription of Allergen Immunotherapy (AIT): patients received significantly more AIT treatments in the French population, compared with the Italian one (17.0% vs. 8.1%; p-value < 0.0001). Another difference concerned sensitization to cypress and birch pollen: in fact, cypress pollen allergy is very common in the Montpellier area, but not in the Pavia area. The opposite consideration is true for birch pollen allergy. We considered these differences very unlikely to influence our objectives.

Characteristics of the children included in the study are shown in Table 1.

198

199

## 2. Primary outcome

200

201

The reversibility criterion of an increase of at least 12% of the FEV₁ after bronchodilation test was confirmed in 266 out of 871 children (Figure 2), with a sensitivity (Se) of 30.4% (Table 2).
202 When considering children with a FEV₁/FVC < 90%, the reversibility criterion showed a 23.5%
203 sensitivity, being recorded in 205 children only. There was no significant difference between the
204 two centers (31.0% and 30.1% sensitivity in the French and Italian population, respectively).
205 Moreover, the mean change in FEV₁ after bronchodilation was similar in the two centers as well
206 (8.1% with 13.1% of SD, and 8.3% with 8.8% of SD, respectively; *p*-value: 0.79).

207

208 3. *Obstruction criterion and small airways criterion*

209 The obstruction criterion proposed by GINA guidelines for children (FEV₁/FVC < 90%) was
210 confirmed in 595 children, with a sensitivity of 67.5% overall (Table 2). The mean value of the
211 FEV₁/FVC ratio in the entire cohort was 85% (SD 10%).

212 The increase of more than 30% in FEF₂₅-₇₅ after bronchodilation test was only found in 198
213 children in our cohort (Se 21.9%), with a mean value of 22.1% (SD 30.0%) (Table 2). Furthermore,
214 older children (>11 years group) were also less likely to achieve this reversibility criterion,
215 compared with patients with less than 7 years of age, or between 7 and 11 years (15.1%, 24.9%, and
216 23.8%, respectively).

217

218 4. *Most sensitive criteria to identify presumed asthma*

219 To assess the variables providing the best sensitivity to identify presumed asthma, we
220 included in the analysis both the spirometric criteria (FEV₁/FVC < 90%, change in FEV₁ > 12%,
221 change in FEF₂₅-₇₅ > 30%), and the clinical ones (dry cough, tight chest, wheezing, pre-school
222 wheezing, exercise-induced dyspnea, atopy, presence of allergic comorbidities). The best single
223 criterion was the presence of "dry cough" (Se 90.9%). Sensitivity of each criterion is shown in
224 Table 3. The best two combined criteria were "dry cough or atopy" (Se 98.5%), followed by both
225 "dry cough or wheezing" or "dry cough or allergic comorbidities" (Se of 97.7%).

226 Furthermore, the best three criteria to identify presumed asthma were "dry cough, or
202 When considering children with a FEV₁/FVC < 90%, the reversibility criterion showed a 23.5%
203 sensitivity, being recorded in 205 children only. There was no significant difference between the
204 two centers (31.0% and 30.1% sensitivity in the French and Italian population, respectively).
205 Moreover, the mean change in FEV₁ after bronchodilation was similar in the two centers as well
206 (8.1% with 13.1% of SD, and 8.3% with 8.8% of SD, respectively; *p*-value: 0.79).

207

208
3. *Obstruction criterion and small airways criterion*

209
The obstruction criterion proposed by GINA guidelines for children (FEV₁/FVC < 90%) was
210
confirmed in 595 children, with a sensitivity of 67.5% overall (Table 2). The mean value of the
211
FEV₁/FVC ratio in the entire cohort was 85% (SD 10%).

212
The increase of more than 30% in FEF₂₅₇₅ after bronchodilation test was only found in 198
213
children in our cohort (Se 21.9%), with a mean value of 22.1% (SD 30.0%) (Table 2). Furthermore,
214
older children (>11 years group) were also less likely to achieve this reversibility criterion,
215
compared with patients with less than 7 years of age, or between 7 and 11 years (15.1%, 24.9%, and
216
23.8%, respectively).

217

218
4. *Most sensitive criteria to identify presumed asthma*

219
To assess the variables providing the best sensitivity to identify presumed asthma, we
220
included in the analysis both the spirometric criteria (FEV₁/FVC < 90%, change in FEV₁ > 12%,
221
change in FEF₂₅₇₅ > 30%), and the clinical ones (dry cough, tight chest, wheezing, pre-school
222
wheezing, exercise-induced dyspnea, atopy, presence of allergic comorbidities). The best single
223
criterion was the presence of "dry cough" (Se 90.9%). Sensitivity of each criterion is shown in
224
Table 3. The best two combined criteria were "dry cough or atopy" (Se 98.5%), followed by both
225
"dry cough or wheezing" or "dry cough or allergic comorbidities" (Se of 97.7%).

226
Furthermore, the best three criteria to identify presumed asthma were "dry cough, or
wheezing or atopy", and "dry cough, or wheezing or exercise-induced dyspnea", with both a sensitivity of 99.5%. The combination of the previously mentioned four criteria (dry cough, wheezing, atopy and exercise-induced dyspnea) was associated to a sensitivity of 100% (Figure 3). In no case, adding spirometric parameters improved the cumulative sensitivity for the identification of presumed asthma. Moreover, when comparing the sensitivity of the different clinical parameters between the subgroup of 383 children with FEV₁/FVC < 90%, but without FEV₁ reversibility and the 205 patients with reversibility criteria, we found no significant difference between the groups (Table 3).

235

236

## 5. Subgroup analysis based on asthma severity

The number of included patients significantly differed in each asthma severity subgroup (respectively for severe, moderate, mild persistent and intermittent asthma: 55, 581, 203, 32; all *p-values* <0,005) (Table 4). The small number of patients included in the « intermittent » group could mainly be explained by the fact they are not representative of the average patient consulting at a tertiary University Hospital, and are therefore under-represented, if compared with the general population. Sex and BMI were not statistically different between those four groups (*p-values* <0,05).

The mean improvement in FEV₁ after bronchodilation was higher when the severity was greater: the severe asthma group showed a significantly higher increase in FEV₁ than the moderate asthma group (13.2% (SD 18.2) and 8.9% (SD 10.7), respectively; *p-value*: 0.008) and the mild group (5.0% (SD 6.9), *p-value* < 0.0001). The same significant difference was also highlighted between the moderate and the mild group as well (*p-value* < 0.0001). There was no significant difference when we compared the intermittent group with any other severity group. When we assessed patients presenting an increase of at least 12% in their FEV₁, there was a significant difference (*p-value* <0.05) in sensitivity between patients suffering from mild persistent asthma (16.3% of increase in FEV₁, in 33 children) and both moderate persistent asthma (34.3%, n=199, *p-*)
wheezing or atopy", and "dry cough, or wheezing or exercise-induced dyspnea", with both a sensitivity of 99.5%. The combination of the previously mentioned four criteria (dry cough, wheezing, atopy and exercise-induced dyspnea) was associated to a sensitivity of 100% (Figure 3). In no case, adding spirometric parameters improved the cumulative sensitivity for the identification of presumed asthma. Moreover, when comparing the sensitivity of the different clinical parameters between the subgroup of 383 children with FEV₁/FVC < 90%, but without FEV₁ reversibility and the 205 patients with reversibility criteria, we found no significant difference between the groups (Table 3).

235

236

## 5. Subgroup analysis based on asthma severity

The number of included patients significantly differed in each asthma severity subgroup (respectively for severe, moderate, mild persistent and intermittent asthma: 55, 581, 203, 32; all *p-values* <0,005) (Table 4). The small number of patients included in the « intermittent » group could mainly be explained by the fact they are not representative of the average patient consulting at a tertiary University Hospital, and are therefore under-represented, if compared with the general population. Sex and BMI were not statistically different between those four groups (*p-values* <0,05).

The mean improvement in FEV₁ after bronchodilation was higher when the severity was greater: the severe asthma group showed a significantly higher increase in FEV₁ than the moderate asthma group (13.2% (SD 18.2) and 8.9% (SD 10.7), respectively; *p-value*: 0.008) and the mild group (5.0% (SD 6.9), *p-value* < 0.0001). The same significant difference was also highlighted between the moderate and the mild group as well (*p-value* < 0.0001). There was no significant difference when we compared the intermittent group with any other severity group. When we assessed patients presenting an increase of at least 12% in their FEV₁, there was a significant difference (*p-value* <0.05) in sensitivity between patients suffering from mild persistent asthma (16.3% of increase in FEV₁, in 33 children) and both moderate persistent asthma (34.3%, n=199, *p-*)
value < 0.0001) and severe persistent asthma (41.8%, n=23, p-value < 0.0001), meaning that, as persistent asthma becomes more severe, the increase in FEV₁ criterion showed a higher sensitivity.

When considering the mean basal obstruction criterion, we found lower values as asthma was more severe. The mean basal FEV₁/FVC was 79.5% (SD 10.5%) in the severe asthma group, 84.1% (SD 9.7%) in the moderate group (p-value: 0,0009), and 87.7% (SD 8.5%) in the mild one (p-value < 0.0001). When we assessed the FEV₁/FVC < 90% criterion per asthma severity, there was a significant difference (p-value <0.005) between each subgroup, showing that when asthma is more severe, patients present increasing obstructive spirometric values (87.5%, 72.1%, 53.2%, in the mild, moderate, and severe persistent asthma subgroups, respectively).

On the other hand, the mean change in FEF₂₅₋₇₅, was statistically different only between mild and moderate persistent asthma.

Atopy had a significant impact on asthma severity: we found more atopic patients in the severe group (51 patients, 92.7%), compared with the moderate and mild groups (78.3% (p-value: 0.0113) and 73.4% (p-value: 0.0023), respectively). No significant difference between groups was found when assessing for specific respiratory allergens and food allergy.
value < 0.0001) and severe persistent asthma (41.8%, n=23, p-value < 0.0001), meaning that, as persistent asthma becomes more severe, the increase in FEV₁ criterion showed a higher sensitivity.

When considering the mean basal obstruction criterion, we found lower values as asthma was more severe. The mean basal FEV₁/FVC was 79.5% (SD 10.5%) in the severe asthma group, 84.1% (SD 9.7%) in the moderate group (p-value: 0,0009), and 87.7% (SD 8.5%) in the mild one (p-value < 0.0001). When we assessed the FEV₁/FVC < 90% criterion per asthma severity, there was a significant difference (p-value <0.005) between each subgroup, showing that when asthma is more severe, patients present increasing obstructive spirometric values (87.5%, 72.1%, 53.2%, in the mild, moderate, and severe persistent asthma subgroups, respectively).

On the other hand, the mean change in FEF₂₅₋₇₅, was statistically different only between mild and moderate persistent asthma.

Atopy had a significant impact on asthma severity: we found more atopic patients in the severe group (51 patients, 92.7%), compared with the moderate and mild groups (78.3% (p-value: 0.0113) and 73.4% (p-value: 0.0023), respectively). No significant difference between groups was found when assessing for specific respiratory allergens and food allergy.
268 **Discussion**

269 Through the present multicenter study, we assessed the sensitivity of the recommended 270 spirometric criteria in real-life settings. No study strongly affirms that the 12% threshold is an 271 adequate cut-off value, showing a good sensitivity for the diagnosis of asthma in children. Indeed, 272 our study, this reversibility criterion showed a very low sensitivity (30.4%) for broncho- 273 reversibility, as a diagnostic tool for asthma in pediatrics. Thus, such a criterion does not seem to be 274 applicable to children, if compared to adults, as previously highlighted in other studies³⁰. In 2016, 275 Hopp et al. proposed a literature review to search for the evidence that the 12% threshold was 276 appropriate to diagnose asthma in children²⁶. The authors found that most studies reported that a 277 smaller improvement in FEV₁ should be applicable in children, and then suggested an alternative 278 interpretative strategy, which our results support. Several authors searched for a different cut-off to 279 assess reversibility response in pediatrics. Martinez et al. proposed a 9% threshold in children aged 280 7-14 years³¹ and, in our population, such cut-off would show a sensitivity of 41.7% (238 children 281 out of 571 in this age group). Kang et al. suggested to look for a 7.5% increase in FEV₁ to obtain a 282 50.7% sensitivity, while, in their study, the increase of 12% correlated to a 28.7% sensitivity³². 283 Their results were similar to ours both for the 12% cut-off, and for the 7.5% one (sensitivity of 284 48.1%, with 419 children out of 871). Jat et al. affirmed that spirometry is a very useful 285 investigation tool to diagnose asthma in children, if the test is well-performed and patients received 286 adequate training; nevertheless, they also admitted that the diagnosis should also be based on 287 clinical symptoms and personal history, to be more reliable²¹.

288 As for the obstruction threshold FEV₁/CVF of 90%, such value should not be used in 289 children to assess airways obstruction, considering the unsatisfying sensitivity of this criterion in 290 ours and in previous studies²⁰. Several authors proposed to evaluate the change in FEF₂₅-₇₅ after 291 bronchodilation test to diagnose asthma in children²³,²⁴,³³,³⁴. Nevertheless, in our study, such 292 criterion showed an even lower sensitivity than FEV₁. In a study by Dufetelle et al., the authors 293 proposed two thresholds suggestive of bronchodilator response in asthmatic children³⁵. Based on
268

**Discussion**

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

Through the present multicenter study, we assessed the sensitivity of the recommended spirometric criteria in real-life settings. No study strongly affirms that the 12% threshold is an adequate cut-off value, showing a good sensitivity for the diagnosis of asthma in children. Indeed, our study, this reversibility criterion showed a very low sensitivity (30.4%) for broncho-reversibility, as a diagnostic tool for asthma in pediatrics. Thus, such a criterion does not seem to be applicable to children, if compared to adults, as previously highlighted in other studies³⁰. In 2016, Hopp et al. proposed a literature review to search for the evidence that the 12% threshold was appropriate to diagnose asthma in children²⁶. The authors found that most studies reported that a smaller improvement in FEV₁ should be applicable in children, and then suggested an alternative interpretative strategy, which our results support. Several authors searched for a different cut-off to assess reversibility response in pediatrics. Martinez et al. proposed a 9% threshold in children aged 7-14 years³¹ and, in our population, such cut-off would show a sensitivity of 41.7% (238 children out of 571 in this age group). Kang et al. suggested to look for a 7.5% increase in FEV₁ to obtain a 50.7% sensitivity, while, in their study, the increase of 12% correlated to a 28.7% sensitivity³². Their results were similar to ours both for the 12% cut-off, and for the 7.5% one (sensitivity of 48.1%, with 419 children out of 871). Jat et al. affirmed that spirometry is a very useful investigation tool to diagnose asthma in children, if the test is well-performed and patients received adequate training; nevertheless, they also admitted that the diagnosis should also be based on clinical symptoms and personal history, to be more reliable²¹.

288

289

290

291

292

293

As for the obstruction threshold FEV₁/CVF of 90%, such value should not be used in children to assess airways obstruction, considering the unsatisfying sensitivity of this criterion in ours and in previous studies²⁰. Several authors proposed to evaluate the change in FEF₂₅-₇₅ after bronchodilation test to diagnose asthma in children²³,²⁴,³³,³⁴. Nevertheless, in our study, such criterion showed an even lower sensitivity than FEV₁. In a study by Dufetelle et al., the authors proposed two thresholds suggestive of bronchodilator response in asthmatic children³⁵. Based on
294 spirometry z-scores, their preliminary results showed that a 0.42 z-score for FEV₁ and a -0.16 z-score for FEV₁/FVC could indicate bronchoreversibility even in children with normal baseline spirometry. In our cohort, when considering patients presenting with these z-score values (n=279), we found a sensitivity of 32.0% (data not shown). Therefore, the usefulness of these thresholds in diagnosing pediatric asthma seems limited.

299 As for patients presenting with intermittent asthma, our data showed that this group of patients reported results which were not consistent with those from the other groups. These patients are not representative of the typical patient referring to a tertiary University Hospital. Indeed, they are most likely to be seen outside the hospital, by a general practitioner or a pediatrician since they do not require a specialized expertise. Further studies in this severity group might be of interest.

304 In our study, the best sensitivity single criterion for pediatric asthma, when evaluating a patient for the first time, was dry cough. When adding three clinical criteria together, such as “dry cough, or wheezing or atopy” or “dry cough, or wheezing or exercise-induced dyspnea”, we reached a very satisfying sensitivity (> 99%), while PFTs values were not providing sufficient support to increase the diagnostic sensitivity. These simple clinical features could therefore be easily and practically used in everyday clinical setting, when first evaluating children for possible asthma. These findings are strongly supported by other previous studies¹²,³²,³⁶ and these criteria are simple to assess during a medical consultation and require no specific tool. Nevertheless, we could not provide information on the accuracy of clinical parameters to diagnose asthma: indeed, to use clinical data as a diagnostic tool, further studies are needed to assess, in a group of asthmatic children and non-asthmatic ones, both sensitivity and specificity; these evaluations will need a further prospective study.

316 In our study, we considered the two populations as one cohort, since there were no differences between French and Italian enrolled children, as for sex and age. On the other hand, children from the two countries differed in terms of mean basal values of FEV₁/FVC (obstruction criterion) and presence of atopic conditions (i.e.: atopy, allergic rhinitis, and food allergy).
294 spirometry z-scores, their preliminary results showed that a 0.42 z-score for FEV₁ and a -0.16 z-score for FEV₁/FVC could indicate bronchoreversibility even in children with normal baseline spirometry. In our cohort, when considering patients presenting with these z-score values (n=279), we found a sensitivity of 32.0% (data not shown). Therefore, the usefulness of these thresholds in diagnosing pediatric asthma seems limited.

299 As for patients presenting with intermittent asthma, our data showed that this group of patients reported results which were not consistent with those from the other groups. These patients are not representative of the typical patient referring to a tertiary University Hospital. Indeed, they are most likely to be seen outside the hospital, by a general practitioner or a pediatrician since they do not require a specialized expertise. Further studies in this severity group might be of interest.

304 In our study, the best sensitivity single criterion for pediatric asthma, when evaluating a patient for the first time, was dry cough. When adding three clinical criteria together, such as “dry cough, or wheezing or atopy” or “dry cough, or wheezing or exercise-induced dyspnea”, we reached a very satisfying sensitivity (> 99%), while PFTs values were not providing sufficient support to increase the diagnostic sensitivity. These simple clinical features could therefore be easily and practically used in everyday clinical setting, when first evaluating children for possible asthma. These findings are strongly supported by other previous studies¹²,³²,³⁶ and these criteria are simple to assess during a medical consultation and require no specific tool. Nevertheless, we could not provide information on the accuracy of clinical parameters to diagnose asthma: indeed, to use clinical data as a diagnostic tool, further studies are needed to assess, in a group of asthmatic children and non-asthmatic ones, both sensitivity and specificity; these evaluations will need a further prospective study.

316 In our study, we considered the two populations as one cohort, since there were no differences between French and Italian enrolled children, as for sex and age. On the other hand, children from the two countries differed in terms of mean basal values of FEV₁/FVC (obstruction criterion) and presence of atopic conditions (i.e.: atopy, allergic rhinitis, and food allergy).
Nevertheless, the sensitivity of the FEV₁ reversibility, separately analyzed in the two countries, was 31.0% in France and 30.1% in Italy, with no statistical difference between countries (*p*-value 0.769).

The strength of our study is the great number of included patients: we present the largest pediatric cohort focusing on this subject and including both spirometric and clinical parameters. Also, our multi-centric approach, allowed us to gather a cohort with data coming from physicians with different backgrounds, and could bring us to speculate that our results could also be extended and applied to other countries and/or settings.

Our study presents some limitations. We present a retrospective cohort study, based on information found in patients' files: for such reason, we had a few missing data for 17 patients, which nevertheless represented less than 2% of our entire cohort. Also, we included asthmatic children only, and a prospective study including any patients consulting for possible asthma could help strengthen our results and provide further insights. Our study aimed at looking at the sensitivity of the reversibility criterion only, since, in clinical practice, and from previous studies²⁶,³⁰⁻³² as well, such a criterion seemed not to allow to properly define as asthmatic many children that present the clinical feature of the disease. Having included asthmatic patients only, we didn't assess the specificity of these parameters. The trade-off between sensitivity and specificity might therefore show that the reversibility criterion is likely to be highly specific. In general, it should be underlined that formal testing (such as spirometry or other objective testing, as methacholine) should always be performed to complete the evaluation of possible asthmatic patients. We believe that children experiencing asthma symptoms and positively responding to asthma therapy, even if presenting with a negative broncho-reversibility test, should be treated to avoid undertreatment, but also frequently re-evaluated to obtain objective results and avoid overtreatment.

Another possible limitation is the lack of information on precise race/ethnicity of patients included in our study. Even though our populations were mainly composed by Caucasian children
Nevertheless, the sensitivity of the FEV₁ reversibility, separately analyzed in the two countries, was 31.0% in France and 30.1% in Italy, with no statistical difference between countries (*p*-value 0.769).

The strength of our study is the great number of included patients: we present the largest pediatric cohort focusing on this subject and including both spirometric and clinical parameters. Also, our multi-centric approach, allowed us to gather a cohort with data coming from physicians with different backgrounds, and could bring us to speculate that our results could also be extended and applied to other countries and/or settings.

Our study presents some limitations. We present a retrospective cohort study, based on information found in patients' files: for such reason, we had a few missing data for 17 patients, which nevertheless represented less than 2% of our entire cohort. Also, we included asthmatic children only, and a prospective study including any patients consulting for possible asthma could help strengthen our results and provide further insights. Our study aimed at looking at the sensitivity of the reversibility criterion only, since, in clinical practice, and from previous studies²⁶,³⁰⁻³² as well, such a criterion seemed not to allow to properly define as asthmatic many children that present the clinical feature of the disease. Having included asthmatic patients only, we didn't assess the specificity of these parameters. The trade-off between sensitivity and specificity might therefore show that the reversibility criterion is likely to be highly specific. In general, it should be underlined that formal testing (such as spirometry or other objective testing, as methacholine) should always be performed to complete the evaluation of possible asthmatic patients. We believe that children experiencing asthma symptoms and positively responding to asthma therapy, even if presenting with a negative broncho-reversibility test, should be treated to avoid undertreatment, but also frequently re-evaluated to obtain objective results and avoid overtreatment.

Another possible limitation is the lack of information on precise race/ethnicity of patients included in our study. Even though our populations were mainly composed by Caucasian children
(>85% in both groups, data not shown), such missing aspect may limit the generalizability of our results. Finally, we did not have data assessing $F_{ENO}$ in our population. However, in a study by Murray et al., the authors showed that $F_{ENO}$ as an objective test to diagnose asthma in children, has a low 44% sensitivity³⁶. Nevertheless, we should consider two different aspects: firstly, our data come from real-life settings, and $F_{ENO}$ measurements are not routinely evaluated by pediatricians, and therefore such data are not systematically included in patients' chart; secondly, this parameter still shows a lower sensitivity if compared with those found by our study.

We believe that our results bring an important contribution to current knowledge on the management of asthma consultations in children. The results strongly suggest that spirometric reversibility values, even though essentials for pediatric asthmatic patients, have a very unsatisfying sensitivity for the diagnosis. Clinical symptoms, on the other hand, show a very high sensitivity. For such reason, general practitioners and pediatricians could suggest a diagnosis of asthma in children, without needing, at least initially, to perform PFTs, through carefully evaluating the clinical history and the symptoms, while asthmatic patients presenting with severe forms or needing a follow-up will still require a more complete assessment in specialized centers.
(>85% in both groups, data not shown), such missing aspect may limit the generalizability of our results. Finally, we did not have data assessing $F_{ENO}$ in our population. However, in a study by Murray et al., the authors showed that $F_{ENO}$ as an objective test to diagnose asthma in children, has a low 44% sensitivity³⁶. Nevertheless, we should consider two different aspects: firstly, our data come from real-life settings, and $F_{ENO}$ measurements are not routinely evaluated by pediatricians, and therefore such data are not systematically included in patients' chart; secondly, this parameter still shows a lower sensitivity if compared with those found by our study.

We believe that our results bring an important contribution to current knowledge on the management of asthma consultations in children. The results strongly suggest that spirometric reversibility values, even though essentials for pediatric asthmatic patients, have a very unsatisfying sensitivity for the diagnosis. Clinical symptoms, on the other hand, show a very high sensitivity. For such reason, general practitioners and pediatricians could suggest a diagnosis of asthma in children, without needing, at least initially, to perform PFTs, through carefully evaluating the clinical history and the symptoms, while asthmatic patients presenting with severe forms or needing a follow-up will still require a more complete assessment in specialized centers.
361 References

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364 2. Pedersen SE, Hurd SS, Lemanske RF, Becker A, Zar HJ, Sly PD, et al., Global Initiative for Asthma. Global strategy for the diagnosis and management of asthma in children 5 years and younger. Pediatr Pulmonol 2011;46(1):1-17.

367 3. Papi A, Brightling C, Pedersen SE, Reddel HK. Asthma. Lancet 2018;391(10122):783-800.

369 4. Global Strategy for Asthma Management and Prevention. 2022 GINA Main Report. Available at: https://ginasthma.org/gina-reports. Accessed September 10, 2022.

371 5. National Heart, Lung, and Blood Institute. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Heart, Lung, and Blood Institute, Bethesda (MD), USA. 2007.

374 6. Marks GB, Mihrshahi S, Kemp AS, Tovey ER, Webb K, Almqvist C, et al. Prevention of asthma during the first 5 years of life: a randomized controlled trial. J Allergy Clin Immunol 2006;118(1):53-61.

377 7. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med 1995;332(3):133-8.

380 8. Kuehni CE, Strippoli MPF, Low N, Brooke AM, Silverman M. Wheeze and asthma prevalence and related health-service use in white and south Asian pre-schoolchildren in the United Kingdom. Clin Exp Allergy 2007;37(12):1738-46.

383 9. Chen E, Langer DA, Raphaelson YE, Matthews KA. Socioeconomic status and health in adolescents: the role of stress interpretations. Child Dev 2004;75(4):1039-52.

385 10. Sedaghat AR, Matsui EC, Baxi SN, Bollinger ME, Miller R, Perzanowski M, et al. Mouse Sensitivity is an Independent Risk Factor for Rhinitis in Children with Asthma. J Allergy Clin Immunol Pr 2016;4(1):82-8.

388 11. Sly PD, Boner AL, Björksten B, Bush A, Custovic A, Eigenmann PA, et al. Early identification of atopy in the prediction of persistent asthma in children. Lancet 2008;372(9643):1100-6.

391 12. Pedersen S. Preschool asthma--not so easy to diagnose. Prim Care Respir J 2007;16(1):4-6.

393 13. Woodcock A, Lowe LA, Murray CS, Simpson BM, Pipis SD, Kissen P, et al.; on behalf of the NAC Manchester Asthma and Allergy Study Group. Early life environmental control: effect on symptoms, sensitization, and lung function at age 3 years. Am J Respir Crit Care Med 2004;170(4):433-9.

397 14. Bufford JD, Gern JE. Early exposure to pets: good or bad? Curr Allergy Asthma Rep 2007;7(5):375-82.

399 15. Ownby DR, Johnson CC, Peterson EL. Exposure to dogs and cats in the first year of life and risk of allergic sensitization at 6 to 7 years of age. JAMA 2002;288(8):963-72.

401 16. Sears MR, Greene JM, Willan AR, Wiecek EM, Taylor DR, Flannery EM, et al. A longitudinal, population-based, cohort study of childhood asthma followed to adulthood. N Engl J Med 2003;349(15):1414-22.

404 17. Grol MH, Postma DS, Vonk JM, Schouten JP, Rijcken B, Koëter GH, et al. Risk factors from childhood to adulthood for bronchial responsiveness at age 32-42 yr. Am J Respir Crit Care Med 1999;160(1):150-6.

407 18. Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, et al.; on behalf of the American Thoracic Society and the European Respiratory Society. Standardization of Spirometry 2019 Update An Official American Thoracic Society and
361 References

362 1. Caimmi D, Marseglia A, Pieri G, Benzo S, Bosa L, Caimmi S. Nose and lungs: one way, one disease. Ital J Pediatr 2012;38:60.

364 2. Pedersen SE, Hurd SS, Lemanske RF, Becker A, Zar HJ, Sly PD, et al., Global Initiative for Asthma. Global strategy for the diagnosis and management of asthma in children 5 years and younger. Pediatr Pulmonol 2011;46(1):1-17.

367 3. Papi A, Brightling C, Pedersen SE, Reddel HK. Asthma. Lancet 2018;391(10122):783-800.

369 4. Global Strategy for Asthma Management and Prevention. 2022 GINA Main Report. Available at: https://ginasthma.org/gina-reports. Accessed September 10, 2022.

371 5. National Heart, Lung, and Blood Institute. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Heart, Lung, and Blood Institute, Bethesda (MD), USA. 2007.

374 6. Marks GB, Mihrshahi S, Kemp AS, Tovey ER, Webb K, Almqvist C, et al. Prevention of asthma during the first 5 years of life: a randomized controlled trial. J Allergy Clin Immunol 2006;118(1):53-61.

377 7. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med 1995;332(3):133-8.

380 8. Kuehni CE, Strippoli MPF, Low N, Brooke AM, Silverman M. Wheeze and asthma prevalence and related health-service use in white and south Asian pre-schoolchildren in the United Kingdom. Clin Exp Allergy 2007;37(12):1738-46.

383 9. Chen E, Langer DA, Raphaelson YE, Matthews KA. Socioeconomic status and health in adolescents: the role of stress interpretations. Child Dev 2004;75(4):1039-52.

385 10. Sedaghat AR, Matsui EC, Baxi SN, Bollinger ME, Miller R, Perzanowski M, et al. Mouse Sensitivity is an Independent Risk Factor for Rhinitis in Children with Asthma. J Allergy Clin Immunol Pr 2016;4(1):82-8.

388 11. Sly PD, Boner AL, Björksten B, Bush A, Custovic A, Eigenmann PA, et al. Early identification of atopy in the prediction of persistent asthma in children. Lancet 2008;372(9643):1100-6.

391 12. Pedersen S. Preschool asthma--not so easy to diagnose. Prim Care Respir J 2007;16(1):4-6.

393 13. Woodcock A, Lowe LA, Murray CS, Simpson BM, Pipis SD, Kissen P, et al.; on behalf of the NAC Manchester Asthma and Allergy Study Group. Early life environmental control: effect on symptoms, sensitization, and lung function at age 3 years. Am J Respir Crit Care Med 2004;170(4):433-9.

397 14. Bufford JD, Gern JE. Early exposure to pets: good or bad? Curr Allergy Asthma Rep 2007;7(5):375-82.

399 15. Ownby DR, Johnson CC, Peterson EL. Exposure to dogs and cats in the first year of life and risk of allergic sensitization at 6 to 7 years of age. JAMA 2002;288(8):963-72.

401 16. Sears MR, Greene JM, Willan AR, Wiecek EM, Taylor DR, Flannery EM, et al. A longitudinal, population-based, cohort study of childhood asthma followed to adulthood. N Engl J Med 2003;349(15):1414-22.

404 17. Grol MH, Postma DS, Vonk JM, Schouten JP, Rijcken B, Koëter GH, et al. Risk factors from childhood to adulthood for bronchial responsiveness at age 32-42 yr. Am J Respir Crit Care Med 1999;160(1):150-6.

407 18. Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, et al.; on behalf of the American Thoracic Society and the European Respiratory Society. Standardization of Spirometry 2019 Update An Official American Thoracic Society and
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19. Quanjer PH, Borsboom GJ, Brunekreef B, et al. Spirometric reference values for white European children and adolescents: Polgar revisited. Pediatr Pulmonol 1995;19(2):135-42.

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20. Quanjer PH, Stanojevic S, Cole TJ, Zach M, Forche G, Cotes JE, et al.; the ERS Global Lung function Initiative. Multi-ethnic reference values for spirometry for the 3-95 year age range: the global lung function 2012 equations. Eur Respir J 2012;40(6):1324-43.

418

21. Jat KR. Spirometry in children. Prim Care Respir J 2013;22(2):221-9.

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22. Crenesse D, Berlioz M, Bourrier T, Albertini M. Spirometry in children aged 3 to 5 years: reliability of forced expiratory maneuvers. Pediatr Pulmonol 2001;32(1):56-61.

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23. Kanchongkittiphon W, Gaffin JM, Kopel L, Petty CR, Bollinger ME, Miller R, et al. The Association of $FEF_{25-75}$ and Bronchodilator reversibility with Asthma Control and Asthma Morbidity in Inner City Children with Asthma. Ann Allergy Asthma Immunol 2016;117(1):97-9.

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24. Rao DR, Gaffin JM, Baxi SN, Sheehan WJ, Hoffman EB, Phipatanakul W. The utility of forced expiratory flow between 25% and 75% of vital capacity in predicting childhood asthma morbidity and severity. J Asthma 2012;49(6):586-92.

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25. NICE guideline. Asthma: diagnosis, monitoring and chronic asthma management. Available at: www.nice.org.uk/guidance/ng80. Accessed September 10, 2022.

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26. Hopp RJ, Pasha MA. A literature review of the evidence that a 12% improvement in FEV1 is an appropriate cut-off for children. J Asthma 2016;53(4):413-8.

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27. Bacharier LB, Strunk RC, Mauger D, White D, Lemanske RF, Sorkness CA. Classifying asthma severity in children: mismatch between symptoms, medication use, and lung function. Am J Respir Crit Care Med 2004;170(4):426-32.

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28. Sharma S, Litonjua AA, Tantisira KG, Fuhlbrigge AL, Szefler SJ, Strunk RC, et al.; Childhood Asthma Management Program Research Group. Clinical Predictors and Outcomes of Consistent Bronchodilator Response in the Childhood Asthma Management Program. J Allergy Clin Immunol 2008;122(5):921-8.

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29. Wollenberg A, Barbarot S, Bieber T, Christen-Zaech S, Deleuran M, Fink-Wagner A, et al.; Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part I. J Eur Acad Dermatol Venereol 2018;32(5):657-682.

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30. Vilozni D, Hakim F, Livnat G, Ofek M, Bar-Yoseph R, Bentur L. Assessment of Airway Bronchodilation by Spirometry Compared to Airway Obstruction in Young Children with Asthma. Can Respir J 2016;2016:5394876.

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31. Pardos Martínez C, Fuertes Fernández-Espinar J, Nerín De La Puerta I, González Pérez-Yarza E. Cut-off point for a positive bronchodilation test. Esp Pediatr 2002;57(1):5-11.

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32. Kang XH, Wang W, Cao L. A clinical study to determine the threshold of bronchodilator response for diagnosing asthma in Chinese children. World J Pediatr 2019;15(6):559-64.

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33. Simon MR, Chinchilli VM, Phillips BR, Sorkness CA, Lemanske RF, Szefler SJ, et al.; Childhood Asthma Research and Education Network of the National Heart, Lung, and Blood Institute. Forced expiratory flow between 25% and 75% of vital capacity and $FEV_1$/forced vital capacity ratio in relation to clinical and physiological parameters in asthmatic children with normal $FEV_1$ values. J Allergy Clin Immunol 2010;126(3):527-34.

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34. Ciprandi G, Cirillo I. Forced expiratory flow between 25% and 75% of vital capacity may be a marker of bronchial impairment in allergic rhinitis. J Allergy Clin Immunol 2011;127(2):549.
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European Respiratory Society Technical Statement. Am J Respir Crit Care Med 2019;200(8):e70-88.

412
413
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19. Quanjer PH, Borsboom GJ, Brunekreef B, et al. Spirometric reference values for white European children and adolescents: Polgar revisited. Pediatr Pulmonol 1995;19(2):135-42.

415
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20. Quanjer PH, Stanojevic S, Cole TJ, Zach M, Forche G, Cotes JE, et al.; the ERS Global Lung function Initiative. Multi-ethnic reference values for spirometry for the 3-95 year age range: the global lung function 2012 equations. Eur Respir J 2012;40(6):1324-43.

418

21. Jat KR. Spirometry in children. Prim Care Respir J 2013;22(2):221-9.

419
420

22. Crenesse D, Berlioz M, Bourrier T, Albertini M. Spirometry in children aged 3 to 5 years: reliability of forced expiratory maneuvers. Pediatr Pulmonol 2001;32(1):56-61.

421
422
423
424

23. Kanchongkittiphon W, Gaffin JM, Kopel L, Petty CR, Bollinger ME, Miller R, et al. The Association of FEF<sub>25-75</sub> and Bronchodilator reversibility with Asthma Control and Asthma Morbidity in Inner City Children with Asthma. Ann Allergy Asthma Immunol 2016;117(1):97-9.

425
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427

24. Rao DR, Gaffin JM, Baxi SN, Sheehan WJ, Hoffman EB, Phipatanakul W. The utility of forced expiratory flow between 25% and 75% of vital capacity in predicting childhood asthma morbidity and severity. J Asthma 2012;49(6):586-92.

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25. NICE guideline. Asthma: diagnosis, monitoring and chronic asthma management. Available at: www.nice.org.uk/guidance/ng80. Accessed September 10, 2022.

430
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26. Hopp RJ, Pasha MA. A literature review of the evidence that a 12% improvement in FEV1 is an appropriate cut-off for children. J Asthma 2016;53(4):413-8.

432
433
434

27. Bacharier LB, Strunk RC, Mauger D, White D, Lemanske RF, Sorkness CA. Classifying asthma severity in children: mismatch between symptoms, medication use, and lung function. Am J Respir Crit Care Med 2004;170(4):426-32.

435
436
437
438

28. Sharma S, Litonjua AA, Tantisira KG, Fuhlbrigge AL, Szefler SJ, Strunk RC, et al.; Childhood Asthma Management Program Research Group. Clinical Predictors and Outcomes of Consistent Bronchodilator Response in the Childhood Asthma Management Program. J Allergy Clin Immunol 2008;122(5):921-8.

439
440
441
442

29. Wollenberg A, Barbarot S, Bieber T, Christen-Zaech S, Deleuran M, Fink-Wagner A, et al.; Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part I. J Eur Acad Dermatol Venereol 2018;32(5):657-682.

443
444
445

30. Vilozni D, Hakim F, Livnat G, Ofek M, Bar-Yoseph R, Bentur L. Assessment of Airway Bronchodilation by Spirometry Compared to Airway Obstruction in Young Children with Asthma. Can Respir J 2016;2016:5394876.

446
447

31. Pardos Martínez C, Fuertes Fernández-Espinar J, Nerín De La Puerta I, González Pérez-Yarza E. Cut-off point for a positive bronchodilation test. Esp Pediatr 2002;57(1):5-11.

448
449
450

32. Kang XH, Wang W, Cao L. A clinical study to determine the threshold of bronchodilator response for diagnosing asthma in Chinese children. World J Pediatr 2019;15(6):559-64.

451
452
453
454
455
456

33. Simon MR, Chinchilli VM, Phillips BR, Sorkness CA, Lemanske RF, Szefler SJ, et al.; Childhood Asthma Research and Education Network of the National Heart, Lung, and Blood Institute. Forced expiratory flow between 25% and 75% of vital capacity and FEV1/forced vital capacity ratio in relation to clinical and physiological parameters in asthmatic children with normal FEV₁ values. J Allergy Clin Immunol 2010;126(3):527-34.

457
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34. Ciprandi G, Cirillo I. Forced expiratory flow between 25% and 75% of vital capacity may be a marker of bronchial impairment in allergic rhinitis. J Allergy Clin Immunol 2011;127(2):549.
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35. Dufetelle E, Bokov P, Delclaux C, Beydon N. Should reversibility be assessed in all asthmatic children with normal spirometry? Eur Respir J 2018;52(2):1800373.

36. Murray C, Foden P, Lowe L, Durrington H, Custovic A, Simpson A. Diagnosis of asthma in symptomatic children based on measures of lung function: an analysis of data from a population-based birth cohort study. Lancet Child Adolesc Health 2017;1(2):114–23.
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35. Dufetelle E, Bokov P, Delclaux C, Beydon N. Should reversibility be assessed in all asthmatic children with normal spirometry? Eur Respir J 2018;52(2):1800373.

36. Murray C, Foden P, Lowe L, Durrington H, Custovic A, Simpson A. Diagnosis of asthma in symptomatic children based on measures of lung function: an analysis of data from a population-based birth cohort study. Lancet Child Adolesc Health 2017;1(2):114–23.
467 **Figures**

468

469 **Figure 1** – Patients included in the study.

470

471 **Figure 2** – Reversibility criteria (FEV₁/FCV < 90% and increase in FEV₁ > 12%) after bronchodilation test in all 871 included children. The line shows the 12% cut-off proposed by GINA guidelines. All children on the left of the line would be considered as non-asthmatics following current recommendations.

475

476 **Figure 3** –Best option for cumulative sensitivity of different variables to predict a diagnosis of asthma in children.

477
467 **Figures**

468

469 **Figure 1** – Patients included in the study.

470

471 **Figure 2** – Reversibility criteria (FEV₁/FCV < 90% and increase in FEV₁ > 12%) after bronchodilation test in all 871 included children. The line shows the 12% cut-off proposed by GINA guidelines. All children on the left of the line would be considered as non-asthmatics following current recommendations.

475

476 **Figure 3** –Best option for cumulative sensitivity of different variables to predict a diagnosis of asthma in children.

477
478 Tables

479 Table 1 – Characteristics of the population included in the study.

<table><thead><tr><th></th><th>Overall</th><th>France</th><th>Italy</th><th>p-value</th></tr></thead><tbody><tr><td>Number of patients, n (%)</td><td>871 (100%)</td><td>342 (39.3)</td><td>529 (60.7)</td><td>&lt; 0.001</td></tr><tr><td>Males, n (%)</td><td>548 (62.9%)</td><td>219 (64.0)</td><td>329 (62.2)</td><td>0.5825</td></tr><tr><td>Age, mean (SD)</td><td>9.2 (3.3)</td><td>9.2 (3.4)</td><td>9.3 (3.2)</td><td>0.6605</td></tr><tr><td>BMI, mean (SD)</td><td>18.1 (3.7)</td><td>17.6 (3.3)</td><td>18.5 (3.8)</td><td>0.0003</td></tr><tr><td>Basal FEV<sub>1</sub>, in liters, mean (SD)</td><td>1.9 (0.80)</td><td>1.8 (0.79)</td><td>1.9 (0.81)</td><td>0.0728</td></tr><tr><td>Mean Change in FEV<sub>1</sub> after bronchodilation, % (SD)</td><td>8.2 (10.7)</td><td>8.1 (13.1)</td><td>8.3 (8.8)</td><td>0.7876</td></tr><tr><td>Mean basal FEV<sub>1</sub>/FVC, % (SD)</td><td>84.9 (9.7)</td><td>86.1 (11.3)</td><td>84.0 (8.5)</td><td>0.0019</td></tr><tr><td>Mean Change in FEF25-75 after bronchodilation, % (SD)</td><td>22.1 (30.0)</td><td>20.0 (38.9)</td><td>23.4 (22.3)</td><td>0.1020</td></tr><tr><td>Patients treated with Anti-IgE, n (%)</td><td>39 (4.5)</td><td>11 (3.2)</td><td>28 (5.3)</td><td>0.148</td></tr><tr><td>Patients treated with AIT, n (%)</td><td>101 (11.6)</td><td>58 (17.0)</td><td>43 (8.1)</td><td>&lt; 0.001</td></tr><tr><td>Any evokative symptom, n (%)</td><td>868 (99.7)</td><td>339 (99.1)</td><td>528 (100)</td><td>0.1418</td></tr><tr><td>Patients presenting with dry cough, n (%)</td><td>791 (90.8)</td><td>322 (94.1)</td><td>469 (88.7)</td><td>0.0061</td></tr><tr><td>Patients presenting with wheezing n (%)</td><td>553 (63.5)</td><td>138 (40.3)</td><td>415 (78.5)</td><td>&lt; 0.001</td></tr><tr><td>Patients presenting with exercise-induced dyspnea, n (%)</td><td>410 (47.1)</td><td>193 (56.4)</td><td>217 (41.0)</td><td>&lt; 0.001</td></tr><tr><td>Patients presenting with tight chest, n (%)</td><td>149 (17.1)</td><td>40 (11.7)</td><td>109 (20.6)</td><td>&lt; 0.001</td></tr><tr><td>Patients with a history of pre-school wheezing, n (%)</td><td>315 (36.2)</td><td>119 (34.8)</td><td>196 (37.1)</td><td>0.4986</td></tr><tr><td>Patients with symptoms improvement after treatment, n (%)</td><td>819 (94.0)</td><td>295 (86.3)</td><td>524 (99.1)</td><td>&lt; 0.001</td></tr><tr><td>Patients presenting with any atopic comorbidity, n (%)</td><td>713 (81.9)</td><td>289 (84.5)</td><td>424 (80.2)</td><td>0.1036</td></tr><tr><td>Patients suffering from Allergic Rhinitis, n (%)</td><td>605 (69.5)</td><td>210 (61.4)</td><td>395 (74.7)</td><td>&lt; 0.001</td></tr><tr><td>Patients suffering from food allergy, n (%)</td><td>108 (12.4)</td><td>28 (8.2)</td><td>80 (15.1)</td><td>0.0024</td></tr><tr><td>Patients suffering from atopic dermatitis, n (%)</td><td>193 (22.2)</td><td>65 (19.0)</td><td>128 (24.2)</td><td>0.0717</td></tr><tr><td>Atopic patients, n (%)</td><td>678 (77.8)</td><td>244 (71.4)</td><td>434 (82.0)</td><td>0.0002</td></tr><tr><td>Patients sensitized to house dust mites, n (%)</td><td>471 (54.1)</td><td>151 (44.2)</td><td>320 (60.5)</td><td>&lt; 0.001</td></tr><tr><td>Patients sensitized to grass, n (%)</td><td>407 (46.7)</td><td>111 (32.5)</td><td>296 (56.0)</td><td>&lt; 0.001</td></tr><tr><td>Patients sensitized to cypress, n (%)*</td><td>109 (12.5)</td><td>103 (30.1)</td><td>6 (1.1)</td><td>&lt; 0.001</td></tr><tr><td>Patients sensitized to birch, n (%)*</td><td>135 (15.5)</td><td>37 (10.8)</td><td>98 (18.5)</td><td>0.0021</td></tr><tr><td>Patients sensitized to animal danders, n (%)</td><td>314 (36.1)</td><td>108 (31.6)</td><td>206 (38.9)</td><td>0.0271</td></tr><tr><td>Patients sensitized to molds, n (%)</td><td>175 (20.1)</td><td>54 (15.8)</td><td>121 (22.9)</td><td>0.0108</td></tr></tbody></table>

Legend – BMI: Body Mass Index; SD: Standard Deviation; FEV₁: Forced Expiratory Volume in 1 second; FVC: Forced Vital Capacity; FEF₂₅-₇₅: mean Forced Expiratory Flow between the 25% and 75% of the FVC; AIT: Allergen Immunotherapy.
478 Tables

479 Table 1 – Characteristics of the population included in the study.

<table><thead><tr><th></th><th>Overall</th><th>France</th><th>Italy</th><th>p-value</th></tr></thead><tbody><tr><td>Number of patients, n (%)</td><td>871 (100%)</td><td>342 (39.3)</td><td>529 (60.7)</td><td>&lt; 0.001</td></tr><tr><td>Males, n (%)</td><td>548 (62.9%)</td><td>219 (64.0)</td><td>329 (62.2)</td><td>0.5825</td></tr><tr><td>Age, mean (SD)</td><td>9.2 (3.3)</td><td>9.2 (3.4)</td><td>9.3 (3.2)</td><td>0.6605</td></tr><tr><td>BMI, mean (SD)</td><td>18.1 (3.7)</td><td>17.6 (3.3)</td><td>18.5 (3.8)</td><td>0.0003</td></tr><tr><td>Basal FEV<sub>1</sub>, in liters, mean (SD)</td><td>1.9 (0.80)</td><td>1.8 (0.79)</td><td>1.9 (0.81)</td><td>0.0728</td></tr><tr><td>Mean Change in FEV<sub>1</sub> after bronchodilation, % (SD)</td><td>8.2 (10.7)</td><td>8.1 (13.1)</td><td>8.3 (8.8)</td><td>0.7876</td></tr><tr><td>Mean basal FEV<sub>1</sub>/FVC, % (SD)</td><td>84.9 (9.7)</td><td>86.1 (11.3)</td><td>84.0 (8.5)</td><td>0.0019</td></tr><tr><td>Mean Change in FEF25-75 after bronchodilation, % (SD)</td><td>22.1 (30.0)</td><td>20.0 (38.9)</td><td>23.4 (22.3)</td><td>0.1020</td></tr><tr><td>Patients treated with Anti-IgE, n (%)</td><td>39 (4.5)</td><td>11 (3.2)</td><td>28 (5.3)</td><td>0.148</td></tr><tr><td>Patients treated with AIT, n (%)</td><td>101 (11.6)</td><td>58 (17.0)</td><td>43 (8.1)</td><td>&lt; 0.001</td></tr><tr><td>Any evokative symptom, n (%)</td><td>868 (99.7)</td><td>339 (99.1)</td><td>528 (100)</td><td>0.1418</td></tr><tr><td>Patients presenting with dry cough, n (%)</td><td>791 (90.8)</td><td>322 (94.1)</td><td>469 (88.7)</td><td>0.0061</td></tr><tr><td>Patients presenting with wheezing n (%)</td><td>553 (63.5)</td><td>138 (40.3)</td><td>415 (78.5)</td><td>&lt; 0.001</td></tr><tr><td>Patients presenting with exercise-induced dyspnea, n (%)</td><td>410 (47.1)</td><td>193 (56.4)</td><td>217 (41.0)</td><td>&lt; 0.001</td></tr><tr><td>Patients presenting with tight chest, n (%)</td><td>149 (17.1)</td><td>40 (11.7)</td><td>109 (20.6)</td><td>&lt; 0.001</td></tr><tr><td>Patients with a history of pre-school wheezing, n (%)</td><td>315 (36.2)</td><td>119 (34.8)</td><td>196 (37.1)</td><td>0.4986</td></tr><tr><td>Patients with symptoms improvement after treatment, n (%)</td><td>819 (94.0)</td><td>295 (86.3)</td><td>524 (99.1)</td><td>&lt; 0.001</td></tr><tr><td>Patients presenting with any atopic comorbidity, n (%)</td><td>713 (81.9)</td><td>289 (84.5)</td><td>424 (80.2)</td><td>0.1036</td></tr><tr><td>Patients suffering from Allergic Rhinitis, n (%)</td><td>605 (69.5)</td><td>210 (61.4)</td><td>395 (74.7)</td><td>&lt; 0.001</td></tr><tr><td>Patients suffering from food allergy, n (%)</td><td>108 (12.4)</td><td>28 (8.2)</td><td>80 (15.1)</td><td>0.0024</td></tr><tr><td>Patients suffering from atopic dermatitis, n (%)</td><td>193 (22.2)</td><td>65 (19.0)</td><td>128 (24.2)</td><td>0.0717</td></tr><tr><td>Atopic patients, n (%)</td><td>678 (77.8)</td><td>244 (71.4)</td><td>434 (82.0)</td><td>0.0002</td></tr><tr><td>Patients sensitized to house dust mites, n (%)</td><td>471 (54.1)</td><td>151 (44.2)</td><td>320 (60.5)</td><td>&lt; 0.001</td></tr><tr><td>Patients sensitized to grass, n (%)</td><td>407 (46.7)</td><td>111 (32.5)</td><td>296 (56.0)</td><td>&lt; 0.001</td></tr><tr><td>Patients sensitized to cypress, n (%)*</td><td>109 (12.5)</td><td>103 (30.1)</td><td>6 (1.1)</td><td>&lt; 0.001</td></tr><tr><td>Patients sensitized to birch, n (%)*</td><td>135 (15.5)</td><td>37 (10.8)</td><td>98 (18.5)</td><td>0.0021</td></tr><tr><td>Patients sensitized to animal danders, n (%)</td><td>314 (36.1)</td><td>108 (31.6)</td><td>206 (38.9)</td><td>0.0271</td></tr><tr><td>Patients sensitized to molds, n (%)</td><td>175 (20.1)</td><td>54 (15.8)</td><td>121 (22.9)</td><td>0.0108</td></tr></tbody></table>

Legend – BMI: Body Mass Index; SD: Standard Deviation; FEV₁: Forced Expiratory Volume in 1 second; FVC: Forced Vital Capacity; FEF₂₅-₇₅: mean Forced Expiratory Flow between the 25% and 75% of the FVC; AIT: Allergen Immunotherapy.
482

483

484

485

486

**Table 2** – Sensitivity of the reversibility criteria in children proposed by GINA guidelines for FEV₁, of bronchial obstruction in children, of the reversibility criteria for FEF₂₅-7₅, and of the association or either the reversibility of the FEV₁ criterion or the FEF₂₅-7₅, in the overall population and in the subgroups based on asthma severity patient's age, and country of origin.

<table><thead><tr><th></th><th></th><th>Persistent severe asthma</th><th>Persistent moderate asthma</th><th>Persistent mild asthma</th><th>Intermittent asthma</th><th>&lt; 7 years</th><th>7-11 years</th><th>&gt; 11 years</th><th>France</th><th>Italy</th></tr></thead><tbody><tr><td>Number of patients (n)</td><td>871</td><td>55</td><td>581</td><td>203</td><td>32</td><td>221</td><td>432</td><td>218</td><td>342</td><td>529</td></tr><tr><td>Sensitivity of reversibility criteria with FEV₁ (%)</td><td>30.4%</td><td>41.8%</td><td>34.3%</td><td>16.3%</td><td>31.3%</td><td>32.1%</td><td>32.4%</td><td>24.8%</td><td>31.0%</td><td>30.1%</td></tr><tr><td>Sensitivity of obstruction criteria (%)</td><td>67.5%</td><td>87.3%</td><td>72.1%</td><td>53.2%</td><td>43.8%</td><td>48.0%</td><td>26.4%</td><td>76.6%</td><td>57.0%</td><td>74.3%</td></tr><tr><td>Sensitivity of reversibility criteria with FEF₂₅-7₅ (%)</td><td>21.9%</td><td>25.5%</td><td>23.8%</td><td>16.7%</td><td>15.6%</td><td>24.9%</td><td>23.8%</td><td>15.1%</td><td>20.8%</td><td>22.7%</td></tr><tr><td>Sensitivity of reversibility of either FEV₁ or FEF₂₅-7₅ (%)</td><td>36.7%</td><td>50.9%</td><td>40.1%</td><td>23.2%</td><td>37.5%</td><td>43.0%</td><td>37.5%</td><td>28.9%</td><td>38.0%</td><td>35.9%</td></tr></tbody></table>

487

488

489

490

**Legend:** FEV₁: Forced Expiratory Volume in 1 second; FVC: Forced Vital Capacity; FEF₂₅-7₅: mean Forced Expiratory Flow between the 25% and 75% of the FVC.

The *p*-value was <0.05:

491

492

- for the FEV₁ criterion: between mild asthma and any other severity group (<0.001, <0.001, and 0.04, if compared with persistent severe, persistent moderate, and intermittent asthma, respectively);

493

494

495

496

- for the obstruction criterion: between severe and any other severity group (0.02, <0.001, and <0.001, if compared with persistent moderate, persistent mild, and intermittent asthma, respectively); between moderate and any other severity group (0.02, <0.001, < 0.001, if compared with persistent severe, persistent mild, and intermittent asthma, respectively); between the <7 years group and any other group (<0.001, and <0.001, if compared with the 7-11 years and the >11 years group, respectively); between France and Italy (<0.001);

497

498

- for the FEF₂₅-7₅ criterion: between moderate and mild (0.04); between the >11 years group and any other group (0.01, and 0.01, if compared with the <7 years and the 7-11 years group, respectively);

499

500

- for either the FEV₁ criterion or the FEF₂₅-7₅ criterion: between severe and mild (0.001); between moderate and mild (<0.001); between the >11 years group and any other group (0.02, and 0.03, if compared with the <7 years and the 7-11 years group, respectively).
482

483

484

485

486

**Table 2** – Sensitivity of the reversibility criteria in children proposed by GINA guidelines for FEV₁, of bronchial obstruction in children, of the reversibility criteria for FEF₂₅-7₅, and of the association or either the reversibility of the FEV₁ criterion or the FEF₂₅-7₅, in the overall population and in the subgroups based on asthma severity patient's age, and country of origin.

<table><thead><tr><th></th><th></th><th>Persistent severe asthma</th><th>Persistent moderate asthma</th><th>Persistent mild asthma</th><th>Intermittent asthma</th><th>&lt; 7 years</th><th>7-11 years</th><th>&gt; 11 years</th><th>France</th><th>Italy</th></tr></thead><tbody><tr><td>Number of patients (n)</td><td>871</td><td>55</td><td>581</td><td>203</td><td>32</td><td>221</td><td>432</td><td>218</td><td>342</td><td>529</td></tr><tr><td>Sensitivity of reversibility criteria with FEV₁ (%)</td><td>30.4%</td><td>41.8%</td><td>34.3%</td><td>16.3%</td><td>31.3%</td><td>32.1%</td><td>32.4%</td><td>24.8%</td><td>31.0%</td><td>30.1%</td></tr><tr><td>Sensitivity of obstruction criteria (%)</td><td>67.5%</td><td>87.3%</td><td>72.1%</td><td>53.2%</td><td>43.8%</td><td>48.0%</td><td>26.4%</td><td>76.6%</td><td>57.0%</td><td>74.3%</td></tr><tr><td>Sensitivity of reversibility criteria with FEF₂₅-7₅ (%)</td><td>21.9%</td><td>25.5%</td><td>23.8%</td><td>16.7%</td><td>15.6%</td><td>24.9%</td><td>23.8%</td><td>15.1%</td><td>20.8%</td><td>22.7%</td></tr><tr><td>Sensitivity of reversibility of either FEV₁ or FEF₂₅-7₅ (%)</td><td>36.7%</td><td>50.9%</td><td>40.1%</td><td>23.2%</td><td>37.5%</td><td>43.0%</td><td>37.5%</td><td>28.9%</td><td>38.0%</td><td>35.9%</td></tr></tbody></table>

487

488

489

490

**Legend:** FEV₁: Forced Expiratory Volume in 1 second; FVC: Forced Vital Capacity; FEF₂₅-7₅: mean Forced Expiratory Flow between the 25% and 75% of the FVC.

The *p*-value was <0.05:

491

492

- for the FEV₁ criterion: between mild asthma and any other severity group (<0.001, <0.001, and 0.04, if compared with persistent severe, persistent moderate, and intermittent asthma, respectively);

493

494

495

496

- for the obstruction criterion: between severe and any other severity group (0.02, <0.001, and <0.001, if compared with persistent moderate, persistent mild, and intermittent asthma, respectively); between moderate and any other severity group (0.02, <0.001, < 0.001, if compared with persistent severe, persistent mild, and intermittent asthma, respectively); between the <7 years group and any other group (<0.001, and <0.001, if compared with the 7-11 years and the >11 years group, respectively); between France and Italy (<0.001);

497

498

- for the FEF₂₅-7₅ criterion: between moderate and mild (0.04); between the >11 years group and any other group (0.01, and 0.01, if compared with the <7 years and the 7-11 years group, respectively);

499

500

- for either the FEV₁ criterion or the FEF₂₅-7₅ criterion: between severe and mild (0.001); between moderate and mild (<0.001); between the >11 years group and any other group (0.02, and 0.03, if compared with the <7 years and the 7-11 years group, respectively).
<table><caption>**Table 3** – Sensitivity of the different clinical criteria in the whole cohort of 871 children, in the subgroup of patients in which normal FEV₁/FVC, in those with FEV₁/FVC < 90% and an increase in FEV₁ < 12% after bronchodilation, and in those presenting with reversibility criteria.</caption><thead><tr><th rowspan="2"></th><th colspan="2">In the whole cohort<br>(N = 871)</th><th colspan="2">Patients with<br>FEV<sub>1</sub>/FVC ≥ 90%<br>(N = 283)</th><th colspan="2">Patients with FEV<sub>1</sub>/FVC<br>&lt; 90% and increase in<br>FEV<sub>1</sub> &lt; 12% after<br>bronchodilation<br>(N = 383)</th><th colspan="2">Patients with FEV<sub>1</sub>/FVC<br>&lt; 90% and increase in<br>FEV<sub>1</sub> ≥ 12% after<br>bronchodilation<br>(N = 205)</th></tr><tr><th>Number of<br>patients (n)</th><th>Sensitivity<br>(%)</th><th>Number of<br>patients (n)</th><th>Sensitivity<br>(%)</th><th>Number of<br>patients (n)</th><th>Sensitivity<br>(%)</th><th>Number of<br>patients (n)</th><th>Sensitivity<br>(%)</th></tr></thead><tbody><tr><td>Dry cough</td><td>792</td><td>90.9%</td><td>250</td><td>88.3%</td><td>350</td><td>91.4%</td><td>192</td><td>95.16</td></tr><tr><td>Wheezing</td><td>553</td><td>63.5%</td><td>162</td><td>57.2%</td><td>251</td><td>65.5%</td><td>140</td><td>68.3%</td></tr><tr><td>Exercise-induced dyspnea</td><td>410</td><td>47.1%</td><td>122</td><td>43.1%</td><td>187</td><td>48.8%</td><td>102</td><td>49.49</td></tr><tr><td>Tight chest</td><td>149</td><td>17.1%</td><td>32</td><td>11.3%</td><td>73</td><td>19.1%</td><td>44</td><td>25.21</td></tr><tr><td>Pre-school wheezing</td><td>315</td><td>36.2%</td><td>108</td><td>38.2%</td><td>134</td><td>35.0%</td><td>73</td><td>35.27</td></tr><tr><td>Atopy</td><td>678</td><td>77.8%</td><td>202</td><td>71.4%</td><td>306</td><td>79.9%</td><td>170</td><td>82.24</td></tr><tr><td>Allergic comorbidities</td><td>713</td><td>81.9%</td><td>219</td><td>77.4%</td><td>320</td><td>83.6%</td><td>174</td><td>83.97</td></tr></tbody></table>

We found a significant difference only between the whole cohort and the subgroup of patients with normal FEV1/FVC for the tight chest (*p-value* 0.0198) and atopy (*p-value* 0.0264) criteria.

501
502
503
504

527
528
529
530
<table><caption>**Table 3** – Sensitivity of the different clinical criteria in the whole cohort of 871 children, in the subgroup of patients in which normal FEV₁/FVC, in those with FEV₁/FVC < 90% and an increase in FEV₁ < 12% after bronchodilation, and in those presenting with reversibility criteria.</caption><thead><tr><th rowspan="2"></th><th colspan="2">In the whole cohort<br>(N = 871)</th><th colspan="2">Patients with<br>FEV<sub>1</sub>/FVC ≥ 90%<br>(N = 283)</th><th colspan="2">Patients with FEV<sub>1</sub>/FVC<br>&lt; 90% and increase in<br>FEV<sub>1</sub> &lt; 12% after<br>bronchodilation<br>(N = 383)</th><th colspan="2">Patients with FEV<sub>1</sub>/FVC<br>&lt; 90% and increase in<br>FEV<sub>1</sub> ≥ 12% after<br>bronchodilation<br>(N = 205)</th></tr><tr><th>Number of<br>patients (n)</th><th>Sensitivity<br>(%)</th><th>Number of<br>patients (n)</th><th>Sensitivity<br>(%)</th><th>Number of<br>patients (n)</th><th>Sensitivity<br>(%)</th><th>Number of<br>patients (n)</th><th>Sensitivity<br>(%)</th></tr></thead><tbody><tr><td>Dry cough</td><td>792</td><td>90.9%</td><td>250</td><td>88.3%</td><td>350</td><td>91.4%</td><td>192</td><td>95.1%</td></tr><tr><td>Wheezing</td><td>553</td><td>63.5%</td><td>162</td><td>57.2%</td><td>251</td><td>65.5%</td><td>140</td><td>68.3%</td></tr><tr><td>Exercise-induced dyspnea</td><td>410</td><td>47.1%</td><td>122</td><td>43.1%</td><td>187</td><td>48.8%</td><td>102</td><td>49.4%</td></tr><tr><td>Tight chest</td><td>149</td><td>17.1%</td><td>32</td><td>11.3%</td><td>73</td><td>19.1%</td><td>44</td><td>25.7%</td></tr><tr><td>Pre-school wheezing</td><td>315</td><td>36.2%</td><td>108</td><td>38.2%</td><td>134</td><td>35.0%</td><td>73</td><td>35.7%</td></tr><tr><td>Atopy</td><td>678</td><td>77.8%</td><td>202</td><td>71.4%</td><td>306</td><td>79.9%</td><td>170</td><td>82.4%</td></tr><tr><td>Allergic comorbidities</td><td>713</td><td>81.9%</td><td>219</td><td>77.4%</td><td>320</td><td>83.6%</td><td>174</td><td>83.9%</td></tr></tbody></table>

We found a significant difference only between the whole cohort and the subgroup of patients with normal FEV1/FVC for the tight chest (*p*-value 0.0198) and atopy (*p*-value 0.0264) criteria.

501
502
503
504

527
528
529
530
531

<table><caption>**Table 4** – Characteristics of the population, per asthma severity.</caption><thead><tr><th>Asthma severity</th><th>Persistent severe asthma</th><th>Persistent moderate asthma</th><th>Persistent mild asthma</th><th>Intermittent asthma</th></tr></thead><tbody><tr><td>Number of patients, n (%)</td><td>55 (6.3)</td><td>581 (66.7)</td><td>203 (23.3)</td><td>32 (3.7)</td></tr><tr><td>Males, n (%)</td><td>34 (61.8)</td><td>375 (64.5)</td><td>122 (60.1)</td><td>17 (53.1)</td></tr><tr><td>Age, mean (SD)</td><td>9.6 (3.3)</td><td>9.4 (3.2)</td><td>8.6 (3.2)</td><td>10.3 (3.6)</td></tr><tr><td>BMI, mean (SD)</td><td>18.6 (3.8)</td><td>18.2 (3.7)</td><td>17.9 (3.5)</td><td>17.3 (2.8)</td></tr><tr><td>Mean Change in FEV<sub>1</sub> after bronchodilation, % (SD)</td><td>13.2 (18.2)</td><td>8.9 (10.7)</td><td>5.0 (6.9)</td><td>7.2 (8.9)</td></tr><tr><td>Mean basal FEV<sub>1</sub>/FVC, n (SD)</td><td>79.5 (10.5)</td><td>84.1 (9.7)</td><td>87.7 (8.5)</td><td>89.4 (10.4)</td></tr><tr><td>Mean Change in FEF<sub>25-75</sub> after bronchodilation, % (SD)</td><td>23.9 (23.8)</td><td>23.1 (32.5)</td><td>19.6 (24.5)</td><td>16.2 (21.1)</td></tr><tr><td>Patients treated with Anti-IgE, n (%)</td><td>37 (67.3)</td><td>2 (0.3)</td><td>0</td><td>0</td></tr><tr><td>Patients treated with AIT, n (%)</td><td>5 (9.1)</td><td>64 (11.0)</td><td>28 (13.8)</td><td>4 (12.5)</td></tr><tr><td>Patients presenting with any atopic comorbidity, n (%)</td><td>47 (85.5)</td><td>493 (84.9)</td><td>149 (73.4)</td><td>24 (75.0)</td></tr><tr><td>Patients suffering from Allergic Rhinitis, n (%)</td><td>42 (76.4)</td><td>418 (71.9)</td><td>128 (63.1)</td><td>17 (53.1)</td></tr><tr><td>Patients suffering from food allergy, n (%)</td><td>6 (10.9)</td><td>75 (12.9)</td><td>23 (11.3)</td><td>4 (12.5)</td></tr><tr><td>Patients suffering from atopic dermatitis, n (%)</td><td>14 (25.5)</td><td>140 (24.1)</td><td>34 (16.8)</td><td>5 (15.6)</td></tr><tr><td>Atopic patients, n (%)</td><td>51 (92.7)</td><td>455 (78.3)</td><td>149 (73.4)</td><td>23 (71.9)</td></tr><tr><td>Patients sensitized to house dust mites, n (%)</td><td>35 (63.6)</td><td>318 (54.7)</td><td>104 (51.2)</td><td>14 (43.8)</td></tr></tbody></table>

<table><thead><tr><th>Between severe and moderate asthma</th><th>Between severe and mild asthma</th><th>Between severe and intermittent asthma</th><th>Between moderate and mild asthma</th><th>Between moderate and intermittent asthma</th><th>Between mild and intermittent asthma</th></tr></thead><tbody><tr><td>0.6867</td><td>0.8170</td><td>0.4273</td><td>0.2577</td><td>0.1903</td><td>0.4557</td></tr><tr><td>0.6588</td><td>0.0422*</td><td>0.3588</td><td>0.0022*</td><td>0.1244</td><td>0.0065*</td></tr><tr><td>0.4448</td><td>0.1977</td><td>0.0955</td><td>0.3136</td><td>0.1761</td><td>0.3566</td></tr><tr><td>0.0084*</td><td>&lt; 0.0001*</td><td>0.0847</td><td>&lt; 0.0001*</td><td>0.3782</td><td>0.1094</td></tr><tr><td>0.0009*</td><td>&lt; 0.0001*</td><td>0.0001*</td><td>&lt; 0.0001*</td><td>0.0028*</td><td>0.3095</td></tr><tr><td>0.8588</td><td>0.2465</td><td>0.1334</td><td>0.1615</td><td>0.2358</td><td>0.4585</td></tr><tr><td>&lt; 0.0001*</td><td>N/A</td><td>N/A</td><td>N/A</td><td>N/A</td><td>N/A</td></tr><tr><td>0.6609</td><td>0.3544</td><td>0.6146</td><td>0.2898</td><td>0.7946</td><td>0.8429</td></tr><tr><td>0.9053</td><td>0.0634</td><td>0.2248</td><td>0.0003*</td><td>0.1354</td><td>0.8429</td></tr><tr><td>0.4839</td><td>0.0648</td><td>0.0253*</td><td>0.0177*</td><td>0.0224*</td><td>0.2829</td></tr><tr><td>0.6707</td><td>0.9301</td><td>0.8225</td><td>0.5582</td><td>0.9464</td><td>0.8470</td></tr><tr><td>0.8222</td><td>0.1411</td><td>0.2846</td><td>0.0301*</td><td>0.2723</td><td>0.8738</td></tr><tr><td>0.0113*</td><td>0.0023*</td><td>0.0085*</td><td>0.1518</td><td>0.3922</td><td>0.8565</td></tr><tr><td>0.2041</td><td>0.1016</td><td>0.0713</td><td>0.3890</td><td>0.2248</td><td>0.4315</td></tr></tbody></table>

532

533

534

**Legend:** BMI: Body Mass Index; SD: Standard Deviation; FEV₁: Forced Expiratory Volume in 1 second; FVC: Forced Vital Capacity; FEF₂₅-7₅: mean Forced Expiratory Flow between the 25% and 75% of the FVC; N/A: not applicable; AIT: Allergen Immunotherapy; *: statistically significant difference between the groups (*-value < 0.05).

535

536

537
531

<table><caption>**Table 4** – Characteristics of the population, per asthma severity.</caption><thead><tr><th>Asthma severity</th><th>Persistent severe asthma</th><th>Persistent moderate asthma</th><th>Persistent mild asthma</th><th>Intermittent asthma</th></tr></thead><tbody><tr><td>Number of patients, n (%)</td><td>55 (6.3)</td><td>581 (66.7)</td><td>203 (23.3)</td><td>32 (3.7)</td></tr><tr><td>Males, n (%)</td><td>34 (61.8)</td><td>375 (64.5)</td><td>122 (60.1)</td><td>17 (53.1)</td></tr><tr><td>Age, mean (SD)</td><td>9.6 (3.3)</td><td>9.4 (3.2)</td><td>8.6 (3.2)</td><td>10.3 (3.6)</td></tr><tr><td>BMI, mean (SD)</td><td>18.6 (3.8)</td><td>18.2 (3.7)</td><td>17.9 (3.5)</td><td>17.3 (2.8)</td></tr><tr><td>Mean Change in FEV<sub>1</sub> after bronchodilation, % (SD)</td><td>13.2 (18.2)</td><td>8.9 (10.7)</td><td>5.0 (6.9)</td><td>7.2 (8.9)</td></tr><tr><td>Mean basal FEV<sub>1</sub>/FVC, n (SD)</td><td>79.5 (10.5)</td><td>84.1 (9.7)</td><td>87.7 (8.5)</td><td>89.4 (10.4)</td></tr><tr><td>Mean Change in FEF<sub>25-75</sub> after bronchodilation, % (SD)</td><td>23.9 (23.8)</td><td>23.1 (32.5)</td><td>19.6 (24.5)</td><td>16.2 (21.1)</td></tr><tr><td>Patients treated with Anti-IgE, n (%)</td><td>37 (67.3)</td><td>2 (0.3)</td><td>0</td><td>0</td></tr><tr><td>Patients treated with AIT, n (%)</td><td>5 (9.1)</td><td>64 (11.0)</td><td>28 (13.8)</td><td>4 (12.5)</td></tr><tr><td>Patients presenting with any atopic comorbidity, n (%)</td><td>47 (85.5)</td><td>493 (84.9)</td><td>149 (73.4)</td><td>24 (75.0)</td></tr><tr><td>Patients suffering from Allergic Rhinitis, n (%)</td><td>42 (76.4)</td><td>418 (71.9)</td><td>128 (63.1)</td><td>17 (53.1)</td></tr><tr><td>Patients suffering from food allergy, n (%)</td><td>6 (10.9)</td><td>75 (12.9)</td><td>23 (11.3)</td><td>4 (12.5)</td></tr><tr><td>Patients suffering from atopic dermatitis, n (%)</td><td>14 (25.5)</td><td>140 (24.1)</td><td>34 (16.8)</td><td>5 (15.6)</td></tr><tr><td>Atopic patients, n (%)</td><td>51 (92.7)</td><td>455 (78.3)</td><td>149 (73.4)</td><td>23 (71.9)</td></tr><tr><td>Patients sensitized to house dust mites, n (%)</td><td>35 (63.6)</td><td>318 (54.7)</td><td>104 (51.2)</td><td>14 (43.8)</td></tr></tbody></table>

<table><thead><tr><th>Between severe and moderate asthma</th><th>Between severe and mild asthma</th><th>Between severe and intermittent asthma</th><th>Between moderate and mild asthma</th><th>Between moderate and intermittent asthma</th><th>Between mild and intermittent asthma</th></tr></thead><tbody><tr><td>0.6867</td><td>0.8170</td><td>0.4273</td><td>0.2577</td><td>0.1903</td><td>0.4557</td></tr><tr><td>0.6588</td><td>0.0422*</td><td>0.3588</td><td>0.0022*</td><td>0.1244</td><td>0.0065*</td></tr><tr><td>0.4448</td><td>0.1977</td><td>0.0955</td><td>0.3136</td><td>0.1761</td><td>0.3566</td></tr><tr><td>0.0084*</td><td>&lt; 0.0001*</td><td>0.0847</td><td>&lt; 0.0001*</td><td>0.3782</td><td>0.1094</td></tr><tr><td>0.0009*</td><td>&lt; 0.0001*</td><td>0.0001*</td><td>&lt; 0.0001*</td><td>0.0028*</td><td>0.3095</td></tr><tr><td>0.8588</td><td>0.2465</td><td>0.1334</td><td>0.1615</td><td>0.2358</td><td>0.4585</td></tr><tr><td>&lt; 0.0001*</td><td>N/A</td><td>N/A</td><td>N/A</td><td>N/A</td><td>N/A</td></tr><tr><td>0.6609</td><td>0.3544</td><td>0.6146</td><td>0.2898</td><td>0.7946</td><td>0.8429</td></tr><tr><td>0.9053</td><td>0.0634</td><td>0.2248</td><td>0.0003*</td><td>0.1354</td><td>0.8429</td></tr><tr><td>0.4839</td><td>0.0648</td><td>0.0253*</td><td>0.0177*</td><td>0.0224*</td><td>0.2829</td></tr><tr><td>0.6707</td><td>0.9301</td><td>0.8225</td><td>0.5582</td><td>0.9464</td><td>0.8470</td></tr><tr><td>0.8222</td><td>0.1411</td><td>0.2846</td><td>0.0301*</td><td>0.2723</td><td>0.8738</td></tr><tr><td>0.0113*</td><td>0.0023*</td><td>0.0085*</td><td>0.1518</td><td>0.3922</td><td>0.8565</td></tr><tr><td>0.2041</td><td>0.1016</td><td>0.0713</td><td>0.3890</td><td>0.2248</td><td>0.4315</td></tr></tbody></table>

532

533

534

**Legend:** BMI: Body Mass Index; SD: Standard Deviation; FEV₁: Forced Expiratory Volume in 1 second; FVC: Forced Vital Capacity; FEF₂₅-7₅: mean Forced Expiratory Flow between the 25% and 75% of the FVC; N/A: not applicable; AIT: Allergen Immunotherapy; *: statistically significant difference between the groups (*-value < 0.05).

535

536

537
<figure><img src="image_3.png" /><figcaption>**Figure 1** – Patients included in the study.</figcaption></figure>
<figure><img src="image_2.png" /><figcaption>**Figure 1** – Patients included in the study.</figcaption></figure>
**Figure 2** – Reversibility criteria (FEV₁/FCV < 90% and increase in FEV₁ > 12%) after bronchodilation test in all 871 included children. The line shows the 12% cut-off proposed by GINA guidelines. All children on the left of the line would be considered as non-asthmatics following current recommendations.

<figure><img src="image_4.png" /></figure>
**Figure 2** – Reversibility criteria (FEV₁/FCV < 90% and increase in FEV₁ > 12%) after bronchodilation test in all 871 included children. The line shows the 12% cut-off proposed by GINA guidelines. All children on the left of the line would be considered as non-asthmatics following current recommendations.

<figure><img src="image_3.png" /></figure>
<figure><img src="image_5.png" /><figcaption>**Figure 3** – Best option for cumulative sensitivity of different variables to predict a diagnosis of asthma in children.</figcaption></figure>
<figure><img src="image_4.png" /><figcaption>**Figure 3** – Best option for cumulative sensitivity of different variables to predict a diagnosis of asthma in children.</figcaption></figure>
## 871 children with a specialized physician diagnosis of asthma

<figure><img src="image_6.png" /></figure>

342 children
University Hospital of Montpellier

<figure><img src="image_7.png" /></figure>

529 children
University Hospital of Pavia

<figure><img src="image_8.png" /></figure>

548 males

<figure><img src="image_9.png" /></figure>

323 females

### Assessment of:

#### Spirometric parameters

* FEV₁ reversibility criterion (+12%) – primary outcome

* Obstruction criterion (FEV₁/FVC < 90%)

* Small airways reversibility (FEF₂₅-₇₅ +30%)

**Clinical parameters:** dry cough, tight chest, wheezing, pre-school wheezing, exercise-induced dyspnea, atopy, allergic comorbidities

**Aim:** Sensitivity of spirometric and clinical parameters to identify presumed asthma in children

## Sensitivity of different parameters

<figure><img src="image_10.png" /></figure>

Dry cough

<figure><img src="image_11.png" /></figure>

Dry cough or atopy

<figure><img src="image_12.png" /></figure>

Dry cough, or wheezing or atopy

<figure><img src="image_13.png" /></figure>

90.9%

<figure><img src="image_14.png" /></figure>

98.5%

<figure><img src="image_15.png" /></figure>

99.5%

## Conclusion

1. Low sensitivity of the broncho-reversibility criterion in children

2. Better sensitivity of clinical parameters
## 871 children with a specialized physician diagnosis of asthma

<figure><img src="image_5.png" /></figure>

342 children
University Hospital of Montpellier

<figure><img src="image_6.png" /></figure>

529 children
University Hospital of Pavia

<figure><img src="image_7.png" /></figure>

548 males

<figure><img src="image_8.png" /></figure>

323 females

### Assessment of:

### Spirometric parameters

- FEV₁ reversibility criterion (+12%) – primary outcome

- Obstruction criterion (FEV₁/FVC < 90%)

- Small airways reversibility (FEF₂₅-₇₅ +30%)

**Clinical parameters:** dry cough, tight chest, wheezing, pre-school wheezing, exercise-induced dyspnea, atopy, allergic comorbidities

**Aim:** Sensitivity of spirometric and clinical parameters to identify presumed asthma in children

## Sensitivity of different parameters

<figure><img src="image_9.png" /></figure>

Dry cough

<figure><img src="image_10.png" /></figure>

Dry cough or atopy

<figure><img src="image_11.png" /></figure>

Dry cough, or wheezing or atopy

<figure><img src="image_12.png" /></figure>

90.9%

<figure><img src="image_13.png" /></figure>

98.5%

<figure><img src="image_14.png" /></figure>

99.5%

## Conclusion

1. Low sensitivity of the broncho-reversibility criterion in children

2. Better sensitivity of clinical parameters