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.