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\begin{document}

\title{Impact of hospitalization for vaso-occlusive crisis on health-related
quality of life in children with sickle cell disease}



\author[1]{Caroline Vuong}%
\author[1]{Ibtissame Moussa}%
\author[1]{Maud van Muilekom}%
\author[1]{Harriët Heijboer}%
\author[1]{Eva Rettenbacher}%
\author[1]{Lotte Haverman}%
\author[2]{Jos Twisk}%
\author[1]{Karin Fijnvandraat}%
\author[1]{Corien L. Eckhardt}%
\affil[1]{Emma Kinderziekenhuis Amsterdam UMC}%
\affil[2]{Amsterdam UMC Locatie VUmc Afdeling Epidemiologie en Biostatistiek}%


\vspace{-1em}



  
  \date{May 15, 2024}


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\selectlanguage{english}
\begin{abstract}
\textbf{Background:} Sickle cell disease (SCD) is characterized by
vaso-occlusive crises (VOCs), that impair the health-related quality of
life (HRQoL). The aim of this study is to evaluate the impact of
hospitalization for VOCs on HRQoL in children with SCD over time.
\textbf{Methods:} In this longitudinal cohort study, children aged 8-18
years diagnosed with SCD at the Amsterdam UMC were included between 2012
and 2021. HRQoL was annually measured as part of standard care using the
Pediatric Quality of Life Inventory. The impact of hospitalization for
VOC on HRQoL was evaluated using linear mixed models 3, 6, 9 and 12
months after hospitalization. The effect of frequency of hospitalization
for VOC on HRQoL was evaluated over the last 12 months.
\textbf{Results:} In total \textbf{,} 94 children with SCD were included
with a median age of 11.8 years (IQR 9-14). Thirty-seven patients (39\%)
had been hospitalized for a VOC. Hospitalization for VOC led to a
decrease of 3.2-4.8 points in total HRQoL compared to patients without
hospitalization, most pronounced 3 months after hospitalization.
Recurrent admission for VOC in the last 12 months was associated with a
decrease of 2.3 points in total HRQoL (p=0.04). The most affected
subscale was physical functioning. \textbf{Conclusion:} The adverse
effects of hospitalization for VOC in children with SCD persist up to 12
months after hospitalization. After hospitalization for VOC, extra
attention and support for its negative impact on HRQoL are recommended.
This study also underlines the importance of systematically measuring
HRQoL allowing clinicians to intervene accordingly.%
\end{abstract}%



\sloppy


\section*{Introduction}

{\label{introduction}}

Sickle cell disease (SCD) is the most common hemoglobinopathy affecting
millions of people worldwide.\textsuperscript{1} SCD is caused by a
single point mutation in the \selectlanguage{greek}β-\selectlanguage{english}globin gene. This gene mutation leads to
formation of abnormal hemoglobin known as hemoglobin S (HbS). Upon
deoxygenation, HbS polymerizes into long chains, thereby changing the
shape of red blood cells into a stiff, sickle-shaped form causing acute
and chronic complications including vaso-occlusion, chronic hemolysis,
and multi-organ damage.\textsuperscript{2} Vaso-occlusion along with
impaired oxygen supply and reperfusion of injured tissues causes acute
pain.\textsuperscript{3} These recurrent and unpredictable so-called
vaso-occlusive crises (VOCs), are frequently located in the chest, back
or abdomen, but may affect every part of the body. In patients with SCD,
the frequency of VOCs ranges between 0 to 18 VOCs per
year.\textsuperscript{4} Although VOCs are primarily managed at home
with oral or suppository analgesic agents, they are the most common
cause for hospitalization and emergency department visits in patients
with SCD.\textsuperscript{5-7} In some cases, VOCs are complicated by
the development of an acute chest syndrome, that may be life-threatening
and require admission to the pediatric intensive care unit.

Nowadays, disease-modifying therapies including
hydroxyurea\textsuperscript{8}, voxelator\textsuperscript{9} and
crizanlizumab,\textsuperscript{10,11} and curative therapies such as
stem cell transplantation are becoming more available for the management
of SCD. Unfortunately not all patients have access to these treatments
and not all VOCs can be prevented.\textsuperscript{12-14} VOCs have a
negative impact on all aspects of patient's lives, not only physically,
but also emotionally and socially.\textsuperscript{15} As screening
programs and preventative measures have led to higher survival among
children with SCD, SCD has now transformed into a more chronic
disease,\textsuperscript{16,17} and more attention is required for the
substantial personal and societal burden.

\subsection*{Health-related quality of
life}

{\label{health-related-quality-of-life}}

Health-related quality of life (HRQoL) refers to the perceived wellbeing
in physical, mental and social domains of health\textsuperscript{18},
and is a patient-reported outcome (PRO) as it is assessed by patients
themselves (self-reported).\textsuperscript{19,20} In children, HRQoL
can be assessed by the caregiver (proxy-reported) as well. Validated
questionnaires to systematically monitor HRQoL are called
patient-reported outcome measures (PROMs). In the Emma Children's
Hospital, the KLIK PROM portal (www.hetklikt.nu) is used to routinely
measure HRQoL in daily clinical practice with
PROMs.\textsuperscript{21-23}

Previous research has shown that HRQoL is significantly affected in
children with SCD, in both self- and proxy-reported HRQoL
studies.\textsuperscript{17,24-28} Children with SCD had a substantially
lower HRQoL compared to both the general pediatric population, and other
children with chronic disorders.\textsuperscript{26,27,29-31} The
painful VOC strongly affects the HRQoL more than any other SCD-related
complication such as avascular necrosis or
stroke.\textsuperscript{32}This is likely due to lack of control,
effective therapeutic interventions\textsuperscript{29} and the
difficulty of pain management.\textsuperscript{33} In particular health
care utilization seems to be a strong predictor for worse HRQoL in
children with SCD.\textsuperscript{34}

While research has been conducted on the impact of VOC on HRQoL of
pediatric patients with SCD, no studies have evaluated the cumulative
longitudinal effect of hospitalization on HRQoL. Longitudinal analyses
allow us to evaluate the impact of hospitalization on HRQoL over time.
Therefore, the aim of this study is to identify the longitudinal impact
of hospitalization for VOC on HRQoL in children with SCD with real-world
data, up to one year after hospitalization. Identifying the impact of
hospitalization allows healthcare providers to provide adequate
psychosocial support as part of interdisciplinary pain management to
improve HRQoL.

\section*{Methods}

{\label{methods}}

In this retrospective cohort study, patients aged between 8 and 18 years
with a confirmed diagnosis of SCD, who received care at the Emma
Children's Hospital, Amsterdam University Medical Centers (Amsterdam
UMC) were eligible for enrollment. As part of standard care procedures,
children routinely filled out PROMs prior to the regular visits through
the online KLIK PROM portal (https://www.hetklikt.nu/). The answers were
returned to the clinician and discussed during consultation. One of the
measures is the Pediatric Quality of Life Inventory 4.0 Generic core
scales (PedsQL\textsuperscript{TM} 4.0). Every child (and/or the parent)
was requested to complete the PedsQL at least once a year. Patients were
included in this study if they had filled out at least two PedsQLs
between January 2012 and September 2021. Data of patients were excluded
if patients were on a chronic transfusion therapy or if permission for
use of data for research purposes had been denied. This project was
reviewed by the Medical Research Ethics Committee of the Amsterdam UMC,
and conducted according to the Declaration of Helsinki.

\subsection*{Study measures}

{\label{study-measures}}

Demographics and disease-related characteristics including age, gender,
SCD genotype, medication use, and hospitalization for VOC were collected
from the electronic health records (EHR). Details of hospitalization for
VOC one year prior to HRQOL measurement were collected from the EHR as
well including length of stay (LOS), analgesic use and complications
during hospital admission such as development of acute chest syndrome.
With this information, the severity of each hospital admission was
scored as mild (1 point), moderate (2 points) or severe (3 points). Mild
severity was defined as a LOS shorter than 4 days; moderate severity was
defined as a LOS between 4 through 6 days; and severe was classified as
the presence of an acute chest syndrome independent of LOS, or a LOS
more or equal to 7 days.

Self-reported HRQoL was collected by completion of the PedsQL through
the online KLIK PROM portal. The PedsQL consists of 23 items covering
the following 4 subscales: physical, emotional, social and school
functioning.\textsuperscript{30,35} The questions address the preceding
week and could be answered with the following options: never (0), almost
never (1), sometimes (2), often (3) and almost always (4). The answer
`0' is converted into the score of 100, `1' into 75, `2' into 50, `3'
into 25 and `4' into 0. Then, a mean score was computed for each of the
23 items, and transformed to a scale that ranges from 0 to 100. Both a
total score as well as a score for each HRQoL subscale was calculated. A
psychosocial score was created from the emotional, social and school
functioning subscales of the PedsQL. A weighted average of the different
PedsQL subscale scores was calculated to derive the total HRQoL score.
The higher the calculated scores, the higher the perceived
HRQoL.\textsuperscript{36} Previous studies confirmed the validity and
reliability of the PedsQL\textsuperscript{TM} for the measurement of
HRQOL in the Dutch population.\textsuperscript{30} To evaluate the
reliability of the PedsQL versions in our study population, we
calculated internal consistency estimates (Cronbach's \selectlanguage{greek}α\selectlanguage{english}). Estimates of
0.70 or greater were considered good, while estimates between 0.60 and
0.70 were considered moderate and estimates below 0.60 were considered
poor.\textsuperscript{37}

\subsection*{Statistical analyses}

{\label{statistical-analyses}}

All data was transformed and analyzed in the Statistical Package for the
Social Sciences (SPSS) version 28.0. Descriptive data were generated for
all variables to describe the study population and its characteristics.
Categorical variables were presented as absolute numbers with
corresponding percentages. Means and standard deviations (SDs) were
calculated for continuous variables that were normally distributed.
Medians with interquartile ranges (IQRs) were calculated for values that
were not normally distributed. The period of follow-up was expressed in
patient-years by summarizing the duration of follow-up in days for all
patients divided by the number of days in a year (365.25). Baseline
characteristics and mean HRQoL scores were compared between the
hospitalization and no hospitalization for VOC group using the
chi-squared test or the unpaired t-test. For analysis purposes, genotype
was categorized in two groups: a clinically mild (HbSC and
HbS\selectlanguage{ngerman}ß+-thalassemia) and clinically severe genotype (HbSS and
HbSß0-thalassemia).

To assess the impact of the occurrence of hospitalization for VOC on
HRQoL over time, linear mixed model (LMM) analysis was used. The
dependent variables were HRQoL scores (both the total and the subscale
scores), and the independent variable was hospitalization for a VOC. In
all analyses, patients were considered as non-hospitalized if they had
not been admitted to the hospital in the last 12 months. Sensitivity
analyses were performed to determine whether the time period between
hospital admission and HRQoL measurement, affected HRQoL. For this, the
analyses were repeated for the time periods 3, 6, 9 and 12 months after
hospitalization. The impact of frequency of hospital admission in 12
months on HRQoL was evaluated using LMM analyses as well. To assess the
impact of the severity of a hospitalization for VOC on HRQoL over time,
a subanalysis with LMM was performed within the hospitalization group
using the calculated severity score. All analyses were adjusted for age
and SCD genotype. The estimates of the LMM analyses were reported as
regression coefficient (\selectlanguage{greek}β\selectlanguage{english}). Significance levels were set at 5\% and all
estimates were reported with 95\% confidence interval (CI).

\section*{Results}

{\label{results}}

In total, 94 patients met the inclusion criteria and were enrolled in
the study as shown in \textbf{Fig. 1.} The total follow-up duration was
451 patient-years with a median follow-up time of 4.0 years (IQR 2.0 -
6.0). The included patients completed the PedsQL 455 times in the period
January 2012 through September 2021. This is 237 times by patients in
the non-hospitalized group, and 218 times by patients in the
hospitalized group (\textbf{Supplemental Fig. S1).} The median number of
PedsQL completions per patient was 4 (IQR 3 - 6).

\textbf{Table 1} shows the baseline characteristics of the study
population. The median age of first completion of the PedsQL was 11.8
years (IQR 9.3 - 14.1) and 64\% of the patients was male. There were 37
patients who had at least one hospitalization for a VOC, while the
remaining 57 patients had no hospitalization for a VOC prior to
measurement of the HRQoL. Patients with HbSS/HbS\selectlanguage{greek}β\selectlanguage{english}\textsuperscript{0}were
more prevalent in the hospitalized group compared to the
non-hospitalized group (89\% vs 42\%, p\textless{}0.01) and a larger
proportion of patients used hydroxyurea (78\%) compared to the
non-hospitalized group (32\%).

There were 37 patients with a total of 122 hospitalizations for VOC. Out
of these 37 children, 22 children (59.5\%) had been admitted more than
once during follow-up. The median admission rate of these children was 4
times (IQR 2 - 6). Intravenous morphine was administered in 62\% of the
hospitalized patients for the median period of 3.0 days (IQR 0.0 - 5.0).
About one-third of the cases (36\%) required oxygen support, while blood
transfusion was administered in 16\% of the cases, mainly because of a
decrease in Hb level to below 5.6 g/dL. During four hospitalizations
(3\%), three patients developed an acute chest syndrome. Admission to
the pediatric intensive care unit occurred in three hospitalizations
(3\%).

In this study, the Cronbach's \selectlanguage{greek}α \selectlanguage{english}for the total HRQoL score was for all
versions greater than 0.8, and therefore good. For the subscales,
Cronbach's \selectlanguage{greek}α \selectlanguage{english}scores for the version 8-12 years version were
moderate/good ranging from 0.64-0.74, except for school functioning (\selectlanguage{greek}α \selectlanguage{english}=
0.49). For the 13-18 years version, Cronbach's \selectlanguage{greek}α \selectlanguage{english}scores were
moderate/good ranging from 0.62-0.78. The mean total HRQoL score from
the completed PedsQLs was significantly lower in the group with
hospitalization (75 points, SD \selectlanguage{ngerman}± 1.5) compared to the total HRQoL score
from the group without hospitalization (80 points, SD ± 1.3)
(\textbf{Table} \textbf{2)} .

\subsection*{Impact of occurrence of hospitalization for
VOC}

{\label{impact-of-occurrence-of-hospitalization-for-voc}}

The impact of occurrence of hospitalizations in the last 3, 6, 9 and 12
months on HRQoL is shown in \textbf{Table 3} . There is a trend showing
that the negative effect of hospitalization for VOC diminishes over time
for all subscales \textbf{(Fig. 2)} . The decrease of the total HRQoL
and all subscales scores were most pronounced 3 months after
hospitalization with decreases between 3.3 and 5.8 points, except for
physical functioning. The impact on physical functioning was most
pronounced 6 months after hospitalization with a decrease of 6.1 points.
Most affected were the total HRQoL and the subscale physical
functioning.

\subsection*{Impact of frequency of hospitalization for
VOC}

{\label{impact-of-frequency-of-hospitalization-for-voc}}

The results for the impact of frequency of hospitalization in the last
12 months are shown in \textbf{Table 4} . There was a significant
decrease in total HRQoL of 2.3 points for every additional
hospitalization over a period of 12 months. The most affected subscales
were physical functioning and school functioning. For every
hospitalization, a decrease of 2.7 points in physical functioning and
2.6 points in school functioning was observed.

\subsection*{Impact of severity of
hospitalization}

{\label{impact-of-severity-of-hospitalization}}

Out of 37 children who had been admitted at least once for a VOC during
follow-up, 15 children (41\%) experienced a hospitalization classified
as severe. Approximately one third of the patients had a hospitalization
classified as mild (32\%). Although not significant, the severity of the
hospitalization had a little negative effect on HRQoL at 3 months, which
disappeared after 3 months. \textbf{(Supplemental Table S2)} .

\section*{Discussion}

{\label{discussion}}

In the first decade of life, VOCs are the most common complication of
SCD,\textsuperscript{38} and associated with an impaired
HRQoL.\textsuperscript{39,40} Generally, SCD is associated with a high
health care utilization including emergency room visits and
hospitalizations due to VOCs.\textsuperscript{41} With age, the
frequency of hospitalization for VOC
increases.\textsuperscript{39,42}This study shows that occurrence of
hospitalization for VOC has a negative effect on total HRQoL, evident up
to 12 months after hospitalization in children with SCD. This effect was
most pronounced if HRQoL was measured closely after hospitalization and
decreased over time independently of the frequency of hospitalization.
As the number of hospitalization increases, the negative effect on total
HRQoL significantly increases as well.

Our study is in line with previous research involving the impact of
hospitalization for VOC on HRQoL in children with
SCD.\textsuperscript{43} Brandow et al. prospectively found a decrease
in HRQoL after hospitalization for VOC, but this effect seemed to
disappear after one week.\textsuperscript{43} The authors compared HRQoL
during hospitalization for VOC with control patients in steady state.
The discrepancy with our study could be attributed to the
cross-sectional design of their study and the comparison with a separate
control group. Instead, we used repeated measures over time to compare
HRQoL between patients and within patients with and without
hospitalization for VOC. Using repeated measures in the same patients
allows us to monitor changes of HRQoL over time, while controlling for
factors that cause variability. In our longitudinal analyses, although
the effect of occurrence of hospitalization on HRQoL was greatest after
3 months, this effect was not significant most probably due to lack of
power. Nevertheless, the trend up to 12 months is evidently present, and
decreasing over time.

In addition, previous studies have showed an inverse correlation between
self-reported HRQoL and the frequency of hospitalizations and emergency
department visits, comparable to our study.\textsuperscript{44-48} As
the effect of frequency of hospitalization on HRQoL in our study does
not look clinically relevant, it will become relevant as healthcare
utilization increases with age. Accordingly, Campball et al. reported
the higher the frequency of VOCs, the lower the self-reported total
HRQoL in children with SCD.\textsuperscript{42}

Dampier et al. found in regression models that mainly occurrence of
pain-related acute care visits was responsible for negatively affected
HRQoL subscales.\textsuperscript{17} All HRQoL subscales are found to be
affected in patients with SCD compared to healthy
norms,\textsuperscript{24,44,49} but the subscale physical functioning
seems to be the most affected across previous
studies.\textsuperscript{25,39} This is line with our study, reinforcing
the fact that hospitalization has a negative impact mainly on the
physical functioning lasting for months. School functioning was only
significantly affected after 12 months, so it seems that the effect of
hospitalization on school functioning only manifests over time. Even
though the reliability of the PedsQL for school functioning was poor in
our study, hospitalization for VOC does result in school absenteeism,
which in turn can lead to poor school performance or academic
functioning.\textsuperscript{50-53} As a matter of fact, the frequency
of hospitalization has been reported to be a predictor of poor HRQoL
with regard to school functioning in children with
SCD.\textsuperscript{50}

In several studies, SCD severity and complications were associated with
worse HRQoL.\textsuperscript{54} In the association between
hospitalization for VOC and HRQoL, the severity of hospitalization has
not been taken into account before. According to our subanalysis,
severity of hospitalization could have affected total HRQoL, but only
until 3 months after hospitalization. After this time, severity does not
seem to affect the total HRQoL score. However, these results were not
significant, as this analysis was conducted within a subgroup of
patients with 45 completed PedsQLs.

\subsection*{Strengths and limitations}

{\label{strengths-and-limitations}}

An important strength of this study is its longitudinal nature with data
covering the last 10 years with at least two measurements of HRQoL per
patient. Also, our study population with SCD is closely monitored at our
SCD comprehensive care center, as each patient is requested to annually
fill out PROMs before a regular visit as part of standard care.

There are also limitations that should be taken into account when
interpreting the data. First of all, patients with SCD who have mainly
VOCs managed at home, are not taken into account in the analyses, while
these VOCs burden patients as well. This also applies to patients with
other SCD-related complications such as chronic pain, that may have a
harmful effect on aspects of HRQoL. We did exclude patients on a chronic
transfusion therapy as they were more likely to have less
hospitalizations for VOC, while carrying the burden of frequent blood
transfusions. Second, the PedsQL was found to have moderate/good
reliability for all subscales, except for school functioning. Therefore,
the PedsQL results for school functioning should be interpreted with
caution. Third, patients without hospitalization completed the PedsQL
more often than the hospitalized patients. Hospitalized patients may
experience a higher disease burden or stress causing them to have less
time for completion of PedsQLs. Another explanation is, when a patient
is hospitalized, while having a visit scheduled at the outpatient
clinic, this visit is not automatically rescheduled to after
hospitalization.

Half of the eligible patients (or caregivers) did not give consent to
use the HRQoL data for scientific research. Moreover, not all children
were able to fill out the PedsQL regularly. For instance, children
and/or caregiver(s) who lack digital literacy, did not complete the
PedsQL via the online platform. However, we are facilitating and
offering technical support at the outpatient clinic for these patients
and their caregivers to overcome this problem. All of the above could
have caused selection bias of the study population affecting the
generalizability. In addition, our dataset was too limited to include
socio-economic status in our analyses. Considering that socio-economic
status is a well-known potential confounder of HRQoL, this may have
caused a bias as well.

Based on findings of this study, there are some implications for
clinical practice and recommendations for future research. Because of
the negative impact of both the occurrence and frequency of
hospitalizations for VOC on HRQoL, it is important to focus on the
prevention of VOCs and the usage of disease-modifying drugs. In case of
hospitalization, close monitoring and psychosocial support aimed at all
aspects of HRQoL, but in particular physical functioning (e.g. by
offering physiotherapy), should be considered. After frequent
hospitalizations, there should be sufficient attention for school
functioning as well. Furthermore, the KLIK PROM portal is an important
tool in clinical practice to assess the need for extra psychosocial
support in patients with SCD. SCD-specific symptom list in addition to
the generic PROMs evaluating aspects of HRQoL could increase the
reliability making research more replicable and easily comparable in
this patients with SCD. Ultimately, a mixed-methods study should be
performed to provide in-depth insights into how HRQoL is affected by
hospitalization for VOC. This could allow healthcare providers to
identify and better respond to the needs of children with SCD, who have
been hospitalized for VOC, and customize their care.

\section*{Conclusion}

{\label{conclusion}}

In conclusion, this study showed that the negative impact of
hospitalization in children with SCD persists at least up to 12 months.
Health care providers should focus on the prevention of VOCs, but in
case hospitalization for VOC occurs, optimal attention and guidance is
recommended for the after effects of hospitalization for VOC. This study
underlines the importance of measuring HRQoL in children with SCD
systematically to identify timely impaired HRQoL and to intervene
accordingly. Future research should focus on how hospitalization for VOC
affects HRQoL and whether this effect persists beyond 12 months. This
may help healthcare providers develop standardized yet tailored
interventions to target specific aspects of functioning such as physical
functioning, improving HRQoL of pediatric patients with SCD.

\section*{Conflict of Interest
Statement}

{\label{conflict-of-interest-statement}}

\section*{All authors declare that they have no conflict of
interest.}

{\label{all-authors-declare-that-they-have-no-conflict-of-interest.}}

\section*{Acknowledgements}

{\label{acknowledgements}}

The authors received no specific grant from any funding agency in the
public, commercial, or not-for-profit sectors.

\section*{Legends}

{\label{legends}}

\textbf{Figures:}

Figure 1. Flowchart study population selection and
classification\emph{.}

Figure 2. The negative effect of occurrence of hospitalization on HRQoL
3, 6, 9 and 12 months after hospitalization, diminishes over time.

\textbf{Tables:}

\begin{itemize}
\tightlist
\item
  Table 1. Baseline characteristics of the study population.
\item
  Table 2. Mean HRQoL scores of the study population as measured by
  PedsQL.
\item
  Table 3\textbf{.} Results of impact of occurrence of hospitalization
  for VOC on HRQoL scores in the last 3, 6, 9 and 12 months adjusted for
  age and genotype.
\item
  Table 4. Results of impact of frequency of hospital admissions for VOC
  on all HRQoL scores in the last 12 months adjusted for age and
  genotype.
\end{itemize}

\textbf{Supplemental figures and tables:}

Supplemental Figure S1. Distribution of completed PedsQLs among the
hospitalized patients and the non-hospitalized patients.

Supplemental Table S2. Results of the effect of severity of
hospitalization for VOC in the last 3, 6, 9 and 12 months on HRQoL
scores adjusted for age and genotype.

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{\label{references}}

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\verb`Figures d.d. 12-05-2023.docx`  available at \url{https://authorea.com/users/572417/articles/643424-impact-of-hospitalization-for-vaso-occlusive-crisis-on-health-related-quality-of-life-in-children-with-sickle-cell-disease}

\textbf{Hosted file}

\verb`Tables d.d. 12-05-2023.docx`  available at \url{https://authorea.com/users/572417/articles/643424-impact-of-hospitalization-for-vaso-occlusive-crisis-on-health-related-quality-of-life-in-children-with-sickle-cell-disease}

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