Discussion
The primary finding of this study is that the ratio of FEV1/FVC in children with persistent asthma appears to follow the same curvilinear curve through childhood as reported in healthy children. The ratio steadily decreased from age 5 to around age 11, then increased briefly during early adolescence before settling out and remaining fairly steady until age 18. This is true both before and after an inhaled bronchodilator, though the curve is somewhat blunted postbronchodilator. Not surprisingly, the ratio remains lower in children with asthma in all ages than healthy children, consistent with their overall pulmonary function. Sitting height/standing height ratio decreases from age 5 to 113, which suggests that during this period, leg length is growing faster than chest cavity height or size. Then, the ratio decreases from age 11 to 16, which suggests that the chest cavity, i.e., TLC, grows more rapidly than legs. If this is true, then both FVC and TLC should have the same curvilinear shape as FEV1/FVC. Just as reported by Quanjer PH, et al3 in healthy children, FVC increased proportionally more than TLC and FEV1 in this cohort of children with asthma from age 5 to 11, then proportionally less from age 11 to 16. The difference in relative growth during early adolescence in FEV1 and FVC is consistent with the ratio increasing, not decreasing as it does throughout life.
The overall decrease in FEV1/FVC in children with asthma, from age 5 to age 11, was proportionally less than reported in the GLI global reference results for healthy children3. This was true for both boys and girls. However, the ratio was already significantly lower than normal by 5 years of age. Children with asthma demonstrated a similar proportional increase in FEV1/FVC to healthy children during their adolescent growth spurt. One contributing factor to the decrease in the ratio during early childhood may be the number and size of alveoli may continue to increase, which is likely to lead to a faster increase in lung volume than in airway caliber11Ochs M, Nyengaard JR, Jung A, Knudsen L, Voigt M, Wahlers T, Richter J, Gundersen HJ. The number of alveoli in the human lung. Am J Respir Crit Care Med. 2004 Jan 1;169(1):120-4..
Girls had overall slightly better pulmonary function than boys, consistent with previous studies22Hibbert M, Lannigan A, Raven J, Landau L, Phelan P. Gender differences in lung growth. Pediatr Pulmonol. 1995 Feb;19(2):129-34.. The early adolescent increase in FEV1/FVC ratio was not shifted to an earlier age in girls compared to boys, as reported by Quanjer PH et al3. There was a gender difference when comparing 5-year-old to 16-year-old children with asthma. FEV1/FVC was 7.3% lower in 16-year-old boys compared to 5-year-old boys. The ratio was higher in 5-year-old girls with asthma than boys and was only 4.5% lower at age 16.
The relationship between age and postbronchodilator FEV1/FVC as seen in figures 1 and 3 are intriguing. The curvilinear shape persists but the decrease from age 5 to 11 is less than that reported for healthy children, so that the curve is almost flat. It could be very interesting to repeat this analysis in healthy children before and after an inhaled bronchodilator.
Children with asthma who were obese demonstrated the most significant differences in the relationship between FEV1/FVC and age. There was an overall change in the ratio from age 5 to age 16 in obese children with asthma of -8.1%, compared to +1.1% in children with asthma with normal weight. Studies on the effects of obesity on pulmonary function in children have reported conflicting results33Huang L, Wang ST, Kuo HP, Delclaux C, Jensen ME, Wood LG, Costa D, Nowakowski D, Wronka I, Oliveira PD, Chen YC, Chen YC, Lee YL. Effects of obesity on pulmonary function considering the transition from obstructive to restrictive pattern from childhood to young adulthood. Obes Rev. 2021 Dec;22(12): e13327.,44Forno E, Han YY, Mullen J, Celedón JC. Overweight, Obesity, and Lung Function in Children and Adults-A Meta-analysis. J Allergy Clin Immunol Pract. 2018 Mar-Apr;6(2):570-581.e10.,55Tantisira KG, Litonjua AA, Weiss ST, Fuhlbrigge AL; Childhood Asthma Management Program Research Group. Association of body mass with pulmonary function in the Childhood Asthma Management Program (CAMP). Thorax. 2003 Dec;58(12):1036-41.. In this cohort of patients with obesity and persistent asthma, obese patients had poorer lung function. Their FEV1/FVC ratio dropped more steeply from age 5 to 11 and did not recover very much from age 11 to age 16. A lower FEV1/FVC in children with obesity and asthma has been shown to be associated with increased hospitalizations and oral steroid bursts66Starr S, Wysocki M, DeLeon JD, Silverstein G, Arcoleo K, Rastogi D, Feldman JM. Obesity-related pediatric asthma: relationships between pulmonary function and clinical outcomes. J Asthma. 2023 Jul;60(7):1418-1427..
Similar to healthy children, TLC, expressed as a % of predicted value, declined very gradually from age 5 to 11 then slowly increased. RV/TLC was higher at all ages than as reported in healthy children, slowly decreased from age 5 to age 11, and then remained relatively stable through adolescence. Whereas in a longitudinal study in healthy children, the RV/TLC ratio gradually increased through adolescence77Merkus PJ, Borsboom GJ, Van Pelt W, Schrader PC, Van Houwelingen HC, Kerrebijn KF, Quanjer PH. Growth of airways and air spaces in teenagers is related to sex but not to symptoms. J Appl Physiol 1985. 1993 Nov;75(5):2045-53..
We chose to compare our cohort of children with persistent asthma to the recently published GLI global reference values, which have been race-corrected88Kanj AN, Scanlon PD, Yadav H, Smith WT, Herzog TL, Bungum A, Poliszuk D, Fick E, Lee AS, Niven AS. Application of GLI Global Spirometry Reference Equations Across a Large, Multicenter Pulmonary Function Lab Population. Am J Respir Crit Care Med. 2023 Jul 31., or sometimes referred to as race-neutral99 Baugh A, Adegunsoye A, Connolly M, Croft D, Pew K, McCormack MC, Georas SN. Towards a Race-Neutral System of Pulmonary Function Test Results Interpretation. Chest. 2023 Jun 17: S0012-3692(23).. One reason this decision was made was that 38% of our patients either declined to indicate race/ethnicity or chose to identify as “other”.
There are many limitations to this study. We do not have our own healthy control patients who performed their pulmonary function tests in the same laboratory with the same technicians. Our data is cross-sectional not longitudinal data. This is also true of the healthy children reference values. In healthy children, the ratio appears to begin to decline in late adolescence, while in our data, the ratio remains stable until 18 years of age. We only enrolled subjects up to their nineteenth birthday, so we have no information about what happens to the ratio after that age. Children with asthma who were obese had decreased ratios compared to children with normal BMIs, but we do not have measurements on children with just obesity and not asthma.
The major strengths of this study are the large sample size; and that we were able to examine the clinical charts of each patient and carefully characterize and enroll subjects who had persistent asthma but without acute symptoms. We limited our study to patients who meet criteria for persistent asthma, so this may not be generalizable for patients with milder disease.
In summary, in this cross-sectional retrospective study, children with persistent asthma had increased obstruction compared to healthy children, but they demonstrated a similar “Shepherd’s Hook” shape to the curve of FEV1/FVC compared to age, increasing in early adolescence. While the ratio was lower in obese patients with asthma, the curvilinear shape of this curve in early adolescence was preserved. Similar to what was seen in healthy children, FVC grew proportionally more than TLC and FEV1 from age 5 to 11, and proportionally more from age 11 to 16. There are subtle differences of unknown clinical or physiological significance between this cohort of children with persistent asthma and the data obtained on healthy children by Quanjer PH et al3, which merit confirmation with prospective studies.
Acknowledgements: The authors acknowledge the important role of Zachary Messer, MPH, Division Research and Regulatory manager. This study was funded by intramural funds of the Division of Pediatric Pulmonology, Allergy, Immunology, and Sleep Medicine of Boston Children’s Health Physicians.