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\begin{document}

\title{MAXIMUM EXERCISE CAPACITY, LUNG FUNCTION AND BODY COMPOSITION IN
CHILDREN WITH CYSTIC FIBROSIS}



\author[1]{Gabriela Motter}%
\author[1]{Marjane Cardoso}%
\author[1]{Carolina Taffarel}%
\author[1]{Caroline Schmidt}%
\author[2]{Miriam Isabel Simon}%
\author[3]{Luiz Felipe Frohlich}%
\author[4]{Paulo José Marostica}%
\author[1]{Paula Maria  Rovedder}%
\affil[1]{Universidade Federal do Rio Grande do Sul}%
\affil[2]{Hospital de Clínicas de Porto Alegre}%
\affil[3]{UFRGS}%
\affil[4]{Universidade Federal do Rio Grande do Sul; Hospital de Clínicas de Porto Alegre}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Objective: To evaluate the oxygen uptake at peak exercise (VO2 peak) and
to correlate with lung volume and capacity and body composition of
children and adolescents with cystic fibrosis (CF). Methodology:
Cross-sectional study with CF patients treated at the pediatric
pulmonology outpatient clinic of a public hospital in Porto Alegre, aged
[?] 7 years up to 18 years. Study assessments included: cardiopulmonary
stress testing, plethysmography, and body composition assessment using
body bioimpedance. Results: Thirty patients were studied, with a mean
peak VO2 of 1.511 \selectlanguage{ngerman}± 0.539 liters in the population studied. Correlation
analysis showed a strong correlation between peak VO2 in liters and lean
mass (r = 0.77 and p \textless{}0.001), and strong and inverse
correlation with fat percentage (r = - 0.77 and p \textless{}0.001). ),
a strong correlation with forced vital capacity (FVC) in liters (r =
0.72 and p \textless{}0.001) and forced expiratory volume in the first
second (FEV1) also in liters (r = 0.69 and p \textless{}0.001). We
observed a strong correlation between load (W) and lean mass and during
CPET (r = 0.64 and p \textless{}0.001), and inversely with fat
percentage (r = -0.64 and p \textless{}0.001). This study showed that
patients with higher lean body composition have a better performance on
cardiopulmonary testing, contributing to greater exercise tolerance.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Introduction}

With advances in the treatment of cystic fibrosis (CF) and consequently
increased survival and quality of life of these patients, the level of
physical activity has been a predictor of morbidity and mortality in
this population\textsuperscript{1}.

Patients with CF often have progressive limitation to physical exercise
and reduced activities of daily living. The main causes of exercise
intolerance are associated with reduced ventilatory and reserve
capacity, loss of peripheral skeletal muscle mass and decreased
cardiovascular function. Limiting factors presented by CF patients
during exercise include fatigue, dyspnea, bronchospasm, ventilatory
limitation, and cardiac dysfunction \textsuperscript{2,3}.

Regular exercise is important for maintaining functional capacity and
pulmonary function in CF patients. Individuals who are more physically
active have an oxygen consumption (VO\textsubscript{2}) within normal
limits during the cardiopulmonary exercise stress test (CPET),
presenting better physical fitness, normal lung function and quality of
life \textsuperscript{4}.

Another contributing factor to better physical fitness and quality of
life is nutritional status. Studies show that good nutritional status is
related to adequate forced expiratory volume in one second
(FEV\textsubscript{1}) in fibrocystic patients, and those who gain
weight may have a concomitant increase in FEV\textsubscript{1} compared
to those who have lost weight and consequently decreased lung
function\textsuperscript{5,6}.

Recently, a systematic review and meta-analysis that included six cohort
studies, with a total of 551 subjects aged 10 to 30 years old, showed a
VO\textsubscript{2} peak below 82\% of predicted or a
VO\textsubscript{2} peak below 45 ml/kg/min is a predictor of mortality
in individuals with CF. Other factors such as FEV\textsubscript{1} and
body mass index (BMI) were also significant for longer survival in this
population \textsuperscript{7}. Hebestreit \emph{et al}
.\textsuperscript{8}, in their ten-year multicenter cohort demonstrated
that in addition to VO\textsubscript{2} peak, other findings on CPET
variables, a lower than predicted lung function, and a low BMI z-score
are predictors of mortality and indication for lung transplantation for
these patients. These studies demonstrate that the assessment of
VO\textsubscript{2} peak through CPET may be an indicator of disease
severity and prognosis beyond FEV\textsubscript{1}.

A study by Sovtic \emph{et al.} \textsuperscript{9} showed that static
hyperinflation assessed by plethysmography is associated with decreased
exercise capacity in children with CF, and that the residual
volume/total lung capacity ratio may be a predictor of hypoxemia and
desaturation during CPET. Alvarez \emph{et al.}
\textsuperscript{10}studied 32 CF patients in which they assessed fat
mass and fat free mass, demonstrating that excess adiposity was
inversely associated with lung function. There are few studies
correlating pulmonary function and evaluation of lung composition by
bioelectrical impedance with CPET in children with CF.

Therefore, the aim of this study was to evaluate oxygen consumption at
peak exercise and to correlate with lung volumes and capacities and body
composition of children and adolescents with CF.

\textbf{Materials and Methods}

The study design was cross-sectional. The study protocol was approved by
the Comit\selectlanguage{ngerman}ê de Ética e Pesquisa do Hospital de Clínicas de Porto Alegre
(HCPA) under number 150635. Free and informed consent was obtained for
each child or adolescent and their legal guardians.

Inclusion criteria for the study were diagnoses of CF, established
according to the European Consensus \textsuperscript{11} criteria, age 7
to 18 years old, clinically stable of respiratory disease in the last 30
days, (defined by the absence of hospitalization and absence of
modification in the maintenance regimen in this period). All patients
were followed by the Ambulatório de Pneumologia Infantil do HCPA. Those
patients and/or guardians who refused to participate in the study,
patients with motor impairment or neurological and cardiac diseases not
related to lung disease were excluded.

All patients underwent CPET, plethysmography and body composition
measurement through bioimpedance.

\textbf{Cardiopulmonary Stress Test}

The CPET was performed on a cycle ergometer following the guidelines
published by the American College of Cardiology/American Heart
Society\textsuperscript{12}. The protocol used was modified Godfrey,
with the load (W) ranging from 5W to 15W depending on the height of the
child or adolescent \textsuperscript{13}.

Ventilation measurements during exercise were performed using a flow
meter that records the gas exchange measurements at each respiratory
cycle. Oxygen consumption (VO\textsubscript{2}), carbon dioxide
production (VCO\textsubscript{2}), ventilatory equivalent of oxygen
(VE/VO\textsubscript{2}) and carbon dioxide (VE/VCO\textsubscript{2})
and respiratory quotient (RER) were recorded \textsuperscript{14}.

The subject was monitored by an electrocardiograph. The Borg scale was
presented to the patient in poster format and the patient manually
showed the subjective sensation of dyspnea and fatigue in the lower
limbs \textsuperscript{14}.

\textbf{Body Composition}

The bioimpedance test was performed with a Bodystat 1500® device. Two
electrodes were placed on the hand and foot unilaterally, with a distal
and a proximal electrode positioned on each limb.

Subjects remained fasting for 4 hours, abstaining from caffeine and
alcohol for 24 hours, and did not exercise during the 24 hours preceding
the exam. The following body composition variables were recorded: fat
percentage (\% G), lean mass percentage (\% MM) and water percentage (\%
water).

\textbf{Anthropometric Evaluation}

The anthropometric evaluation was performed using Filizola electronic
scale, with a maximum load of 150 kg. Height was measured using a Sanny\selectlanguage{english}-
anthropometer, fixed to the smooth wall and without footer, with movable
rod, graduated in centimeters and smaller division in millimeters. To
measure the weight and height data, the Z score and percentile were used
according to WHO reference values for the Weight/Age (W/A), Stature/Age
(S/A), Weight/Height (W/H) and body mass index for age
(BMI/A)\textsuperscript{15, 16}.

\textbf{Pulmonary Function Tests}

Spirometry

Spirometry was performed using a spirometer (MasterScreen, v4.31,
Jaeger, Wurzburg, Germany). Forced vital capacity (FVC) and forced
expiratory volume in one second (FEV\textsubscript{1}) were recorded.
All parameters were expressed as absolute values and as a percentage of
predicted for age, height and gender according to reference data from
the Brazilian Society of Pulmonology and Tisiology \textsuperscript{17}.
The Z-score for FVC and FEV\textsubscript{1} were calculated according
to the Global Lung Function Initiative reference
values\textsuperscript{18}.

Plethysmography

Plethysmography was conducted in the sitting position in a hermetically
sealed cabin with the subjects using nasal clips and holding their
cheeks with their hands. Then, they were asked to breathe normally,
followed by the commands of a specialist technician to perform the exam.
Total lung capacity (TLC), inspiratory capacity (IC), expiratory
residual volume (ERV), residual volume (RV) and effective resistance
(Reff) were recorded. All parameters were expressed as absolute values
and as a percentage of predicted for age, height and gender according to
the guidelines for pulmonary function tests \textsuperscript{19}.

\textbf{Clinical Score}

The clinical score of Shwachman and Kulczycki \textsuperscript{20} was
used for clinical evaluation of CF patients. This clinical assessment
system considers four different characteristics: general activity,
nutrition, physical examination and chest radiological findings. Each
one of them was scored on a scale of 5 to 25 points, and a final score
of 100 points represents the patient in the best possible clinical
condition \textsuperscript{20}. The clinical score of each patient was
scored by the specialist physician with experience in treating CF
patients.

\subsubsection*{Statistical Analysis}

{\label{statistical-analysis}}

Data were expressed as percentages or means (SD). Categorical variables
were compared using the chi-square test with adjusted standardized
residuals, followed by Yates' correction or Fisher's exact test when
appropriate.

The Kolmogorov-Smirnov test was used to assess the normality of the
data. Relationships between variables were determined using Pearson's
correlation and Spearman correlation. A linear regression analysis was
performed on the independent variables and were associated with the
outcomes of interest in ECPT for VO\textsubscript{2} peak. Data were
analyzed using SPSS software package, version 20.0. The level of
significance was set at p\selectlanguage{english} \textless{}\selectlanguage{english} 0.05. All statistical tests were
two-tailed.

We calculated the sample size using a correlation coefficient of r=0.5
between the VO\textsubscript{2} peak and fat mass index. An adequate
sample size in the present study was found to be at least 30 subjects \selectlanguage{english}[?]

Student's t test was used for comparison between groups with for data
analysis, patients were divided into two groups according to the
predicted percentage of peak VO\textsubscript{2}; patients with peak
VO\textsubscript{2} below 80\% of predicted and with peak
VO\textsubscript{2} above 80\% of predicted\textsuperscript{7}.

\textbf{Results}

Thirty CF patients were evaluated from March 2016 to June 2018. Table 1
presents patients general characteristics according to peak
VO\textsubscript{2} consumption. There was no significant difference
between the groups.

Table 2 presents the values of CPET variables in children and
adolescents with CF. Peak VO\textsubscript{2} presented an mean of 1.511
+- 0.539 liters, mean RER 1.07 +- 0.08 and maximum load at 103 +- 40.29
watts.

Correlation analysis showed a strong correlation between peak
VO\textsubscript{2} in liters and lean mass (r = 0.77 and p \textless{}
0.001), and a strong and inverse correlation with fat percentage (r = -
0.77 and p \textless{} 0.001), a strong correlation with FVC in liters
(r = 0.72 and p \textless{} 0.001) and FEV\textsubscript{1} also in
liters (r = 0.69 and p \textless{} 0.001). Correlating
VO\textsubscript{2} ml/kg/min, a moderate correlation was found with
lean mass (r = 0.40 and p = 0.031) and a moderate and inverse
correlation was found with fat percentage (r = - 0.40 and p = 0.031).
With the total lung capacity (TLC), we found a moderate and inverse
relationship (r = -0.41 and p = 0.030).

We observed a strong correlation between load (W) and lean mass during
CPET, (r=0.64 e p \textless{}0.001), and inversely with fat percentage
(r= -0.64 e p \textless{}0.001), these data suggest that those patients
who have reached high loads have better fitness and more lean mass, this
is due to good nutritional status and regular physical activity. This
study also found a strong correlation between lactate threshold and lean
mass (r = 0.67 and p \textless{}0.001) and a strong inverse correlation
with fat percentage (r = -0.67 and p \textless{}0.001), a moderate
correlation with FVC in liters (r = 0.53 and p = 0.002) and with
FEV\textsubscript{1} in liters (r = 0.50 and p = 0.004).

MV/MVV correlated moderately and inversely with inspiratory capacity
(CI) (r = -0.50 and p = 0.008) and lean mass (r = -0.45 and p = 0.015).
When comparing the relationship between CPET and pulmonary functions,
there were no statistically significant differences. Other correlations
between CPET, body composition and pulmonary function are described in
table 3.

Figure 1 shows the correlation between lean mass and fat with peak
VO\textsubscript{2} and lactate threshold. Figure 2 shows the
correlation between pulmonary function and peak VO\textsubscript{2}.

Table 4 presents the regression analysis of the variables that were
associated with peak VO\textsubscript{2}. We observed that lean mass and
fat independently associated with peak VO\textsubscript{2} (p
\textless{}0.05).

\textbf{Discussion}

The present study showed that children and adolescents with CF who had
higher peak VO\textsubscript{2} values had better body composition, with
higher lean mass index and lower body fat index. A recent study by
Charatsi \emph{et al} .\textsuperscript{21} evaluated 54 young adults
with CF, and showed that those individuals with lean mass depletion had
worse pulmonary function, corroborating our findings. Although without
statistical difference, those patients with lower lean mass index had a
lower lung mass index, more severe lung disease and consequently reduced
values of peak VO\textsubscript{2} on CPET.

Fifteen patients had peak VO\textsubscript{2} lower than 80\% of
predicted. Studies have shown that CF patients present a reduction in
peak VO\textsubscript{2}, mainly due to the lung disease progression,
impacting their quality of life. A study by Nixon \emph{et
al.}\textsuperscript{4} compared the survival of 109 CF patients over 8
years and divided them into 3 groups according to the physical fitness,
using the Godfrey cycle ergometer protocol. They observed that those
with the highest survival rate over 8 years were in the group with a
high level of physical fitness and a peak VO\textsubscript{2} above or
equal to 82\% of predicted.

Tomlinson \emph{et al.} \textsuperscript{22}, evaluated 72 children and
adolescents, the CF group had mild and moderate pulmonary disease and
the healthy group was matched for age and gender, in order to compare
the responses of oxygen uptake during CPET. This study demonstrated CPET
may be a predictor of prognosis for these patients, as lower
FEV\textsubscript{1} correlated strongly with lower peak
VO\textsubscript{2}. A cohort of CF patients investigated 28 subjects
with age of 10 to 13 years old and demonstrated a decrease in peak
VO\textsubscript{2} consumption proportionally to a fall in
FEV\textsubscript{1}, while those patients with normal
FEV\textsubscript{1} remained with stable peak
VO\textsubscript{2}\textsuperscript{23}. This shows that patients with
pulmonary function loss have decreased VO\textsubscript{2} consumption.
The present study showed CF patients with normal pulmonary function had
sufficient ventilatory reserve to achieve a maximum CPET, without
physical effort limitation. These findings coincide with the study by
Dodd \emph{et al} .\textsuperscript{24} ,who showed that CF patients
with mild obstructive disorder were able to perform complete CPET,
reaching the maximum effort level. No significant correlations were
found between CPET and spirometry data.

The current study found mean peak VO\textsubscript{2} values of 1.51
L/min, close to a recent study that showed a peak VO\textsubscript{2} of
1.74 L/min in CF children, with a mean age of 13 years
old\textsuperscript{22}. In our study, we observed that half of children
and adolescents with CF had peak VO\textsubscript{2} values above 80\%
of predicted. Weir \emph{et al} .\textsuperscript{25} found a peak
VO\textsubscript{2} of 1.6 L/min, but they observed that those
individuals who lost body weight had a peak VO\textsubscript{2} decline
of approximately 3.8 mL/kg/min after 18 months.

This study showed that lean mass and fat were independently associated
with peak VO\textsubscript{2}, being the best predictor of peak
VO\textsubscript{2} in children and adolescents with CF. Higher lean
mass values predict higher peak VO\textsubscript{2} consumption values,
while higher fat values are associated with lower oxygen consumption
values in these patients.

Charasti \emph{et al} . \textsuperscript{21} validated an equation for
the use of bioimpedance in children and adolescents with CF using DXA as
a reference for the equation. The study included 54 CF individuals with
a median of 12 years old, and they observed that the use of bioimpedance
associated with the equation is reliable for body composition
assessment. They also observed that those individuals with greater lean
mass depletion were older and had worse lung function.

Some limitations were observed in the present study. No control group to
compare plethysmography, body composition and VO\textsubscript{2} peak
values. We do not use the gold standard to assess body composition, a
recent study suggests that bioimpedance may underestimate lean mass and
fat-free mass in CF patients and presents DXA as a better predictor for
body composition assessment, however biompedance is a valid and of good
reproducibility instrument for research and clinical practice
use\textsuperscript{26}.

In our study, we observed that half of children and adolescents with CF
had peak VO\textsubscript{2} values above 80\% of predicted. This study
showed that patients with higher percentage of lean mass and lower
percentage of fat had higher oxygen consumption, contributing to greater
exercise tolerance. The patients' nutritional status proved to be the
best predictor of exercise capacity.

\textbf{Acknowledgements:} Not applicable

\textbf{Conflict of Interest:} None.

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\end{enumerate}

\textbf{Hosted file}

\verb`Table I.doc`  available at \url{https://authorea.com/users/341931/articles/468805-maximum-exercise-capacity-lung-function-and-body-composition-in-children-with-cystic-fibrosis}

\textbf{Hosted file}

\verb`Table II.doc`  available at \url{https://authorea.com/users/341931/articles/468805-maximum-exercise-capacity-lung-function-and-body-composition-in-children-with-cystic-fibrosis}

\textbf{Hosted file}

\verb`Table III.doc`  available at \url{https://authorea.com/users/341931/articles/468805-maximum-exercise-capacity-lung-function-and-body-composition-in-children-with-cystic-fibrosis}

\textbf{Hosted file}

\verb`Table IV.docx`  available at \url{https://authorea.com/users/341931/articles/468805-maximum-exercise-capacity-lung-function-and-body-composition-in-children-with-cystic-fibrosis}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

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\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
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\selectlanguage{english}
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