Abstract
Background
Airway obstruction is a characteristic spirometric finding in asthma but the clinical significance of other abnormal spirometric patterns is less well described. We aimed to explore pre- and post-bronchodilator (BD) prevalences and clinical characteristics of preserved ratio impaired spirometry (PRISm), dysanapsis and airflow obstruction with low forced expiratory volume in 1 s (FEV1) in children diagnosed with asthma.
Methods
We extracted specialist care data (clinical and spirometry) from the Swedish National Airway Register (n=3301, age 5–17 years). Normal spirometry was defined as FEV1≥ lower limit of normal (LLN) and FEV1/forced vital capacity (FVC)≥LLN. PRISm was defined as forced FEV1< LLN and FEV1/FVC≥LLN, dysanapsis as FEV1/FVC<LLN and FEV1≥LLN, and airflow obstruction with reduced FEV1 as FEV1/FVC<LLN and FEV1<LLN. The BD response (BDR) was calculated as ((post-BD(L)−pre-BD(L))/predicted (L))×100. Values >10% were considered positive (BDRpos). Groups were compared using parametric tests and associations were explored using logistic regression analysis.
Results
Pre-/post-BD PRISm, dysanapsis and obstruction with low FEV1 were identified in 9%/7%, 10%/4% and 8%/2%, respectively. Compared with normal spirometry, all three groups were associated with older age and BDRpos in pre-BD analyses. Furthermore, dysanapsis was associated with overweight/obesity and obstruction with low FEV1 with uncontrolled asthma and more treatment.
Interpretation
In this paediatric asthma cohort, PRISm and dysanapsis were associated with BDRpos and they were at least as common as airflow obstruction with reduced FEV1. These spirometric phenotypes should be addressed in the management of childhood asthma and testing of BDR should be considered also in children with PRISm and dysanapsis.
Shareable abstract
PRISm (preserved ratio impaired spirometry) and dysanapsis are common spirometric phenotypes in children with asthma. Both are associated with a positive bronchodilator response and specific clinical characteristics. https://bit.ly/3QLtO37
Introduction
Spirometry plays a crucial role in diagnosing and monitoring asthma based on evaluation of airflow limitation and bronchodilator (BD) response (BDR) [1]. Obstruction is defined as a reduced ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) [2]. The European Respiratory Society (ERS) recommends that either a reduced FEV1/FVC or a reduced FEV1 is used as a criterion to diagnose asthma [3]. Thus, children with reduced FEV1 but without airway obstruction (i.e. normal FEV1/FVC) – a pattern referred to as preserved ratio impaired spirometry (PRISm) [4] – may be diagnosed with asthma. Studies on PRISm in adults [5] and in children with prematurity-associated lung disease [6] have recently been published, but the prevalence and clinical features of PRISm in paediatric asthma are largely unexplored.
Airway obstruction with normal FEV1 is a spirometric pattern associated with unequal growth in lung parenchyma size and airway calibre [7], a phenomenon referred to as airway dysanapsis [8]. Dysanapsis is associated with airway hyperreactivity [9], asthma [10] and overweight [11], and asthmatic children with dysanapsis seem to have increased morbidity [12].
Current asthma guidelines do not provide advice on the interpretation of PRISm and dysanapsis [13], probably because there is still a lack of data regarding the significance of these spirometric phenotypes in a clinical asthma context. To contribute to the understanding of the role of these phenotypes in paediatric asthma, we used real-life register-based data from paediatric specialist care clinics in Sweden to identify and describe these spirometric patterns. Specifically, we aimed to 1) explore pre- and post-BD prevalence and clinical characteristics of PRISm, dysanapsis and airflow obstruction with low FEV1 and 2) identify factors associated with transitions from these spirometric phenotypes to normal post-BD spirometry.
Methods
The study subjects were identified from the Swedish National Airway Register (SNAR), which comprises data on patients with a doctor's diagnosis of asthma from primary or secondary care (International Classification of Diseases v.10 code J45) [14]. Registrations in the SNAR can be made at each healthcare visit for asthma and include data on age, sex, asthma control test (ACT) scores, medication and pulmonary function measurements. For this study, children aged 5–17 years with asthma were identified from paediatric specialist care recordings in the SNAR from 1 January to 31 December 2019 (n=7338). A total of 3301 children with complete pre- and post-BD spirometry data were identified and included in the study. Ethical approval was obtained from the Swedish Ethical Review Authority (approval no. 2019-04915) and informed consent was waived due to the register-based nature of the study.
Lung function measurements
Spirometry was performed at each paediatric specialist care clinic and the quality of spirometry was assessed by clinic staff before the results were entered into the SNAR database.
Lung function was assessed based on pre- and post-BD FEV1, FVC and FEV1/FVC. z-scores and per cent of predicted values were calculated using reference equations provided by the Global Lung Initiative [15]. The lower limit of normal (LLN) and upper limit of normal (ULN) were defined by a z-score <−1.645 and >1.645, respectively. Normal lung function was defined as FEV1/FVC≥LLN and FEV1≥LLN.
Preserved ratio impaired spirometry (PRISm) was defined as FEV1/FVC≥LLN and FEV1<LLN. Airflow obstruction was defined as FEV1/FVC<LLN. Dysanapsis (i.e. airflow obstruction with normal FEV1,) was defined as FEV1/FVC<LLN and FEV1≥LLN. Airflow obstruction with reduced FEV1 was defined as FEV1/FVC<LLN and FEV1<LLN.
BDR was calculated in accordance with ERS/American Thoracic Society (ATS) guidelines [2], BDR=((post-BDFEV;;1 (L)−pre-BDFEV;;1 (L))/predicted value (L))×100. A change of >10% was considered positive (BDR>10%) and denoted BDRpos.
Demographic and clinical variables
Sex was classified as male or female. Age was categorised as younger child (5–11 years) or adolescent (12–17 years).
Body mass index (BMI) was calculated as (weight/height2 (kg·m−2)) and ISO-BMI was used for age-dependent cut-offs for normal weight, overweight, and obesity [16]. Using these cut-offs, we dichotomised BMI as normal weight or overweight/obesity.
Asthma control was assessed using validated questionnaires – the ACT for children aged ≥12 years, and the childhood ACT for children aged 5–11 years. A score of ≤19 in either questionnaire signifies uncontrolled asthma, with better control indicated by higher values [17].
Treatment for asthma at the time of enrolment could be reported in the SNAR as short-acting β2 agonist (SABA), short-acting muscarinic antagonist (SAMA), inhaled corticosteroid (ICS), long-acting β2 agonist (LABA), leukotriene receptor antagonist (LTRA), long-acting muscarinic antagonist (LAMA) or biological treatment such as omalizumab, dupilumab or mepolizumab. The use of asthma medications was categorised in accordance with a modified version of GINA 2018 as step 1: SABA, SAMA or LABA as needed; step 2: single therapy with ICS or LTRA as controller medication; step 3: treatment with two controller medications (ICS+LABA, ICS+ LTRA or LTRA+LABA); step 4: treatment with at least three controller medications (ICS, LABA, LAMA and/or LTRA); and step 5: biological treatments and/or other step 5 options in accordance with national Swedish guidelines [18]. Treatment was categorised as step 1–2 or step 3–5.
Statistical analysis
Descriptive data for the entire study population, and stratified by sex and age group, are presented as n (%) for categorical variables and mean±sd for numerical variables. To assess differences between strata, independent sample t-tests or chi-squared tests were used.
Logistic regression analyses were performed with the following outcomes: 1) pre- and post-BD spirometric phenotypes (PRISm, dysanapsis, obstruction with low FEV1) using children with normal pre- or post-BD spirometry, respectively, as references; and 2) children who changed from pre-BD PRISm, dysanapsis or obstruction with low FEV1 to normal post-BD spirometry, using children who did not change spirometric phenotype between pre- and post-BD examinations as references.
Exposures in both models were sex (reference, male), age group (reference, age 5–11 years), overweight/obesity (reference, normal weight), uncontrolled asthma (reference, controlled asthma), step 3–5 treatment (reference, step 1–2 treatment) and BDRpos (reference, BDR negative, i.e. BDR<10%).
Analyses were performed with and without adjustment for potential confounders identified a priori (complete case analysis), as indicated in tables.
The results from the regression analyses are presented as odds ratios (ORs) with 95% confidence intervals (CIs). All statistical analyses were conducted using SPSS 29.0.1 and p-values <0.05 were considered statistically significant.
Results
Demographic characteristics
Demographic characteristics are shown in table 1. Among the included children (n=3301), 53.3% were aged 5–11 years (younger children) and the majority were male (61.3%). The mean±sd FEV1 and FEV1/FVC z-scores were −0.65±1.1 and −0.57±1.1 pre-BD and −0.25±0.89 and 0.01±1.1 post-BD, respectively. Adolescents had lower pre- and post-BD z-scores for FEV1, FVC and FEV1/FVC. There were no sex differences in z-scores (supplementary table S1). Characteristics of children with normal spirometry, PRISm, dysanapsis and obstruction with low FEV1 are presented in table 2.
TABLE 1.
Characteristics, abnormal spirometry and bronchodilator responses among all children, and stratified by sex and age group
| All n=3301 |
Female n=1276 |
Male n=2025 |
p-value# | 5–11 years n=1760 |
12–17 years n=1541 |
p-value# | |
|---|---|---|---|---|---|---|---|
| Characteristics | |||||||
| Female | 1276 (38.7) | 644 (36.6) | 632 (42%) | <0.001 | |||
| Age 12–17 years | 1760 (53.3) | 632 (49.5) | 909 (44.9) | 0.009 | |||
| Overweight/obesity¶ | 753 (22.8) | 285 (22.3) | 468 (23.1) | 0.59 | 416 (23.6) | 337 (21.9) | 0.23 |
| ACT score ≤19+ | 778 (26.3) | 370 (32.6) | 408 (22.3) | <0.001 | 361 (23.3) | 417 (29.6) | <0.001 |
| Step 3–5 treatment§ | 1191 (36.1) | 451 (42.8) | 740 (44.3) | 0.44 | 516 (35.8) | 67 (52.7) | <0.001 |
| Pre-BD | |||||||
| FEV1<LLN | 545 (16.5) | 211 (16.5) | 334 (16.5) | 0.98 | 222 (12.6) | 323 (21.0) | <0.001 |
| FVC <LLN | 322 (9.8) | 127 (10.0) | 195 (9.6) | 0.76 | 143 (8.1) | 179 (11.6) | <0.001 |
| FEV1/FVC<LLN | 577 (17.5) | 238 (18.7) | 339 (16.7) | 0.16 | 279 (15.9) | 298 (19.3) | 0.009 |
| Post-BD | |||||||
| FEV1<LLN | 302 (9.2) | 125 (9.8) | 178 (8.8) | 0.33 | 113 (6.4) | 190 (12.3) | <0.001 |
| FVC <LLN | 306 (9.3) | 119 (9.3) | 187 (9.2) | 0.93 | 123 (7.0) | 183 (11.9) | <0.001 |
| FEV1/FVC<LLN | 204 (6.2) | 88 (6.9) | 116 (5.7) | 0.18 | 97 (5.5) | 107 (6.9) | 0.09 |
| BDR | |||||||
| BDR%ƒ | 4.7 (6.4) | 4.5 (6.6) | 4.9 (6.3) | 0.06 | 5.4 (7.1) | 4.0 (5.5) | <0.001 |
| BDRpos | 501 (15.2) | 185 (14.5) | 316 (15.6) | 0.39 | 350 (19.9) | 151 (9.8) | <0.001 |
Data are presented as n (%) or mean±sd. ACT: asthma control test; BD: bronchodilator; BDR: BD response; BDRpos: positive BDR; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; LLN: lower limit of normal. #: t-tests or chi-squared tests. ¶: body mass index missing, n=3. +: ACT score missing, n=345. §: treatment missing, n=576. ƒ: (post-FEV1 (L)−pre-FEV1 (L))/FEV1 predicted)×100. Data in bold are statistically significant.
TABLE 2.
Characteristics of children (n=3301) with different spirometry patterns
| Normal | PRISm | Dysanapsis | Obstruction with low FEV1 | |
|---|---|---|---|---|
| Pre-bronchodilator | n=2428 | n=296 | n=328 | n=249 |
| Female | 927 (38.2) | 111 (37.5) | 138 (42.1) | 100 (40.2) |
| Age 12–17 years | 1064 (43.8) | 179 (60.5) | 154 (47.0) | 144 (57.8) |
| Overweight/obesity# | 545 (22.5) | 50 (16.9) | 95 (29.0) | 63 (25.3) |
| ACT score≤19¶ | 539 (24.8) | 83 (30.4) | 69 (23.7) | 87 (39.0) |
| Step 3–5 treatment+ | 810 (40.7) | 123 (48.0) | 125 (46.0) | 133 (63.6) |
| BDRpos | 237 (9.8) | 42 (14.2) | 123 (37.5) | 99 (39.8) |
| Post-bronchodilator | n=2866 | n=231 | n=133 | n=71 |
| Female | 1097 (38.3) | 91 (39.4) | 54 (40.6) | 34 (47.9) |
| Age 12–17 years | 1291 (45.0) | 143 (61.9) | 61 (45.9) | 46 (64.8) |
| Overweight/obesity# | 647 (22.6) | 43 (18.6) | 44 (33.1) | 19 (26.8) |
| ACT score≤19¶ | 668 (26.0) | 62 (29.5) | 29 (25.0) | 19 (30.6) |
| Step 3–5 treatment+ | 994 (42.1) | 104 (52.2) | 46 (42.2) | 47 (75.8) |
| BDRpos | 453 (15.8) | 11 (4.8) | 24 (18.0) | 10 (18.3) |
Data are presented as n (%). PRISm: preserved ratio impaired spirometry; FEV1: forced expiratory volume in 1 s; ACT: asthma control test; BDRpos: bronchodilator response positive. #: body mass index missing, n=3. ¶: ACT score missing, n=345. +: treatment missing, n=576.
Preserved ratio impaired spirometry
Pre- and post-BD PRISm was identified in 9.0% and 7.0% of the cohort, respectively. The majority of children with PRISm had FVC<LLN both pre-BD (68.9%) and post-BD (78.8%) (figure 1a, b). Pre-BD PRISm was associated with higher age (adjusted OR (ORadj) 1.94, 95% CI 1.45–2.59) and BDRpos (ORadj 2.02, 95% CI 1.35–3.03). Post-BD PRISm was associated with higher age (ORadj 1.65, 95% CI 1.19–2.28) and step 3–5 treatment (ORadj 1.46, 95% CI 1.07–2.00), and with BDRpos (ORadj 0.28, 95% CI 0.13–0.57) (table 3). No significant associations between pre- or post-BD PRISm and sex, overweight/obesity or uncontrolled asthma were observed in the adjusted analyses.
FIGURE 1.
a) Study population with prevalences of pre-bronchodilator (BD) obstruction, preserved ratio impaired spirometry (PRISm), dysanaptic airflow obstruction and obstruction with low forced expiratory volume in 1 s (FEV1). b) Study population with prevalences of post-BD obstruction, PRISm, dysanaptic airflow obstruction and obstruction with low FEV1. FVC: forced vital capacity; LLN: lower limit of normal; ULN: upper limit of normal; BDR: BD response; BDRpos: BDR positive. #: Percentage of all children in the cohort (n=3301); ¶: Percentage of children with PRISm; +: Percentage of children with dysanapsis.
TABLE 3.
Pre- and post-BD associations between clinical characteristics and PRISm, dysanapsis and obstruction with low FEV1
| PRISm | Dysanapsis | Obstruction with low FEV1 | ||||
|---|---|---|---|---|---|---|
| Pre-BD | ORcrude | ORadj# | ORcrude | ORadj# | ORcrude | ORadj# |
| Female sex | 0.97 (0.76–1.25) | 0.84 (0.63–1.12) | 1.18 (0.93–1.49) | 1.23 (0.93–1.64) | 1.09 (0.83–1.42) | 1.10 (0.79–1.54) |
| Age 12–17 years | 1.96 (1.53–2.51) | 1.94 (1.45–2.58) | 1.14 (0.90–1.43) | 1.67 (1.25–2.23) | 1.76 (1.35–2.29) | 2.19 (1.55–3.10) |
| Overweight/obesity | 0.70 (0.51–0.96) | 0.83 (0.63–1.10) | 1.41 (1.09–1.82) | 1.45 (1.15–1.82) | 1.17 (0.87–1.58) | 1.21 (0.92–1.59) |
| ACT score≤19 | 1.32 (1.01–1.75) | 1.19 (0.88–1.62) | 0.94 (0.71–1.26) | 0.82 (0.59–1.14) | 1.93 (1.46–2.58) | 1.76 (1.26–2.46) |
| Step 3–5 treatment | 1.35 (1.04–1.75) | 1.31 (0.99–1.72) | 1.24 (0.96–1.60) | 1.17 (0.88–1.56) | 2.55 (1.89–3.42) | 2.50 (1.79–3.49) |
| BDRpos | 1.53 (1.07–2.18) | 2.02 (1.35–3.03) | 5.55 (4.27–7.20) | 5.92 (4.31–8.14) | 6.10 (4.58–8.13) | 9.20 (6.38–13.30) |
| Post-BD | ORcrude | ORadj# | ORcrude | ORadj# | ORcrude | ORadj# |
|---|---|---|---|---|---|---|
| Female sex | 1.05 (0.80–1.38) | 1.00 (0.73–1.38) | 1.10 (0.77–1.57) | 1.19 (0.79–1.80) | 1.48 (0.93–2.38) | 1.22 (0.71–2.12) |
| Age 12–17 years | 1.98 (1.51–2.61) | 1.65 (1.19–2.28) | 1.03 (0.73–1.47) | 1.06 (0.70–1.60) | 2.25 (1.37–3.67) | 1.85 (1.04–3.31) |
| Overweight/obesity | 0.78 (0.56–1.10) | 0.93 (0.69–1.24) | 1.69 (1.17–2.46) | 1.42 (1.03–1.96) | 1.25 (0.74–2.13) | 1.27 (0.83–1.96) |
| ACT score≤19 | 1.19 (0.88–1.63) | 1.06 (0.75–1.51) | 0.95 (0.62–1.46) | 0.82 (0.59–1.51) | 1.26 (0.73–2.18) | 1.20 (0.67–2.14) |
| Step 3–5 treatment | 1.63 (1.21–2.19) | 1.46 (1.07–2.00) | 1.00 (0.68–1.48) | 0.95 (0.63–1.45) | 4.31 (2.40–7.76) | 3.90 (2.07–7.37) |
| BDRpos | 0.27 (0.14–0.49) | 0.28 (0.13–0.57) | 1.17 (0.75–1.84) | 1.20 (0.71–2.05) | 1.54 (0.65–2.20) | 1.54 (0.77–3.06) |
Data are presented as odds ratios (ORs) with 95% confidence intervals. BD: bronchodilator; PRISm: preserved ratio impaired spirometry; FEV1: forced expiratory volume in 1 s; ORcrude: crude OR; ORadj: adjusted OR; ACT: asthma control test; BDRpos: BD response positive. #: Complete case analysis, all variables used in crude analysis were included in the adjusted models. Data in bold are statistically significant.
Among the 296 children who had pre-BD PRISm, 129 (43.6%) had normal values post-BD, whereas 165 (55.7%) had PRISm also in post-BD spirometry (figure 2) and online repository (table 2). The transition from pre-BD PRISm to post-BD normal was associated with BDRpos (ORadj 19.5, 95% CI 5.56–68.4) (table 4). No associations were found for sex, age, overweight/obesity, uncontrolled asthma or step 3–5 treatment in adjusted analysis.
FIGURE 2.
Transitions of spirometric phenotypes from pre- to post-bronchodilator (BD) measurements. FEV1: forced expiratory volume in 1 s; PRISm: preserved ratio impaired spirometry.
TABLE 4.
Associations with transitions from pre-BD, PRISm, dysanapsis or obstruction with low FEV1 to normal post-BD spirometry
| Transition from | Pre-BD PRISm | Pre-BD dysanapsis | Pre-BD obstruction with low FEV1 | |||
|---|---|---|---|---|---|---|
| ORcrude | ORadj# | ORcrude | ORadj# | ORcrude | ORadj# | |
| Female | 0.93 (0.58–1.50) | 0.85 (0.46–1.54) | 0.99 (0.59–1.65) | 0.92 (0.49–1.72) | 0.56 (0.30–1.05) | 0.53 (0.23–1.21) |
| Age 12–17 years¶ | 0.59 (0.37–0.95) | 1.06 (0.57–1.94) | 0.85 (0.51–1.42) | 1.21 (0.63–2.32) | 0.57 (0.30–1.11) | 0.79 (0.33–1.89) |
| Overweight/obesity+ | 0.73 (0.39–1.38) | 1.12 (0.64–1.95) | 0.73 (0.42–1.26) | 0.87 (0.54–1.41) | 0.94 (0.46–1.94) | 0.86 (0.44–1.68) |
| ACT score≤19§ | 1.23 (0.73–2.06) | 1.25 (0.67–2.34) | 1.58 (0.79–3.17) | 1.44 (0.66–3.14) | 1.72 (0.86–3.45) | 1.89 (0.83–4.30) |
| Step 3–5 treatment§ | 0.75 (0.45–1.23) | 0.94 (0.53–1.66) | 1.00 (0.57–1.75) | 0.77 (0.40–1.50) | 0.27 (0.12–0.59) | 0.38 (0.15–0.96) |
| BDRpos | 23.4 (7.03–77.9) | 19.5 (5.56–68.4) | 5.79 (2.85–11.8) | 4.94 (2.19–11.2) | 4.68 (2.29–9.56) | 3.22 (1.36–7.62) |
Data are presented as odds ratios (ORs) with 95% confidence intervals. BD: bronchodilator; PRISm: preserved ratio impaired spirometry; FEV1: forced expiratory volume in 1 s; ORcrude: crude OR; ORadj: adjusted OR; ACT: asthma control test; BDRpos: BD response positive.#: complete case analysis, all variables used in crude analysis were included in the adjusted models. ¶: body mass index missing, n=3. +: ACT missing, n=345. §: treatment missing, n=576. Data in bold are statistically significant.
Dysanapsis
Among all children, the proportions with pre- or post-BD dysanapsis were 9.9% and 4.0%, respectively (figure 1). The majority of children with dysanapsis had FVC<ULN both pre-BD (86.3%) and post-BD (80.5%) (figure 1a, b). Pre-BD dysanapsis was associated with higher age (ORadj 1.67, 95% CI 1.25–2.23), overweight/obesity (ORadj 1.45, 95% CI 1.15–1.82) and BDRpos (ORadj 5.92, 95% CI 4.31–8.14). Post-BD dysanapsis was associated with obesity (ORadj 1.42, 95% CI 1.03–1.96). We found no significant associations between pre- and post-BD dysanapsis and sex, uncontrolled asthma or treatment (table 3).
Among the 328 children who had dysanapsis in pre-BD spirometry, 248 (75.6%) had normal post-BD spirometry and 78 (23.8%) had dysanapsis in post-BD spirometry (figure 2) and online repository (table 2). The transition from pre-BD dysanapsis to normal post-BD spirometry was associated with BDRpos (ORadj 4.94, 95% CI 2.19–11.2), (table 4), whereas no associations were found for sex, age, overweight/obesity, uncontrolled asthma or step 3–5 treatment.
Airflow obstruction with low FEV1
Obstruction with low FEV1 was identified in 7.5% and 2.2% in pre- and post-BD spirometry, respectively. Pre-BD obstruction with low FEV1 was associated with higher age (ORadj 2.19, 95% CI 1.55–3.10), uncontrolled asthma (ORadj 1.76, 95% CI 1.26–2.46), step 3–5 treatment (ORadj 2.50, 95% CI 1.79–3.49), and BDRpos (ORadj 9.20, 95% CI 6.38–13.30). Post-BD obstruction with low FEV1 was associated with step 3–5 treatment (ORadj 3.90, 95% CI 2.07–7.37).
Among the 249 children who had obstruction with low FEV1 in pre-BD spirometry, 117 (46.9%) had normal post-BD spirometry and 61 (24.5%) had obstruction in post-BD spirometry (figure 2 and supplementary table S2). The transition from pre-BD obstruction with low FEV1 to normal post-BD spirometry was associated with step 3–5 treatment (ORadj 0.38, 95% CI 0.15–0.96) and BDRpos (ORadj 3.22, 95% CI 1.36–7.62) (table 4). We found no associations for sex, age, overweight/obesity or uncontrolled asthma.
Discussion
Interpretation of spirometry results is straightforward in children with either normal results or clearly obstructive patterns. However, few studies have examined the prevalence and clinical significance of other potentially pathological patterns, such as PRISm and dysanapsis, in children diagnosed with asthma. In this nationwide, real-world, register-based study, we analysed spirometry data from over 3000 school-aged children with asthma who were followed in specialised paediatric care. Our findings show that both PRISm and dysanapsis were associated with BDRpos and were at least as common as airflow obstruction with reduced FEV1 in both pre- and post-BD analyses.
PRISm might be an important phenotype in children with asthma, as it is associated with COPD, cardiovascular disease and all-cause mortality in adults [4, 19]. PRISm has previously been identified in 9% of children born preterm and 4.6% of term-born babies [6]. We found that PRISm was common both based on pre-BD (9%) and post-BD (7%) spirometry and had significant associations with older age and a positive BDR. The finding of normal post-BD spirometry in the majority of children with pre-BD PRISm contrasts with results from adults with PRISm [5], and indicates that these children will respond to BD treatment.
The PRISm criterion has significant overlap with restrictive lung disease or generally smaller airways and measuring total lung capacity would have been useful to provide a more objective assessment. A problem with identifying PRISm in childhood is that many children are not capable of exhaling their actual FVC during spirometry, which results in a shift of the FEV1/FVC ratio into the normal range. In our study, FVC was reduced in the majority of children with PRISm both pre- and post-BD. A low FVC has previously been associated with asthma severity [20] and peripheral airway obstruction [21], and despite the limitation mentioned above, it is possible that a number of patients in our study had peripheral obstruction. We found that 14% of children with PRISm had a positive BDR. A possible explanation for this finding is that the patients actually had airway obstruction with low FEV1, but this appeared as PRISm due to inability to fully expire the FVC. Taken together, our findings show that PRISm is a common spirometric phenotype in children with asthma, associated with BDRpos and thus worth recognising in the clinical assessment of these patients. Possible explanations of PRISm in this cohort include small lungs, peripheral airway obstruction or inability of the children to fully expire the FVC. The long-term prognosis for children with asthma and PRISm needs to be further explored in longitudinal studies.
Airway obstruction with normal FEV1 is a spirometric pattern that could be caused by airway dysanapsis [8]. The spectrum of dysanapsis ranges from individuals with large lung volumes (FVC>ULN) and normal airway calibre (normal FEV1) to those with borderline patterns, where FEV1 might be just above LLN and FVC just above a z-score of 0. We found that dysanapsis was at least as common as airway obstruction with low FEV1 in both pre-BD (9.9%) and post-BD (4%) spirometry. Further, only a minority of children with dysanapsis had FVC>ULN. We also found significant associations with overweight in both pre- and post-BD analyses, and an association with a positive BDR in pre-BD analysis only, which confirms results from previous studies [10, 12, 22]. The mechanism explaining association between dysanapsis and overweight might be related to the adipose tissue in obese patients, which has been shown to release proinflammatory substances and also regulate growth and development of lung structures [7]. Notably, 76% of the children with pre-BD dysanapsis had normal post-BD spirometry. To the best of our knowledge, this is a novel finding, suggesting that many of these children do not have true dysanapsis with disproportionate parenchyma/airway growth and that also these children will respond to BD treatment. The long-term impact of dysanapsis in children with asthma needs to be studied in longitudinal analyses, but previous studies have shown that a third of subjects with a dysanaptic obstructive lung function in childhood have the same pattern in adolescence [10].
The strengths of our study included the size of this paediatric specialist care cohort with pre- and post-BD lung function measurements. Previous studies have demonstrated the robustness, validity, and reliability of data extracted from the SNAR [23–27]. In Sweden spirometry is generally performed by specialised paediatric nurses, many of whom will have a national license for performing spirometry. The quality of the spirometry was assessed by clinic staff before the results were entered into the SNAR database. The study also had several limitations. The majority of children with asthma in Sweden are of European ancestry. While many receive treatment in primary care, our study focused on a selected group of patients in specialist care who underwent pre- and post-BD spirometry. These limitations suggest that our findings may not be generalisable to all children with asthma. Furthermore, we do not know whether the recordings in the SNAR originate from new referrals or follow-up visits and we do not have information regarding the children's adherence to prescribed medication.
In summary, data from this nationwide specialist care paediatric asthma cohort showed that PRISm and dysanapsis are common spirometric phenotypes in both pre- and post-BD analyses. Both PRISm and dysanapsis were associated with a positive BDR, and the majority of patients with pre-BD PRISm and dysanapsis had normal post-BD spirometry. This suggests that these children will respond to BD treatment. The results indicate that these common spirometric patterns, identified through careful evaluation of both FEV1 and FEV1/FVC, should be addressed in the management of childhood asthma. Furthermore, testing of BDR should be considered in children with PRISm and dysanapsis.
Footnotes
Provenance: Submitted article, peer reviewed.
Ethics statement: The current study complied with the Declaration of Helsinki and was approved by the Swedish Ethical Review Authority (2019-04915).
Note: Some of the results in this article were presented as a poster at the European Respiratory Society Congress in Vienna, Austria, in September 2024.
Author contributions: C. Stridsman and J.R. Konradsen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors contributed substantially to the study design, data analysis and interpretation, and the writing of the manuscript. J.R. Konradsen is responsible for all content of the manuscript.
Conflict of interest: C. Stridsman reports personal fees from AstraZeneca and GSK, and institutional fees from Chiesi and TEVA outside the submitted work. J.R. Konradsen reports advisory board fees from Novartis and ALK, and institutional fees from Regeneron Pharmaceuticals and Thermo Fisher Scientific outside the submitted work. A. Asarnoj reports lecture fees from Orion Pharma, Nestlé, Semper, ACO, Scandinavian Biopharma, Thermo Fisher Scientific and ALK, and advisory board fees from Novartis, Sanofi, Danone, and Nestlé, all outside the submitted work. L.E.G.W. Vanfleteren reports grants from AstraZeneca, and personal fees for lectures and/or advisory boards from AstraZeneca, GSK, Novartis, Boehringer, Pulmonx, Grifols and Chiesi. A. Lindberg reports personal fees and/or advisory board fees from AstraZeneca and GSK. H. Backman reports personal fees from AstraZeneca. A. Bossios reports institutional fees from Chiesi, GSK and AstraZeneca, and institutional grants from AstraZeneca outside the submitted work. H. Ljungberg holds minority stock and is a board member of Medituner AB, and is an expert group member (respiratory) of the Drug Therapeutic Committee and the Health and Medical Care Administration of the Region of Stockholm, Sweden.
Support statement: C. Stridsman is funded by the Swedish Heart–Lung Foundation (20230537 and 20230473), Region Norrbotten, and through a regional agreement between Umeå University and Region Västerbotten (ALF). J.R. Konradsen is supported by a scholarship from Region Stockholm, and by grants from the Freemason Child House Foundation, the Konsul Th.C. Bergh's Foundation, the Swedish Asthma and Allergy Association's Research Foundation, the Swedish Heart–Lung Foundation and the Pediatric Research Foudation of Astrid Lindgren Children's Hospital. A. Asarnoj is supported by the Swedish Asthma and Allergy Association's Research Foundation, Region Stockholm (clinical research appointment), and the Swedish Association for Allergology. L.E.G.W. Vanfleteren is supported by the Family Kamprad Foundation (20190024), the Swedish Heart–Lung Foundation (20200150), and a Swedish government and country council ALF grant (ALFGBG-824371). H. Backman is supported by grants from the Swedish Research Council for Health, Working Life and Welfare (FORTE, Dnr 2022-00381), the Swedish Research Council (Dnr 2019-00247), the Swedish Heart–Lung foundation, ALF and Region Norrbotten. H. Ljungberg is supported by an ALF grant from the Stockholm region. A. Bossios is supported by grants from the Swedish Heart–Lung Foundation (2022-0478). Funding information for this article has been deposited with the Open Funder Registry.
Supplementary material
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material
00023-2025.SUPPLEMENT
Data availability
The dataset is held and managed by Region Norrbotten, Luleå, Sweden. Relevant anonymised data are available on reasonable request following approval from the Swedish Ethical Review Authority.
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Associated Data
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Supplementary Materials
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material
00023-2025.SUPPLEMENT
Data Availability Statement
The dataset is held and managed by Region Norrbotten, Luleå, Sweden. Relevant anonymised data are available on reasonable request following approval from the Swedish Ethical Review Authority.