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\begin{document}

\title{Relationship between FEV \textsubscript{1}/FVC and age in children with
asthma}



\author[1]{Ahmed A}%
\author[1]{Brown A}%
\author[1]{Pollack Y}%
\author[2]{Vazhappilly J}%
\author[2]{Perry C}%
\author[2]{Thomas E}%
\author[1]{Krishnan S}%
\author[1]{Dozor AJ}%
\affil[1]{Boston Children's Health Physicians}%
\affil[2]{New York Medical College}%


\vspace{-1em}



  
  \date{June 18, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
FEV \textsubscript{1}/FVC normally decreases through childhood,
increases briefly during early adolescence, and then declines throughout
life. The physiology behind this temporary increase during early
adolescence is not well understood. The objective of this study was to
determine if this pattern also occurs in children with asthma.
\textbf{Design:} Single-center, cross-sectional, retrospective analysis
of pulmonary function tests (PFTs) obtained over a 5-year period in
children 5 to 18 years of age with persistent asthma. \textbf{Results:}
1,793 patients satisfied all inclusion and exclusion criteria. Mean age
(\selectlanguage{ngerman}± SD) was 10.4 ± 3.8 years. 48\% were female. Mean FEV
\textsubscript{1} /FVC was 0.83 ± .09. FEV \textsubscript{1} /FVC in
children with persistent asthma declined from age 5 to age 11 by 5.7 \%
compared to 7.3\% in healthy girls, and 5.8\% compared to 9.4\% in
healthy boys. FEV \textsubscript{1}/FVC increased by 1.2\% until age 16
in children with asthma, compared to 2.2\% in healthy girls, and 2.5\%
compared to 2.3\% in healthy boys. The ratio was lower in obese children
with asthma at all ages but demonstrated the same curvilinear shape as
in healthy children. In absolute terms, FEV \textsubscript{1} grew
proportionately more than FVC during early adolescence, so the ratio of
FEV \textsubscript{1}/FVC increased during that period. The curvilinear
shape of the curve remained in postbronchodilator testing, though
significantly blunted. \textbf{Conclusions}: The ``Shepherd's Hook''
pattern in the FEV \textsubscript{1}/FVC curve is preserved in children
with persistent asthma. This was also true in obese patients with
asthma, although their FEV \textsubscript{1}/FVC ratios were lower
throughout all stages of childhood and adolescence.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Introduction}

The Global Lung Function Initiative (GLI), an international
collaboration with the goal of developing universal reference equations
for children and adults11\textbf{References}Cooper BG, Stocks J, Hall
GL, Culver B, Steenbruggen I, Carter KW, Thompson BR, Graham BL, Miller
MR, Ruppel G, Henderson J, Vaz Fragoso CA, Stanojevic S. The Global Lung
Function Initiative (GLI) Network: bringing the world's respiratory
reference values together. Breathe (Sheff). 2017 Sep;13(3): e56-e64.,
published reference equations for spirometry in 201222Quanjer PH,
Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright PL, Hankinson
JL, Ip MS, Zheng J, Stocks J; ERS Global Lung Function Initiative.
Multi-ethnic reference values for spirometry for the 3-95-yr age range:
the global lung function 2012 equations. Eur Respir J. 2012
Dec;40(6):1324-43.. These reference equations, obtained from healthy
children, may potentially add to a better understanding of lung growth.
A careful analysis of changes in the forced expiratory volume in the
first second of the maneuver (FEV\textsubscript{1}) as a proportion of
the forced vital capacity (FVC), or the FEV\textsubscript{1}/FVC ratio,
with age through childhood and adolescence demonstrated a remarkable
shape to the curve33Quanjer PH, Stanojevic S, Stocks J, Hall GL, Prasad
KV, Cole TJ, Rosenthal M, Perez-Padilla R, Hankinson JL, Falaschetti E,
Golshan M, Brunekreef B, Al-Rawas O, K\selectlanguage{ngerman}ühr J, Trabelsi Y, Ip MS; Global
Lungs Initiative. Changes in the FEV\selectlanguage{english}1/FVC ratio during childhood and
adolescence: an intercontinental study. Eur Respir J. 2010
Dec;36(6):1391-9.. Figure 1a demonstrates that the mean ratio of
FEV\textsubscript{1}/FVC rapidly decreases through childhood in healthy
children, at least up to about 10-12 years of age, followed by a small
increase during early adolescence, before resuming an inexorable
downhill decrease throughout life44Quanjer PH, Stocks J, Polgar G, Wise
M, Karlberg J, Borsboom G. Compilation of reference values for lung
function measurements in children. Eur Respir J Suppl. 1989 Mar;
4:184S-261S.. It is generally accepted that FEV\textsubscript{1}/FVC
decreases from childhood to old age55Quanjer PH, Stocks J, Polgar G,
Wise M, Karlberg J, Borsboom G. Compilation of reference values for lung
function measurements in children. Eur Respir J Suppl. 1989
Mar;4:184S-261S.,falling with both age and height66Stanojevic S, Wade A,
Cole TJ, Lum S, Custovic A, Silverman M, Hall GL, Welsh L, Kirkby J,
Nystad W, Badier M, Davis S, Turner S, Piccioni P, Vilozni D, Eigen H,
Vlachos-Mayer H, Zheng J, Tomalak W, Jones M, Hankinson JL, Stocks J;
Asthma UK Spirometry Collaborative Group. Spirometry centile charts for
young Caucasian children: the Asthma UK Collaborative Initiative. Am J
Respir Crit Care Med. 2009 Sep 15;180(6):547-52.. The reasons for this
``Shepherd's Hook'' appearance in early adolescence are not well
understood. One suggestion is that this age-dependent increase in the
ratio may be due to well-recognized changes in thoracic configuration,
and as a result, decreased chest-wall compliance in adolescents77Merkus
PJ, ten Have-Opbroek AA, Quanjer PH. Human lung growth: a review.
Pediatr Pulmonol. 1996 Jun;21(6):383-97.\textsuperscript{,viii,ix,x} ,
particularly during the adolescent growth spurt and puberty88Schrader
PC, Quanjer PH, van Zomeren BC, Wise ME. Changes in the FEV1-height
relationship during pubertal growth. Bull Eur Physiopathol Respir. 1984
Jul-Aug;20(4):381-8.. This might result in slower growth in measured
vital capacity relative to FEV\textsubscript{1}99Degroodt EG, Quanjer
PH, Wise ME, et al. Changing relationships between stature and lung
volumes during puberty. Respir Physiol 1986; 65:
139-153.\textsuperscript{,}1010Smeets M, Brunekreef B, Dijkstra L,
Houthuijs D. Lung growth of pre-adolescent children. Eur Respir J. 1990
Jan;3(1):91-6.\textsubscript{.}

The primary objective of this study was to analyze the relationship
between FEV\textsubscript{1}/FVC and age in children and adolescents
with asthma. The cross-sectional area of the airways may not increase
relative to alveolar volume in adolescents with asthma, as much as in
healthy adolescents. If so, this might result in a reduced
FEV\textsubscript{1}/FVC ratio. If individuals with asthma do not have
this temporary adolescent growth spurt in FEV\textsubscript{1}/FVC ratio
noted in healthy adolescents, the trajectory of FEV\textsubscript{1}/FVC
throughout adulthood might remain permanently lower. Secondary
objectives were to assess the role of gender, obesity, and measurements
of lung volumes on the relationship between age and
FEV\textsubscript{1}/FVC.

\textbf{Methods}

This study was exempt from IRB review by the New York Medical College
Institutional Review Board under federal guidelines 45CFR46.104, section
4ii, as the data was de-identified, and the investigators did not
contact or re-identify the subjects. A retrospective data extraction of
all children with a diagnosis of asthma who underwent complete pulmonary
function tests (PFTs) over a 5-year period (January 2014 to January
2019) from the Pediatric Pulmonary Function Laboratory at Maria Fareri
Children's Hospital at Westchester Medical Center was performed, and
subsequently, a review of individual clinical records was conducted.
Patients were selected if they met the following inclusion criteria: age
5 and older, physician-defined persistent asthma, documented ongoing
symptoms within the past year, and on treatment with an asthma
controller. Patients were excluded if they had any diagnoses other than
asthma that might affect pulmonary function; or had acute symptoms at
the time of the PFTs. After deidentification, demographic data and all
pulmonary function data, before and after inhaled albuterol, were
extracted from the most recent pulmonary function test performed by each
patient. FEV\textsubscript{1} and FVC, expressed as \% of predicted
values, were recalculated with the 2022 GLI global reference
equations11Bowerman C, Bhakta NR, Brazzale D, Cooper BR, Cooper J,
Gochicoa-Rangel L, Haynes J, Kaminsky DA, Lan LTT, Masekela R, McCormack
MC, Steenbruggen I, Stanojevic S. A Race-neutral Approach to the
Interpretation of Lung Function Measurements. Am J Respir Crit Care Med.
2023 Mar 15;207(6):768-774.. Lung volumes and specific airway
conductance (sGaw) were estimated with whole body
plethysmography22Dubois AB, Botelho SY, Comroe JH Jr. A new method for
measuring airway resistance in man using a body plethysmograph: values
in normal subjects and in patients with respiratory disease. J Clin
Invest. 1956 Mar;35(3):327-35.. Total Lung Capacity (TLC) and Residual
Volume (RV) are expressed as \% of predicted as determined by standard
reference equations33Zapletal A, Chalupov\selectlanguage{ngerman}á J, Kucera J. Lung volumes in
healthy children and adolescents: methods, reference values. Monaldi
Arch Chest Dis. 1995 Feb;50(1):6-18.\textsuperscript{,}44Zapletal
A,~\selectlanguage{polish}Š\selectlanguage{english}am\selectlanguage{ngerman}ánek M,~Paul T. Lung Function in Children and Adolescents.
Methods, reference values. Progress in Respiratory Research, Vol.
22,~Basel: Karger,~1987.\textsuperscript{,}55Stocks J, Quanjer PH.
Reference values for residual volume, functional residual capacity and
total lung capacity. ATS Workshop on Lung Volume Measurements. Official
Statement of The European Respiratory Society. Eur Respir J. 1995
Mar;8(3):492-506..

\textbf{Statistical Methods}

Means and standard deviations (SD) are reported for the entire cohort
and stratified by gender. Proportions were compared using chi-square
tests and unpaired t-tests were used to compare means between groups.
Obese patients (BMI \emph{\textgreater{}}
95\textsuperscript{th}percentile for age) were compared to patients with
normal BMI (5\textsuperscript{th} to \textless{}
85\textsuperscript{th}percentile). Pulmonary function tests were graphed
against age, in years. Percent changes in the ratio of
FEV\textsubscript{1}/FVC were compared for differences between children
with asthma and healthy children as previously reported, as well as
between obese children and children with a BMI within the normal range.
Two-sided p values were considered statistically significant.
Statistical analyses were performed using STATA 15.0 (Statacorp LLC, TX,
USA).

\textbf{Results}

3,854 children completed pulmonary function tests during the 5-year
period, of which 1,793 met all inclusion and exclusion criteria (Fig 2).
Lung volumes and specific airway conductance obtained via
plethysmography were obtained in 1,790 patients. Patient characteristics
and pulmonary function tests are in Table 1. The cohort included a
higher proportion of boys, who were on average, slightly younger than
girls, and more likely to be obese. There were no significant gender
differences by ancestry. Children with asthma had lower pulmonary
function on average than healthy children at all ages. Mean
FEV\textsubscript{1}, \% predicted, for children with asthma was
94.8\emph{+} 16.5 prebronchodilator and 99.7 \emph{+} 16.9
postbronchodilator (p \textless{} 0.001). Mean FEV\textsubscript{1}/FVC
was .83 \emph{+} .09 prebronchodilator and .87 \emph{+} .08
postbronchodilator (p \textless{} 0.001). Patients had, on average, low
specific conductance, which was reversed with an inhaled bronchodilator.
Specific conductance remained remarkably steady throughout the age range
of this study. TLC was within the normal range, but RV was on average,
higher than the normal reference range and RV/TLC ratio mildly elevated
(Table 1). FEV\textsubscript{1}/FVC at age 16 in male children with
asthma was 5.6\% lower than healthy children, 5.4 \% lower in females
(Table 2). Postbronchodilator FEV\textsubscript{1}/FVC in 16-year-old
male children with asthma was 1.1\% lower than healthy children and
3.3\% lower in females. Female patients had a higher
FEV\textsubscript{1}/FVC ratio than males at all ages.

Figure 1b demonstrates that the curvilinear shape to the relationship
between FEV\textsubscript{1}/FVC and age was preserved in children with
asthma. Similar to healthy children, FEV\textsubscript{1}/FVC decreased
from age 5 to around age 11, increased until about the age of 13, and
remained stable or even increased until the age of 18.
Post-bronchodilator, these trajectories remained, though blunted.

Table 2 demonstrates that the decrease from age 5 to age 11 in
FEV\textsubscript{1}/FVC in children with asthma was proportionately
less than reported in healthy children in the GLI cohort, -5.8\%
compared to about -9.4\% in boys, and -5.7\% compared to -7.3\% in
girls. This difference from healthy children was even more striking
postbronchodilator, with a - 4.1\% decrease from age 5 to 11 in boys
with asthma and -2.1\% decrease in girls with asthma.

The increase in FEV\textsubscript{1}/FVC from age 11 to age 16 was
similar in children with asthma as compared to healthy children.
FEV\textsubscript{1}/FVC increased 2.5\% in boys with asthma from age 11
to age 16, compared to 2.3\% in healthy boys; and 1.2\% in girls with
asthma, as compared to 2.2\% in healthy girls. Postbronchodilator, the
increase in the ratio in children with asthma was 2.6\% in boys and
1.0\% in girls. At age 16, FEV\textsubscript{1}/FVC was 7.3\% less than
at age 5 in boys with asthma compared to 5.2\% less in healthy boys, and
4.5\% less than at age 5 in girls with asthma compared to 5.2\% less in
healthy girls. Obese children with asthma had, on average, an 8.1\%
decrease in the FEV1/FVC ratio between ages 5 and 11, as compared to
+1.1\% in children with a BMI within the normal range.

Figure 3 demonstrates that the curvilinear shape to the graph appears
similar regardless of gender. In this cross-sectional cohort of children
with asthma, there do not appear to be gender differences in the age of
onset of the increase in FEV\textsubscript{1}/FVC ratio that were
reported for healthy children.

FEV\textsubscript{1}/FVC of obese patients was lower as compared to
patients with BMIs in the normal range, .80 \emph{+} .09 versus
.84\emph{+} .09, p\textless{} 0.0001, prebronchodilator; and .85
\emph{+}.08 compared to .88 \emph{+} .08. p \textless{} 0.0001,
postbronchodilator. Children with asthma that were obese maintained a
curvilinear shape to the relationship between FEV\textsubscript{1}/FVC
and age but differed from patients with a normal BMI. (Figure 4). At 16
years of age, their mean FEV\textsubscript{1}/FVC was .79 compared to
.86 in children with a BMI in the normal range, p\textless{} 0.0001.

In absolute terms, FVC increased proportionally more than TLC between
age 5 and age 11, 101.5\% compared to 88.9\%, which resulted in a
decrease in mean RV/TLC ratio from .34 to .29. Between age 11 and age
16, FVC and TLC increased similarly, 45.1\% compared to 43.8\%, so mean
RV/TLC ratio in 16-year-old children with asthma was .28. The growth in
FEV\textsubscript{1} was quite similar to TLC, increasing 90.3\% between
ages 5 and 11, and 49.3\% from 11 to 16. From age 11 to age 16,
FEV\textsubscript{1} grew, on average, by 49.3\%, compared to a 45.0\%
increase in FVC, consistent with an increase in the ratio of the two
during early adolescence.

\textbf{Discussion}

The primary finding of this study is that the ratio of
FEV\textsubscript{1}/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 11\textsuperscript{3}, 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 FEV\textsubscript{1}/FVC. Just as reported by Quanjer PH, et
al\textsuperscript{3} in healthy children, FVC increased proportionally
more than TLC and FEV\textsubscript{1} 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
FEV\textsubscript{1} and FVC is consistent with the ratio increasing,
not decreasing as it does throughout life.

The overall decrease in FEV\textsubscript{1}/FVC in children with
asthma, from age 5 to age 11, was proportionally less than reported in
the GLI global reference results for healthy
children\textsuperscript{3}. 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 FEV\textsubscript{1}/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
FEV\textsubscript{1}/FVC ratio was not shifted to an earlier age in
girls compared to boys, as reported by Quanjer PH et
al\textsuperscript{3}. There was a gender difference when comparing
5-year-old to 16-year-old children with asthma. FEV\textsubscript{1}/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
FEV\textsubscript{1}/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 FEV\textsubscript{1}/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.\textsuperscript{,}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.\textsuperscript{,}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 FEV\textsubscript{1}/FVC ratio
dropped more steeply from age 5 to 11 and did not recover very much from
age 11 to age 16. A lower FEV\textsubscript{1}/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 FEV\textsubscript{1}/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 FEV\textsubscript{1} 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 al\textsuperscript{3}, which merit
confirmation with prospective studies.

\textbf{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.\selectlanguage{english}
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