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\begin{document}

\title{Influenza Vaccination Uptake in Pediatric Patients with Cancer and
Sickle Cell Disease}



\author[1]{James Yarnall}%
\author[2]{Ann Mertens}%
\author[1]{Marianne Yee}%
\author[1]{Evan Orenstein}%
\author[3]{Karen Wasilewski-Masker}%
\affil[1]{Emory University School of Medicine}%
\affil[2]{Aflac Cancer Center \& Blood Disorders Service}%
\affil[3]{Aflac Cancer Center at Center \& Blood Disoders Service at Children's Healthcare of Atlanta/Emory University}%


\vspace{-1em}



  
  \date{May 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: Influenza causes greater morbidity in pediatric patients
with cancer or sickle cell disease (SCD). Limited data exists on
influenza vaccination uptake for these populations in a low-vaccination
state. Outpatient interventions improve vaccine uptake but isolated
inpatient interventions remain unstudied. Procedure: We reviewed
influenza vaccination of pediatric patients with cancer or SCD treated
at Children's Healthcare of Atlanta (CHOA) during three influenza
seasons. An opt-out inpatient admission order set was implemented prior
to the 2019-2020 influenza season. Vaccination status of patients that
were admitted during an influenza season was compared pre- and
post-intervention via Chi-squared analysis and multivariate logistic
regression. Results: 1548 and 2549 patients with cancer and SCD
(respectively) were eligible. The oncology (60\%-62\%) and SCD cohorts
(61\%-65\%) had similar-to-higher vaccination uptake to the US (58-64\%,
p=0.01-0.79) and higher uptake compared to Georgia (51\%-56\%,
p\textless{}0.01). There was no significant improvement in uptake after
implementation of the inpatient intervention for admitted patients with
cancer (40\% vs 56\%, p=0.05-0.88) or SCD (44\% vs 56\%, p=0.01).
Multivariate logistic regression also found no significant increase in
vaccine uptake (Hematologic Malignancy: 0.8 {[}0.73-0.98{]}, Solid
Tumor: 0.9 {[}0.80-1.90{]}, CNS Tumor: 0.9 {[}0.71-1.14{]}, SCD: 0.9
{[}0.85-0.99{]}). Conclusion: Pediatric patients with cancer and SCD
have similar-to-greater influenza vaccination uptake compared to Georgia
and the United States. An intervention focused on vaccinating
hospitalized patients did not significantly improve the proportion of
cancer or SCD patients who received influenza vaccine in each season.
Future studies are needed to identify alternative approaches to
improving vaccine uptake in these cohorts.%
\end{abstract}%



\sloppy


\textbf{Influenza Vaccination Uptake in Pediatric Patients with Cancer
and Sickle Cell Disease}

J. Nathan Yarnall, MD MPH\textsuperscript{1,2}; Ann Mertens,
PhD\textsuperscript{1,2}; Marianne Yee, MD\textsuperscript{1,2}; Evan
Orenstein, MD\textsuperscript{1}; Karen Wasilewski-Masker, MD
MS\textsuperscript{1,2}

\emph{\textsuperscript{1}Emory University School of Medicine Department
of Pediatrics, Atlanta, GA; \textsuperscript{2}Aflac Cancer and Blood
Disorders Center, Children's Healthcare of Atlanta/Emory University,
Atlanta, GA}

Corresponding Author: J. Nathan Yarnall, Emory University School of
Medicine, 100 Woodruff Circle, Atlanta, GA 30322. jyarnal@emory.edu.
919-345-3484.

Word Count (Abstract): 249

Word Count (Manuscript): 3464

Tables: 4; Figures: 2

Short Running Title: Flu Vaccination in Children with Cancer and SCD

Keywords: Influenza, Vaccine, Pediatric, Cancer, Sickle Cell Disease

Abbreviations:\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
SCD & Sickle Cell Disease\tabularnewline
\midrule
\endhead
ACIP & Advisory Community on Immunization Practices\tabularnewline
CNS & Central Nervous System\tabularnewline
IIV & Inactivated Influenza Vaccine\tabularnewline
CHOA & Childrens Healthcare of Atlanta\tabularnewline
CDC & Center for Disease Control and Prevention\tabularnewline
HSCT & Hematopoietic Stem Cell Transplant\tabularnewline
GRITS & Georgia Registry of Immunization Transactions and
Services\tabularnewline
EHR & Electronic Health Record\tabularnewline
REDCap & Research Electronic Data Capture\tabularnewline
\bottomrule
\end{longtable}

Previously published as a meeting abstract at the 2021 American Society
for Pediatric Hematology-Oncology (ASPHO) National Conference (April
20-23, 2021): ``Influenza Vaccination Uptake in Pediatric Cancer and
Sickle Cell Disease Patients before and after an Inpatient Opt-Out
Admission Order Set.''
https://onlinelibrary.wiley.com/doi/full/10.1002/pbc.29060

\emph{}

\emph{Abstract}

Background: Influenza causes greater morbidity in pediatric patients
with cancer or sickle cell disease (SCD). Limited data exists on
influenza vaccination uptake for these populations in a low-vaccination
state. Outpatient interventions improve vaccine uptake but isolated
inpatient interventions remain unstudied.

Procedure: We reviewed influenza vaccination of pediatric patients with
cancer or SCD treated at Children's Healthcare of Atlanta (CHOA) during
three influenza seasons. An opt-out inpatient admission order set was
implemented prior to the 2019-2020 influenza season. Vaccination status
of patients that were admitted during an influenza season was compared
pre- and post-intervention via Chi-squared analysis and multivariate
logistic regression.

Results: 1548 and 2549 patients with cancer and SCD (respectively) were
eligible. The oncology (60\%-62\%) and SCD cohorts (61\%-65\%) had
similar-to-higher vaccination uptake to the US (58-64\%,\emph{p}
=0.01-0.79) and higher uptake compared to Georgia (51\%-56\%,\emph{p}
\textless{}0.01). There was no significant improvement in uptake after
implementation of the inpatient intervention for admitted patients with
cancer (40\% vs 56\%, \emph{p} =0.05-0.88) or SCD (44\% vs 56\%,
p=0.01). Multivariate logistic regression also found no significant
increase in vaccine uptake (Hematologic Malignancy: 0.8 {[}0.73-0.98{]},
Solid Tumor: 0.9 {[}0.80-1.90{]}, CNS Tumor: 0.9 {[}0.71-1.14{]}, SCD:
0.9 {[}0.85-0.99{]}).

Conclusion: Pediatric patients with cancer and SCD have
similar-to-greater influenza vaccination uptake compared to Georgia and
the United States. An intervention focused on vaccinating hospitalized
patients did not significantly improve the proportion of cancer or SCD
patients who received influenza vaccine in each season. Future studies
are needed to identify alternative approaches to improving vaccine
uptake in these cohorts.

\emph{}

\emph{Introduction}

Pediatric cancer affects 15 000 new patients less than 20 years of age
every year, while sickle cell disease (SCD) affects approximately 100
000 Americans and occurs in 1 out of every 365 Black or African-American
births.\textsuperscript{1,2} Morbidity from seasonal influenza is
significantly higher for pediatric patients with cancer and sickle cell
disease compared to the general pediatric population in the United
States. Children with SCD are hospitalized for influenza at 56 times the
rate of children without SCD, though disease severity and length of
hospitalization tend to be similar.\textsuperscript{3} Among pediatric
patients with cancer that contract influenza, 30-70\% of patients
require hospitalization and 10-20\% require intensive care; this was
found to be more common with the 2008-2009 pandemic H1N1
strain.\textsuperscript{4--6} Importantly, delays in chemotherapy caused
by viral infections like influenza affect up to a third of all pediatric
cancer patients, increasing the risk of treatment
failure.\textsuperscript{7}

The Advisory Committee on Immunization Practices (ACIP) recommends
annual inactivated influenza vaccination (IIV) for all immunocompromised
individuals.\textsuperscript{8} Historically, IIV uptake has been poor
in both SCD and pediatric cancer populations, ranging from 20-60\% in
SCD, 40-50\% in solid and central nervous system (CNS) tumors, and
60-70\% in hematologic malignancies.\textsuperscript{9--13} Quality
improvement studies have shown the efficacy of outpatient
interventions.\textsuperscript{12--16} In prior work, we demonstrated
that opt-out clinical decision support (CDS) promoting influenza vaccine
increased the chances that eligible children would receive influenza
vaccine prior to hospital discharge in the general
population.\textsuperscript{17} However, it remains unknown whether such
an intervention improves total IIV vaccine coverage in oncology and SCD
populations.

This study aimed to compare influenza vaccination rates in pediatric
patients with oncologic diagnoses or SCD to that of the general
pediatric population in the United States and in the state of Georgia, a
historically low uptake state for influenza vaccination (ranked fifth
lowest state in influenza vaccination uptake nationally during the
2019-2020 influenza season).\textsuperscript{18} We hypothesized that
influenza vaccine uptake among pediatric patients with cancer and SCD
are higher than both the state and national general pediatric
populations. We also explored contributing patient factors to influenza
vaccine uptake in these two patient populations to inform future
interventions. Lastly, we examined the efficacy of an inpatient opt-out
CDS intervention for improving influenza vaccination uptake among
patients admitted during an influenza season. We hypothesized that
pediatric patients with cancer or sickle cell disease admitted at least
once during an influenza season and exposed to the order set would have
higher IIV uptake than those admitted patients that were not exposed to
the intervention.

\emph{Methods}

Participants

Our study sample consisted of pediatric patients with cancer and SCD
treated at the Aflac Cancer and Blood Disorders Center at Children's
Healthcare of Atlanta (CHOA), a large pediatric hematology-oncology
program in the southeastern United States. Across a three-hospital
system, CHOA sees approximately 450-500 new oncology diagnoses a year
and cares for approximately 1900 children and adolescents with SCD
annually. All study participants were active patients aged six months to
20.99 years at the beginning of at least one of three recent influenza
seasons (September 1 to April 30; 2017-2018, 2018-2019, 2019-2020).
Influenza season date ranges are based on influenza season data from the
Centers of Disease Control and Prevention (CDC) and the first
availability of influenza vaccines at CHOA.\textsuperscript{19} Patient
eligibility was unique to each influenza season and a patient could be
eligible for more than one season based on their age and/or off-therapy
date.

Active pediatric oncology patients were categorized as children
undergoing active, cancer-targeted treatment (``on therapy'') or who had
completed treatment (``off therapy'') less than six months prior to the
study date range described above. For example, a patient eligible for
the 2019-2020 influenza season cohort would either be on therapy during
the season or have an off-therapy date on or after March 1, 2019 (six
months prior to the start of the season). Active sickle cell patients
were defined as patients with a documented SCD genotype who had at least
one health maintenance visit annually during the calendar year of the
start of the influenza season (i.e., January-December 2017 for the
2017-2018 season). Patients with sickle cell trait were excluded.
Patients that underwent hematopoietic stem cell transplant (HSCT) during
an influenza season could still be eligible for that season; if the HSCT
concluded their active anti-neoplastic therapy, the patient's transplant
date was considered their off-therapy date. Patients that lived or were
treated outside of the state of Georgia at any point during an influenza
season were excluded because vaccination status was ascertained from the
Georgia Registry of Immunization Transactions and Services (GRITS) for
this study.

To analyze the effect of the inpatient admission order set, we utilized
the subset of the eligible cohort above that had been admitted at least
once during an influenza season. Like the general cohort above, the
inpatient cohort was unique for each influenza season. Admitted patients
were identified through admission billing codes of ``Inpatient'',
``Observation'', or ``Surgery Admit -- IP'' for greater than 24 hours.

Intervention

For the 2019-2020 influenza season, a quality improvement group at CHOA
implemented a system-wide opt-out influenza vaccination order set within
every inpatient admission order set for both general pediatrics and
subspecialty services to improve vaccination rates, described
elsewhere.\textsuperscript{17} Briefly, the CDS system checked to see if
the patient was in the appropriate age group, whether they had already
received an influenza vaccine that season, and checked for any history
of anaphylaxis to influenza vaccination. If the patient was deemed
eligible by these criteria, the algorithm placed pre-selected orders for
the influenza vaccine and nursing instructions to administer the vaccine
prior to discharge. The admitting provider had the option to deselect
the orders if clinically indicated, and the patient or parent had the
option to refuse the vaccine at the time of
discharge.\textsuperscript{20} These orders were incorporated into
Oncology and SCD admission order sets on October 3, 2019, and October
23, 2019, respectively, 4-8 weeks after influenza vaccinations became
available. There were no other novel concurrent interventions for
improving influenza vaccine uptake implemented during the study period.
CHOA had previously implemented non-interruptive opt-in reminders in the
electronic health record (EHR) for influenza vaccine at all outpatient
clinic encounters using the same eligibility criteria.

Data Abstraction and Management

Patient demographic data, disease-specific data, and vaccination status
were abstracted from the EHR (Epic Systems, Verona, WI) and from
clinical databases of all patients with cancer and SCD that are
maintained internally within CHOA. The Cancer Registry of CHOA reports
detailed demographic and cancer-related information on all patients with
pathology or imaging-confirmed pediatric cancer to the Georgia Cancer
Registry (GCR), a statewide population-based cancer registry that is
part of the National Cancer Institute's SEER Program. Additionally, any
history of relapsed, progressive, or refractory disease was abstracted
from the CHOA Cancer Registry. Off-therapy dates for study eligibility
were updated through October 2020. Off-therapy dates were set as the
last day of chemotherapy or radiation, or the day of definitive surgical
resection, whichever occurred later. Patients who were off-therapy prior
to January 1, 2017, who died due to their primary disease, who
transferred to another institution prior to the end of therapy, who were
lost to follow up, or whose end of therapy date was otherwise not
available (i.e., completed therapy at another institution prior to
coming to CHOA) were deemed ineligible. Patients with solid or CNS
tumors who did not undergo definitive resection or receive chemotherapy
treatment were excluded.

For the SCD cohort we utilized the Sickle Cell Disease Clinical Database
of CHOA, a comprehensive, prospective database housed in REDCap tasked
with capturing utilization data from all patients with a
laboratory-confirmed diagnosis of SCD with [?]1 healthcare encounter at
CHOA from 2010 onward. Data capture includes laboratory-verified SCD
genotype, SCD treatment history (specifically hydroxyurea, chronic
transfusions, and HSCT), and dates and diagnoses of all healthcare
utilization at CHOA. Any history of pneumococcal vaccine polyvalent 23
administration (as a marker of vaccine acceptance), splenectomy,
hydroxyurea use, acute chest syndrome, and chronic transfusion were also
abstracted from the Sickle Cell Database.

Age at the start of each season, race, ethnicity, sex, history of
influenza vaccination in prior influenza seasons, IIV administration
during the target influenza season, prior pneumococcal vaccination,
number of admissions per season, and history of stem cell transplant
were auto-abstracted from the EHR for all patients. Vaccine data were
drawn from the GRITS database, a statewide registry of all immunizations
given in the state of Georgia since 1996. Medical providers and any
other persons licensed to administer vaccines in the state of Georgia
are mandated to submit documentation of all immunizations within 30 days
of administration.\textsuperscript{21} Through a partnership between
GRITS and CHOA, every new CHOA encounter (inpatient or outpatient) for a
patient queries the GRITS database and pulls the updated immunization
record into the EHR. Exposure to the inpatient CDS intervention was
abstracted automatically as described elsewhere.\textsuperscript{17}

Twenty patient charts for each were randomly chosen for manual
abstraction to verify the validity of data obtained from
auto-abstraction. Overall influenza vaccination uptake for the general
pediatric population of the United States and the state of Georgia were
acquired from the CDC's Influenza Seasons Vaccination Coverage Trend
Report, which provides national and state-specific data on influenza
vaccination uptake since 2010.\textsuperscript{18}

Statistical Analysis

The unit of analysis was the proportion of patients per season that
received the IIV (patient-season). Age was calculated for September 1 of
the eligible seasons. Sex was recorded as binary (boy/girl). Race and
Ethnicity were combined into groups of Asian, Hispanic/Latino,
Non-Hispanic White/Caucasian, Non-Hispanic Black/African American, and
Other (American Indian or Alaskan Native, Native Hawaiian or Pacific
Islander, Multiple Races, Unknown, or Refused to Answer). SCD genotype
categories were hemoglobin HbSS, HbSC,
HbS/\selectlanguage{greek}β\selectlanguage{english}\textsuperscript{+}thalassemia, HbS/\selectlanguage{greek}β\selectlanguage{english}\textsuperscript{0}
thalassemia, and Other.

Statistical analysis was performed through R version
4.1.0.\textsuperscript{22} Chi-squared analysis was performed to compare
the proportion of influenza vaccination uptake among the pediatric
oncology subgroups (hematologic malignancies, non-CNS solid tumors,
primary CNS tumors) and patients with SCD with uptake in the general
pediatric population for Georgia and the United States. Multivariate
logistic regression was performed to explore potential contributing
factors to differences in IIV uptake between disease groups. For the
inpatient cohort, Chi-squared analysis was performed to determine
differences in IIV uptake between admitted patients eligible and exposed
to the intervention and those eligible but not exposed to the
intervention (i.e., only admitted prior to the intervention's start
date, including historical controls from the first two influenza
seasons). Multivariate logistic regression modeling was performed to
determine which covariates mentioned above may contribute to IIV uptake;
this was repeated using hospital admission as the unit of analysis.

\emph{Results}

Overall, 1548 pediatric patients with cancer were eligible for at least
one season (range 812-1323 patients per season). Of those oncology
patients, 654 (42.2\%) had hematologic malignancies, 473 (30.6\%) had
non-CNS solid tumors, and 421 (27.2\%) had primary CNS tumors that met
criteria for being on-therapy or within six months of their off therapy
dating during at least one influenza season. At least one influenza
vaccination for any previous influenza season was documented for 80-88\%
of oncology patients. There were 2539 pediatric patients with SCD that
were eligible for the study. At least one influenza vaccination for any
previous influenza season was documented for 76-94\% of patients with
SCD, and 66-92\% had a history of prior pneumococcal vaccination (if
eligible) (\textbf{Table 1} ).

Influenza Vaccine Uptake Compared to the United States and Georgia

IIV uptake for the general pediatric population of the United States
ranged between 58-64\% over the three influenza seasons, compared to
51-56\% for the state of Georgia. Pediatric oncology patients overall
had influenza vaccination uptake 60-62\%, differing by disease subtype.
Influenza vaccination uptake for pediatric patients with SCD ranged
between 61-65\% (\textbf{Figure 1} ).

In comparison to Georgia's pediatric population, patients with
hematologic malignancies had significantly higher IIV uptake
(67-75\%,\emph{p} \textless{}0.01). Patients with solid and CNS tumors
had similar uptake to the state population (Solid tumor 47-52\%,
\emph{p} =0.15-0.26; CNS tumor 52-58\%, \emph{p} =0.38-0.80). Compared
to the national pediatric population, patients with hematologic
malignancies had similar-to-higher IIV uptake (67-75\%, \emph{p}
=0.01-0.15), while patients with solid and CNS tumors had
similar-to-lower uptake (Solid tumor 47-52\%, \emph{p} \textless{}0.01;
CNS tumor 52-58\%,\emph{p} =0.04-0.10). Patients with SCD had
significantly higher uptake than both state (61-64\%, \emph{p}
\textless{}0.01) and national (61-64\% , \emph{p} =0.01-0.02)
populations, even among the national population of Non-Hispanic African
American children (61-64\% vs 55\%-60\%,\emph{p} \textless{}0.01)
(\textbf{Table 2} ).\textsuperscript{18}

Correlates to Influenza Vaccine Uptake

Patients with hematologic malignancies had significantly higher IIV
uptake compared to patients with solid and CNS tumors combined (OR 1.09
{[}1.06-1.13{]}, \emph{p} \textless{}0.01). Younger age (OR per year
0.996 {[}0.994-0.999{]}, \emph{p} \textless{}0.01), prior IIV
vaccination (OR 1.94 {[}1.85-2.03{]}, \emph{p} \textless{}0.01), greater
number of admissions per season (OR per admission 1.007
{[}1.001-1.014{]},\emph{p} =0.04), absence of relapsed or refractory
disease (OR 0.95 {[}0.92-0.99{]}, \emph{p} =0.01), and chemotherapy
given during the season (OR 1.07 {[}1.03-1.11{]}, \emph{p}
\textless{}0.01) were significantly associated with increased IIV
uptake, while race, sex, history of hematopoietic stem cell transplant
(HSCT) were not. There was no significant difference in IIV uptake
between patients with cancer and SCD (OR 1.01 {[}0.99-1.03{]}, \emph{p}
=0.54).

Influenza Vaccine Uptake After the Opt-Out Admission Order Set

From the initial cohort, 1143 oncology patient-seasons (592 with
hematologic malignancy, 331 with non-CNS solid tumors, and 220 with
primary CNS tumors) and 2135 sickle cell patient-seasons were eligible
for the inpatient cohort. Eligible patients per season ranged from
354-423 for oncology and 686-734 for SCD. Among the three influenza
seasons, 17\%, 19\%, and 27\% of admitted patients with cancer received
their IIV while inpatient, respectively. For SCD, 8\%, 7\%, and 27\% of
admitted patients received their IIV while inpatient, respectively.
During the 2019-2020 season, 46\% of admitted patients with cancer and
52\% of admitted patients with SCD were eligible for the admission order
set. At the time of implementation, 48\% of patients with cancer and
56\% of patients with SCD had already received the IIV (\textbf{Figure
2} ). Due to the stepwise implementation of the order set, 63\%
(121/193) of order set-eligible oncology encounters were exposed to the
order set; 40\% (48/121) of exposed oncology encounters received the IIV
that season compared to 60\% (43/72) for the unexposed. Similarly, 64\%
(197/307) of order set-eligible admitted patients with SCD were exposed;
44\% (87/197) of exposed patients with SCD received the IIV that season
compared to 78\% (86/110) for the unexposed patients. The inpatient
cohort saw no difference in uptake comparing before and after the order
set implementation for patients with hematologic malignancies (56\% vs
44\%, \emph{p} =0.07), solid tumors (59\% vs 38\%, \emph{p} =0.05), and
CNS tumors (47\% vs 41\%, \emph{p} =0.88) but decreased uptake for
patients with SCD (56\% vs 44\%, p\textless{}0.01).

In multivariate analysis, there was no significant difference in vaccine
uptake after order set implementation for patients with solid tumors
(\emph{p} =0.38) or CNS tumors (\emph{p} =0.37) but decreased uptake for
patients with hematologic malignancies (\emph{p} =0.03) and SCD
(\emph{p} =0.02) (\textbf{Table 3} ). A history of prior influenza
vaccination was strongly associated with greater IIV uptake for all
subgroups (\emph{p} \textless{}0.01). Except for patients with
hematologic malignancies, a greater number of admissions during the
influenza season was strongly associated with greater IIV uptake for all
subgroups. Older patients with SCD were also more likely to have higher
IIV uptake.

Adjusting the unit of analysis to hospital admission for those
unvaccinated at the time of admission, we found a significant difference
in IIV uptake between patients exposed to the order set and those not
exposed to the order set for both the inpatient oncology (22\% vs
18\%,\emph{p} \textless{}0.01) and SCD (24\% vs 13\%, \emph{p}
\textless{}0.01) cohorts. Mixed effects multivariate logistic regression
also found a significant increase in IIV for oncology (OR 2.0
{[}1.14-3.45{]}) and SCD (OR 4.3 {[}2.66-7.03{]}); fewer complex chronic
medical conditions correlated with increased IIV uptake in the oncology
cohort (\textbf{Table 4} ).

\emph{Discussion}

Immunization against influenza is an important preventative health
measure for all individuals, with potential benefit for vulnerable
populations with chronic illness; yet nationwide, vaccine acceptance
remains sub-optimal. We found that patients with cancer had similar
rates of vaccination to the general pediatric national population but
higher rates of vaccination than their healthy peers in a low
vaccination state. Conversely, patients with SCD had significantly
higher rates of influenza vaccination than the state and nation, which
remained true when compared to the United States' general population of
Black or African-American children.\textsuperscript{18} Our findings are
similar to the IIV uptake rates found in other states' pediatric cohorts
with cancer or SCD, suggesting similar uptake among these pediatric
populations across states with different degrees of IIV
uptake.\textsuperscript{9--13}

Prior studies have shown significant improvement in influenza uptake
among pediatric patients with cancer through outpatient interventions
such as provider reminders, clinic flow changes, and telephone and mail
recall systems. The greatest improvements were seen in interventions
that targeted the outpatient clinic, though the effect tended to
diminish later in the influenza
season.\textsuperscript{12--16}Similarly, outpatient interventions in
provider and patient education, electronic medical record enhancement,
patient registries, and reminder/recall systems have shown to improve
vaccine uptake among patients with SCD.\textsuperscript{23} Our study
sought to optimize opportunities for increasing IIV uptake through
planned and unplanned inpatient encounters. The probability of influenza
vaccination prior to discharge increased in the oncology cohort (aOR
1.98 {[}1.14-3.45{]}) although less than the general pediatrics cohort
(aOR 3.25 {[}2.94-3.59{]}).\textsuperscript{17} The impact during
hospitalization was even greater among SCD patients (aOR 4.33
{[}2.66-7.03{]}). Nonetheless, the proportions of \emph{patients per
season} receiving the vaccine did not significantly change with the
intervention for either cohort, regardless of the number of admissions
that each patient had.

Reasons underlying our results include the staggered study design of the
order set intervention and the prevalence of outpatient influenza
vaccination. \textbf{Figure 2} shows that about half of all patients
with cancer and SCD that were eligible for the inpatient cohort and the
intervention received their IIV prior to the start of the intervention.
A portion of those patients could have received their IIV during an
admission prior to receiving it in the outpatient setting; however,
those patients would likely be willing to receive their IIV early
regardless of the location, so the inpatient intervention would not have
added much to the existing outpatient systems. One prior study included
an inpatient order set concurrently with other outpatient and education
interventions to boost IIV uptake among pediatric patients with cancer,
but due to the nature of concurrent interventions, the authors were
unable to assess the specific utility of the inpatient intervention.
They speculated that the effect was minor, as only 10\% of their
vaccines were administered on an inpatient basis.\textsuperscript{12}Our
study found that 17-27\% and 8-27\% of vaccinated patients in the
admitted oncology and SCD cohorts received their IIV while inpatient,
respectively, with marked increase of inpatient vaccination for both
inpatient cohorts during the 2019-2020 influenza season. Additionally,
IIV uptake fell for our full eligible (inpatient and outpatient)
oncology and SCD cohorts (particularly among patients with hematologic
malignancies) while national and state uptake improved or remained
stable, questioning the representativeness of the 2019-2020 season for
our two cohorts.

Our study has limitations. The retrospective nature of the study limited
our ability to control for confounding bias when assessing the efficacy
of the inpatient intervention. Eligible patients who underwent HSCT may
have been ineligible for vaccination if their transplant date occurred
during the influenza season. Eligible patients born in September or
October of their eligible influenza season would be much less likely to
receive an influenza vaccination. Finally, the COVID-19 pandemic
starting in the early months of 2020 could have affected IIV uptake
during the second half of the 2019-2020 influenza season, though the
effect was likely small as 88-92\% of influenza immunizations were given
prior to December 31 for each influenza season.

By determining the effect of an inpatient intervention, we sought to
further define strategies for enhancing vaccine uptake among
immunocompromised populations and better capitalize on vaccination
opportunities in patients' existing healthcare encounters. Our results
suggest that pediatric patients with cancer or SCD living in a
low-vaccination state tend to follow national rather than local uptake
trends. Our inpatient admission order-set intervention was ineffective
at improving IIV uptake in these populations followed at our
institution, though the rise of inpatient vaccinations and fall of
overall vaccine uptake in 2019-2020 suggests that inpatient
interventions may still be a viable strategy for increasing influenza
vaccine uptake. The intervention continues to go through iterative
changes with each influenza season, so a follow up study focusing on
subsequent influenza seasons will help assess the full effect of the
intervention. As our study confirmed that 30-50\% of pediatric patients
with cancer or SCD remain unvaccinated against influenza, additional
qualitative or mixed-methods studies could explore additional barriers
to influenza vaccine uptake, while follow up intervention studies could
explore methods of increasing influenza vaccination among the patients'
families as well. Greater optimization of seasonal vaccine uptake like
influenza will improve infectious outcomes among immunocompromised
pediatric patients with cancer and SCD.

\emph{Conflict of Interest}

Dr. Evan Orenstein is a co-founder and equity holder in Phrase Health, a
clinical decision support analytics company.

\emph{Acknowledgements}

The authors would like to acknowledge Judy Lee and Kristina Lai for
their support in data abstraction.\emph{}

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\textbf{FIGURE 1:} Influenza vaccine uptake among patients with cancer
and sickle cell disease treated at CHOA compared to state and national
general pediatric populations over three influenza seasons.

\textbf{FIGURE 2} : Influenza vaccine uptake among inpatient oncology
(A) and sickle cell disease (B) cohorts. The vertical line represents
the date of order set implementation in 2019-2020 season.

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