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\begin{document}

\title{FUNCTIONAL CAPACITY and quality of life IN CHILDREN AND ADOLESCENTS WITH
SICkLE CELL ANEMIA}



\author[1]{Jonathan Luiz da Silva}%
\author[2]{Bruno Alvarenga Soares}%
\author[1]{Jaksoel Silva}%
\author[3]{Patrícia Belintani Blum}%
\author[1]{Mariana Mazzuca Reimberg}%
\author[1]{Simone Dal Corso}%
\author[1]{Fernanda Lanza}%
\affil[1]{Universidade Nove de Julho - Campus Vergueiro}%
\affil[2]{Universidade Federal de Minas Gerais}%
\affil[3]{Darcy Vargas Children's Hospital – São Paulo – SP – Brazil}%


\vspace{-1em}



  
  \date{May 15, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Objective}: To evaluate the functional capacity, pulmonary
function and quality of life of children and adolescents with sickle
cell anemia (SCA) and to test the reproducibility of functional capacity
tests in this population. \textbf{Method}: Cross-sectional study with
~volunteers with SCA genotype Hb-SS (SCAG), aged 6 to 18 years matched
in age and ~gender to the control group (CG). Spirometry, 5-repetition
sit-to-stand test (5STS-test), ~modified shuttle walk test (MSWT), and
Pediatric Quality of Life Questionnaire (PedsQL) were performed. The
reproducibility of 5STS-test and MSWT was evaluated: ~ \textbf{Results}:
48 volunteers of SCAG and 48 of CG were evaluated. Pulmonary function of
SCAG (FVC: 92 \selectlanguage{ngerman}± 15\% pred.; FEV 1 /FVC: 84 ± 8\% pred.) was worse than
the CG (104 ± 15\% pred.; FEV 1 /FVC: 90 ± 6\% pred.) p \textless{}
0.05. SCAG had worse functional capacity registered by distance walked:
576m (515-672m) and 5STS-test: 8 seconds (7.4-8.9seconds) compared to
the CG who showed distance walked: 1010m (887- 1219m) and 5STS-test: 7
seconds (7.0-8.1seconds), p \textless{} 0.001. SCAG had worse quality
compared to CG, p \textless{} 0.05. The reproducibility was good of MSWT
(ICC 0.99 (0.98-0.99 IC-95\%)) and 5STS-test (ICC 0.80 (0.69 -- 0.88), p
\textless{} 0.001 \textbf{. Conclusion}: Children and adolescents with
sickle cell anemia showed worse capacity to walk or run, and to perform
sit-to-stand test. Additionally, they have poor quality of life when
compared with their control peers. The MSWT and 5STS-test showed
reproducible to be applied in pediatric individual with SCA.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Introduction}

Sickle cell anemia (SCA) is the most common monogenic disease in the
world, predominant among people of African descent and brown skin. It is
characterized by the occurrence of sickle cells due to the mutant
presence of hemoglobin S (HbS).\textsuperscript{1} The altered
erythrocytes present difficulty in circulating in the blood, which
causes vaso-occlusive phenomena and infarction in the affected area. In
addition, this altered physiology causes permanent damage to tissues and
organs, with the cardiorespiratory system being the target of acute and
chronic manifestations.\textsuperscript{2} Thus, lung function and
cardiovascular impairments changes favor a sedentary lifestyle, reduced
functional capacity and worsening quality of life
(QOL).\textsuperscript{3,5,6} Different tests that assess functional
capacity are available. Hostyn\textsuperscript{4} et al. (2013), showed
higher number of hospitalizations in children and adolescents with SCA
(genotype Hb-S\selectlanguage{greek}β\selectlanguage{english}\textsuperscript{0}--thalassemia) who walked shorten
distance at the 6-minute walk test (6MWT). This test has been widely
used, however there are some limitations as self-paced test, floor
effect. Thus, the Modified Shuttle Walk Test (MSWT) in patients with SCA
can be an alternative, considering it has already been described in
children and adolescents' other chronic conditions.\textsuperscript{7
-10}

The MST is simple and low cost, needs corridor of 10 meters (m), limited
by symptoms, externally paced, and allows the volunteer walk or
run.\textsuperscript{4} This test is appropriated to assess exercise
intolerance in individuals with different severity status. Additionally,
the MSWT can be used to exercise prescription. \textsuperscript{11} The
sit and stand movement are considered fundamental for mobility and
functional independence. This movement is part of several activities of
daily living (ADL) and the literature has already described the
5-repetition sit-to-stand test (5STS-test) as a simple and low coast
test to measure lower limb strength, balance control, risk of falling
and exercise capacity.\textsuperscript{13} Thus, the 5STS-test is
another alternative to assess different aspects of functional capacity
compared to MSWT. This study aims to evaluate and compare the functional
capacity, pulmonary function and quality of life of children and
adolescents with SCA with their healthy peers and to analyze the
reproducibility of the functional capacity tests on the sickle cell
anemia group. The hypotheses are that SCA individuals have reduced
exercise capacity, lung function and quality of life.

\textbf{Methods}

This is a cross-sectional study carried out in individuals diagnosed
with SCA genotypes (HbS-S) between 6 and 18 years old, from the
Pediatric Hematology Outpatient Clinic of Darcy Vargas Children
Hospital, Sao Paulo, Brazil. The control group (CG) was composed by
healthy individuals matched for age and sex, recruited from educational
institutions in the city of Sao Paulo, Brazil. The research was approved
by the Research Ethics Committee (Protocol number: 2.843.860). The
informed consent form for the study was signed by the legal guardians.
All participants signed the consent form and the parents or guardians
signed the informed consent form.

Individuals who had neurological or musculoskeletal diseases or did not
perform the tests properly were excluded, also those who were
hospitalized in the last four weeks. Individuals in the control group
who presented lung function \textless{} 80\% of the predicted value were
also excluded.

\textbf{Protocol}

All evaluations were carried out in a single day. The sickle cell anemia
group (SCAG) was evaluated in the Pediatric Hematology Outpatient Clinic
of Darcy Vargas Children Hospital, Sao Paulo, Brazil, while the CG was
evaluated in public or private schools. Data was performed between
October 2018 and July 2019. The present comorbidities and medications in
use in the SCAG were obtained from medical records and confirmed in the
interview. The mean values of the last three hemoglobin collected in the
last 12 months were used to estimate the basal hemoglobin. The
assessments were carried out in the following sequence: Pediatric
Quality of Life Inventory\textsuperscript{TM} 4.0
(PedsQl\textsuperscript{TM}4.0) quality of life questionnaire,
assessment of lung function (spirometry and respiratory muscle strength)
and functional capacity (modified shuttle test and 5-repetition
sit-to-stand).

\textbf{Pulmonary function}

Spirometry was performed by KOKO Sx1000\selectlanguage{ngerman}\textsuperscript{®} device
(n-Spire-HealthTM, Longmont, USA) previously calibrated according to
recommendations.\textsuperscript{12} The variables analyzed were forced
vital capacity (FVC), forced expiratory volume in the first second
(FEV\textsubscript{1}) , FEV\textsubscript{1} / FVC ratio, forced
expiratory flow between 25-75\% of FVC (FEF \textsubscript{25-75\%}) and
peak expiratory flow (PEF)\textsuperscript{12, 13} Values were expressed
in absolute values and as a percentage of the predicted
value.\textsuperscript{12}

Maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP)
were measured with a manovacuometer (GERAR®, scale between +120 to
--120cmH2O) following the guidelines.\textsuperscript{14} To measure
MIP, maneuvers were performed from the residual volume; and, to measure
MEP from total lung capacity. The patient was asked for a maximum
inspiratory or expiratory effort. At least five maneuvers were performed
or until reproducible values were obtained.\textsuperscript{8} The best
value was used for analysis. Values are expressed in absolute terms and
as a percentage of the predicted value.\textsuperscript{15}

\textbf{Quality of life}

Quality of life was assessed by PedsQl\textsuperscript{TM}4.0
questionnaire applied according to the age group. This questionnaire has
versions for five to seven years old (answered by their parents), eight
to twelve years old and thirteen to eighteen years old. The domains are
physical, emotional, social and school aspects. Each problem was asked
for the adolescent or parents in the last month on a five-level response
scale (0 = never a problem; 1 = almost never a problem; 2 = sometimes a
problem; 3 = often a problem; 4 = almost always a problem). For children
aged 5 to 7, the scale is simplified to three points (1 = not at all; 2
= sometimes; 3 a lot), with each answer anchored on a similar scale
visual with happy, neutral and sad faces respectively. The items are
score-reverse and linearly transformed to a scale from 0 to 100 (0 =
100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). Therefore, high scores indicate
better QOL. PedsQl \textsuperscript{TM}4.0 scores are computed by adding
the items divided by the number of items
answered.\textsuperscript{16,17}

\textbf{Functional Capacity}

Both 5STS-test and MSWT were performed twice on the same day (test and
retest), with an interval of 30 minutes between them. The 5STS-test was
performed with the subject sitting on a chair with his arms crossed over
his chest. The patient should perform five movements of getting up and
sitting down as quickly as possible. The height of the chair was
adjusted to reach the angle of flexion of the hips and knees at 90º and
feet flat on the floor. The test outcome was the execution time in
seconds (s).\textsuperscript{18}

The MSWT was performed in a 10 m long corridor according to the original
description\textsuperscript{19}. It is a test externally paced by an
audible signal, in which the speed increases every minute, varying from
1.79 to 10.2 km / h.\textsuperscript{20} The test ends when the
volunteer is unable to follow the speed or needs to stop the test due to
fatigue, dyspnea or when SpO\textsubscript{2} remains below 82\%. The
outcome is the distance walked in meters and the percentage of the
predicted value.\textsuperscript{21}

The order of the tests (MSWT and 5STS-test) was randomized. Heart rate
(HR), dyspnea and lower limb fatigue (modified Borg
scale\textsuperscript{22}) were assessed at the beginning and at the end
of all the tests.

\textbf{Statistical analysis}

Sample size was calculated based on a pilot study, with the distance
walked in the MSWT for the SCAG being 598 ± 129 m and in the CG 900 ±
193 m. Based on power of 95\% and alpha of 0.05, the effect size was
1.8, the number of subjects was 10 for each group. The 5STS-test showed
an average time of 9 ± 2 seconds for SCAG and 8 ± 1 seconds for the CG
in the pilot study. Based on power of 80\% and alpha of 0.05, the effect
size was 1.0 and the number of subjects was 41 for each group.

The normality of the studied variables was analyzed using the Shapiro
Wilk test. Parametric data were represented by mean and standard
deviation, and nonparametric data were expressed as median and
interquartile range. For comparisons between groups, the unpaired
student t test or the Mann-Whitney test was used depending on the
normality of the data.

The intraclass correlation coefficient (ICC) and the Bland-Altman
analysis were used to test the reproducibility of tests MSWT (distance
walked) and 5STS-test (time to perform) test and retest, in the SCAG.
The ICC was characterized as follows: low reliability \textless{}0.40;
moderate reliability 0.40 - 0.75; strong reliability 0.75 - 0.90;
excellent reliability \textless{}0.90.\textsuperscript{23,24}Statistical
significance was considered p \textless{}0.05. Data analysis was
performed with the software SPSS version 22.

\textbf{Results}

One hundred and eighteen volunteers were eligible for this study, of
them 22 excluded due to the lack of understanding the execution of some
of the tests. In total, 96 volunteers were evaluated, with the sickle
SCAG consisting of 48 volunteers (56\% female) with mean age of 13 ± 3
years. The characteristics of the volunteers are described
in\textbf{Table 1} .

Spirometric values of the SCAG were worse when compared to the CG (p
\textless{}0.05). Regarding respiratory muscle strength, there was
difference between groups with lower MEP values in the SCAG compared to
the CG, p = 0.03 (\textbf{Table 2} ).

The SCAG spent more time to perform 5STS-test, 8 seconds (7-9 seconds),
compared to the CG, 7 seconds (7-8 seconds), p \textless{} 0.001.
Similar result was observed at the MST, which distance walked was
shorter at SCAG 576m (515-672m), compared to the CG, 1010m (887-1219m),
p \textless{} 0.001 (\textbf{Table 2} ).

The SCAG had poorer quality of life scores than the CG according to the
Pedsql \textsuperscript{TM}4.0 domains: physical functioning 66 (59 -
74) vs 94 (79 - 97), emotional functioning 65 (50 - 80) vs 75 (60 - 89),
social functioning 80 (66 - 94) vs 95 (81 - 100) and school functioning
50 (40 - 70) vs 87 (74 - 91), p \textless{}0.05.

To test the reproducibility between the SCAG functional capacity tests,
the outcomes were compared between test and retest. The ICC was
excellent between the two MSWT: 0.99 (0.98-0.99 IC-95\%) p
\textless{}0.001. The Bland-Altman analysis showed bias of -1.6m ( -42m
- 39m) were observed (\textbf{Figure 1A} ). Similar results were
observed at 5STS-test with an excellent ICC: 0.8 (0.7 -- 0.9) p
\textless{}0.001. The Bland Altman's analysis showed bias of 0.36
seconds was observed (-2.6 - 3.3 seconds) (\textbf{Figure 1B} ).

\textbf{Discussion}

In the present study, we identified that children and adolescents with
SCA showed reduced functional capacity, quality of life and pulmonary
function when compared to their healthy peers. Additionally, the
clinical field tests MSWT and 5STS-test proved to be reproducible to
assess the functional capacity in these volunteers. As far as we know,
this is the first study that includes these tests of functional capacity
in the evaluation of individuals with SCA.

Cardiorespiratory morbidity of SAC contributes to functional capacity
decreasing.\textsuperscript{25,26} This can be associated with
anthropometric variables such as weight and height that were worse in
patients of the SCAG compared to control
group.\textsuperscript{26}Several studies have shown that the resting
energy expenditure of these patients is up to 20\% higher when compared
to healthy individuals, this is due to erythropoiesis, increased cardiac
work, chronic hemolysis and hypoxia in
tissues.\textsuperscript{22,27,28}

Studies have already pointed out the relationship between low hemoglobin
and decreased performance in the 6MWT in children with
SAC.\textsuperscript{29,30} The status of chronic anemia and the
reduction in hemoglobin transport in the SCAG, may have caused a lower
carrying of the oxygen and may have provided worse performance during
the tests. In this study, the mean Hb of the SCAG was 8 ± 1g/Dl. The
chronic hemolysis may impair the performance in the MSWT for promoting
greater fatigue. Additionally, patients with SCA tend to have sedentary
behavior due to the chronicity of the disease, which is an important
aspect in reducing functional capacity.\textsuperscript{31,32}

Hospital admissions due to cardiopulmonary complications occur due to
frequent episodes of acute chest syndrome (ACS) and lower lung function.
In SCA, patients tend to have the syndrome of high cardiac output,
described as the disease that most increases cardiac output at rest,
contributing to the lower performance in activities such as walking fast
or running and playing.\textsuperscript{33} In this study, both groups
reached higher values of heart rate (more than 80\% of the maximum heart
rate), at the peak of the MSWT. However, the patients of the SCAG
reached these values with a much shorter distance than the CG, which
highlights the aspect of sedentary lifestyle, lower exercise capacity
and chronicity of the disease.\textsuperscript{34,35}

Children and adolescents with SCA are exposed to several factors that
contribute to the decrease in QOL in the physical and social fields. The
results of this study showed a significant difference in all domains of
the PedsQl.\textsuperscript{16, 17} In the physical functioning domain,
several studies reported that pain has a greater impact on QoL in
patients with SCA, although its intensity is variable and depends on the
individual characteristics of each patient. Pain is the main symptom
that lead to frequent hospital admissions and higher school
absenteeism.\textsuperscript{42,43,44} Acute or chronic pain affect
functional status, which predisposes these children and adolescents to
remain at rest and sedentary behavior.\textsuperscript{25,28,44}

The 5STS-test and MSWT showed to be reproducible in SACG. Additionally,
we observed an excellent value in the ICC and Bland Altman analysis with
a small difference between the measurements and acceptable limits of
agreement. Similar results for the MST were observed in pediatric
patients with cerebral palsy\textsuperscript{45} and cystic
fibrosis.\textsuperscript{46} Bohannon et al, described test and retest
reliability for 5STS-test from strong to excellent in the ICC analysis
for healthy adults.\textsuperscript{47} This shows that two test
(5STS-test and MSWT) should be performed to assess functional capacity
in SAC individuals.

The main limitation of the study was the lack of stratification of
patients by disease severity; however, the choice was made to select the
group with the greatest impairment, so that a greater number of
individuals were evaluated.

We conclude that children and adolescents with SCA-HbS-S genotype have
reduced functional capacity when compared to their healthy peers, as
well as having a worse quality of life and lung function. Additionally,
MSWT and 5STS-test proved to be reproducible in this population and can
be used as an alternative to evaluate functional capacity.

\textbf{List figure legends:}

\textbf{Figure-1} Bland Altman of the distance in meters in the first
and second MSWT (A) and the time in seconds in the first and second
5STS-test (B). Solid lines indicates the reference mean bias and the
dashed lines indicate the central mean bias and the upper and lower
limits of 95\% agreement between tests.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{Variables}\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{Control Group} \textbf{(n=48)}\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{Sickle Cell Anemia Group (n=48)}\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
p\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Age, years}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
13 (10 -15)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
13 (9 -15)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.811\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Height, cm}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
159 (140 -167)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
147 (132 -158)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.003\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Weight, Kg}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
47 (35.7 -58.3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
37 (28 -51)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.012\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{BMI, Kg/m\textsuperscript{2}}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
19 (16.2 -21.8)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
17 (15.5 -20.1)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.086\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Hb, g/Dl}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8 \selectlanguage{ngerman}± 1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Use of Hydroxyurea, n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
34 (70.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{FVC, L (\%prev.)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3.3 \selectlanguage{ngerman}± 1.0 (104 ± 15)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2.4 \selectlanguage{ngerman}± 0.8 (92 ± 15)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{FEV\textsubscript{1}, L (\%prev.)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2.91 \selectlanguage{ngerman}± 0.9 (101 ± 13)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2.0 \selectlanguage{ngerman}± 0.6 (83 ± 15)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{FEV\textsubscript{1}/FVC, \%}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
90 \selectlanguage{ngerman}± 6\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
84 \selectlanguage{ngerman}± 8\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{PEF, L (\%prev.)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5.7 \selectlanguage{ngerman}± 1.8 (92 ± 18)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3.9 \selectlanguage{ngerman}± 1.3 (72 ± 22)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{FEF\textsubscript{25-75\%}, L (\%prev.)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3.5 \selectlanguage{ngerman}± 1.2 (108 ± 22)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2.3 \selectlanguage{ngerman}± 0.7 (82 ± 22)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
cm: centimeters; Kg: kilogram; Kg / m2: kilogram per square meter; BMI:
body mass index; Hb: hemoglobin; g / dL: grams deciliters; FVC: forced
vital capacity, L: liters; \% pred: percentage of predicted; FEV1:
forced expiratory volume in the first second; FEV\textsubscript{1}/FVC:
ratio of forced expiratory volume in the first second divided by forced
vital capacity; PEF: peak forced expiratory flow; FEF25-75\%: forced
expiratory flow 25-75 percent.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
cm: centimeters; Kg: kilogram; Kg / m2: kilogram per square meter; BMI:
body mass index; Hb: hemoglobin; g / dL: grams deciliters; FVC: forced
vital capacity, L: liters; \% pred: percentage of predicted; FEV1:
forced expiratory volume in the first second; FEV\textsubscript{1}/FVC:
ratio of forced expiratory volume in the first second divided by forced
vital capacity; PEF: peak forced expiratory flow; FEF25-75\%: forced
expiratory flow 25-75 percent.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
cm: centimeters; Kg: kilogram; Kg / m2: kilogram per square meter; BMI:
body mass index; Hb: hemoglobin; g / dL: grams deciliters; FVC: forced
vital capacity, L: liters; \% pred: percentage of predicted; FEV1:
forced expiratory volume in the first second; FEV\textsubscript{1}/FVC:
ratio of forced expiratory volume in the first second divided by forced
vital capacity; PEF: peak forced expiratory flow; FEF25-75\%: forced
expiratory flow 25-75 percent.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
cm: centimeters; Kg: kilogram; Kg / m2: kilogram per square meter; BMI:
body mass index; Hb: hemoglobin; g / dL: grams deciliters; FVC: forced
vital capacity, L: liters; \% pred: percentage of predicted; FEV1:
forced expiratory volume in the first second; FEV\textsubscript{1}/FVC:
ratio of forced expiratory volume in the first second divided by forced
vital capacity; PEF: peak forced expiratory flow; FEF25-75\%: forced
expiratory flow 25-75 percent.\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 1.} Characteristic of the included volunteers.

\textbf{Table 2.} Comparison of modified shuttle walk test (MSWT) and
5-repetition sit-to-stand test (5STS-test), and muscle strength between
groups.\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Variables}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Variables}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Control Group} \textbf{(n=48)}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Sickle Cell Anemia Group (n=48)}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
P\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{MSWT}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{MSWT}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{MSWT}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{MSWT}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{MSWT}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Distance walked, m\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Distance walked, m\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1010 (887 - 1219)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
576 (515 - 672)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Distance walked, \%prev.\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Distance walked, \%prev.\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
101 (89 - 111)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
58 (50 - 64)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Heart rate, maximal, bpm\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Heart rate, maximal, bpm\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
200 (193 - 203)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
193 (185 - 199)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.058\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Borg Dyspnea\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Borg Dyspnea\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
5 (3 - 7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
5 (4 - 7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.344\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Borg Lower limb\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Borg Lower limb\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
5 (3 - 7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
5 (3 - 7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.227\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
SpO\textsubscript{2}\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
SpO\textsubscript{2}\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
97 (96 - 98)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
91 (89 - 96)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{5STS-test}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{5STS-test}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{5STS-test}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{5STS-test}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{5STS-test}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Time, seconds\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Time, seconds\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
7 (7 - 8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8 (7 - 9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
SpO\textsubscript{2}\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
SpO\textsubscript{2}\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
97 \selectlanguage{ngerman}± 1\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
93 \selectlanguage{ngerman}± 3\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Heart rate, maximal, bpm\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Heart rate, maximal, bpm\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
106 \selectlanguage{ngerman}± 17\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
109 \selectlanguage{ngerman}± 13\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.409\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Borg, Dyspnea\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Borg, Dyspnea\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0 (0-1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0 (0-1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.352\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Borg, Lower limb\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Borg, Lower limb\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1(1-2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1(1-3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.411\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Muscle strengh}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Muscle strengh}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
MIP, \%pred\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
MIP, \%pred\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
91 (80-111)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
91(78-103)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.205\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
MEP, \%pred\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
MEP, \%pred\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
96(87-108)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
87(71-107)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.039\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

MIP: maximal inspiratory pressure; MEP: maximum expiratory pressure.

\textbf{Table 3.} Reproducibility of modified shuttle walk test (MSWT)
and 5-repetition sit-to-stand test (5STS-test) at the sickle cell anemia
group (N= 48).\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Variables} & \textbf{Test 1} & \textbf{Test 2} &
P\tabularnewline
\midrule
\endhead
\textbf{MSWT} & & &\tabularnewline
Distance walked, m & 595 \selectlanguage{ngerman}± 123 & 596 \selectlanguage{ngerman}± 126 & 0.602\tabularnewline
Distance walked, \%prev. & 58 \selectlanguage{ngerman}± 12 & 58 \selectlanguage{ngerman}± 13 & 0.723\tabularnewline
Heart rate maximal, bpm & 189 \selectlanguage{ngerman}± 10 & 192 \selectlanguage{ngerman}± 9 & 0.002\tabularnewline
\textbf{5STS-test} & & &\tabularnewline
Time, seconds & 9 \selectlanguage{ngerman}± 1 & 8 \selectlanguage{ngerman}± 1 & 0.108\tabularnewline
Hear rate, maximal, bpm & 110 \selectlanguage{ngerman}± 14 & 109 \selectlanguage{ngerman}± 13 & 0.268\tabularnewline
\bottomrule
\end{longtable}

m: meters; \% prev: percentage of predicted; HRmax: maximum heart rate;
bpm: beats per minute, s: seconds

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\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1--Bland-Altman/Figure-1--Bland-Altman}

\end{center}
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