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\begin{document}

\title{Impact of Telehealth Visit and Socioeconomic Status (SES) on Hydroxyurea
Response in Sickle Cell Anemia}



\author[1]{Sarah Shaner}%
\author[2]{Lee Hilliard}%
\author[3]{Thomas Howard}%
\author[3]{Brandi Pernell}%
\author[2]{Smita Bhatia}%
\author[3]{Jeffrey Lebensburger}%
\affil[1]{The University of Alabama at Birmingham School of Medicine}%
\affil[2]{University of Alabama at Birmingham}%
\affil[3]{University of Alabama-Birmingham}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background It is important to ensure access to hydroxyurea (HU) for
patients with sickle cell anemia (SCA) living in rural areas without
easy access to experts in sickle cell management. The UAB Pediatric
Sickle Cell program's satellite clinics reduce the barrier of
transportation to the university-based clinic. However, as compared to
the university clinic, these satellite clinics do not offer immediate
access to HU dosing laboratory results. Therefore, a nurse clinician
calls families with HU dose adjustments after the completion of the
clinic visit. This study evaluated the impact of telehealth dosing
adjustments on HU laboratory and clinical response as compared to
university-based patients. Methods A one year retrospective chart
reviewed was performed to evaluate HU laboratory and clinical response
based on clinic location and socioeconomic status for patients with SCA.
We identified the number of clinic and acute care visits for one year
and calculated the mean CBC and HbF values for each patient. Results We
identified 107 academic center participants with SCA prescribed HU and
65 satellite clinic participants. We identified no difference in HbF,
Hb, MCV, or ANC by clinic location. We also identified no difference in
hospital admissions based on clinic location. Finally, mean
socioeconomic indicators by zip code were lower in satellite clinic
patients but not associated with a difference in HbF response.
Conclusions The use of telehealth did not negatively impact laboratory
response to HU. Future studies should identify novel approaches to
improve access to HU among patients with SCA living in rural areas.%
\end{abstract}%



\sloppy


\textbf{Impact of Telehealth Visit and Socioeconomic Status (SES) on
Hydroxyurea Response in Sickle Cell Anemia}

Shaner, Sarah\textsuperscript{1}, Hilliard, Lee\textsuperscript{2},
Howard ,Thomas\textsuperscript{2}, Pernell, Brandi\textsuperscript{2},
Bhatia ,Smita\textsuperscript{2}, and Lebensburger
Jeffrey\textsuperscript{2}.

\textsuperscript{1}University of Alabama at Birmingham School of
Medicine, Birmingham, AL

\textsuperscript{2}Division of Pediatric Hematology and Oncology,
University of Alabama at Birmingham, Birmingham, AL

\textbf{Correspondence:}

Jeffrey Lebensburger, DO, MSPH

1600 7\textsuperscript{th} Ave. S., Lowder Building, Suite 512,
Birmingham AL 35233

Phone: (205) 638-9285

Fax: (205) 975-6377

jlebensburger@peds.uab.edu

\textbf{Word Count}

\textbf{Abstract:} 250

\textbf{Main Text:} 2223

\textbf{Tables:} 4

\textbf{Figures:} 0

\textbf{Supporting Information:} 0

\textbf{Running Title:} Impact of Telehealth on HU Response

\textbf{Key Words} : Sickle Cell Disease, Hydroxyurea, Telehealth,
Socioeconomic Status\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{Abbreviation} & \textbf{Full Term}\tabularnewline
\midrule
\endhead
SCA & Sickle cell anemia\tabularnewline
HU & Hydroxyurea\tabularnewline
UAB & University of Alabama at Birmingham\tabularnewline
HbF & Fetal hemoglobin\tabularnewline
SES & Socioeconomic status\tabularnewline
CBC & Complete blood count\tabularnewline
EMR & Electronic medical record\tabularnewline
ANC & Absolute neutrophil count\tabularnewline
ED & Emergency department\tabularnewline
Hb & Hemoglobin\tabularnewline
MCV & Mean corpuscular volume\tabularnewline
\bottomrule
\end{longtable}

Portions of this manuscript were presented as an abstract titled
``Outcomes of Hydroxyurea Dose Adjustment Via Telehealth'' at the
62\textsuperscript{nd} ASH Annual Meeting and Exposition, December 5-8
2020.

\textbf{Abstract}

\emph{Background}

It is important to ensure access to hydroxyurea (HU) for patients with
sickle cell anemia (SCA) living in rural areas without easy access to
experts in sickle cell management. The UAB Pediatric Sickle Cell
program's satellite clinics reduce the barrier of transportation to the
university-based clinic. However, as compared to the university clinic,
these satellite clinics do not offer immediate access to HU dosing
laboratory results. Therefore, a nurse clinician calls families with HU
dose adjustments after the completion of the clinic visit. This study
evaluated the impact of telehealth dosing adjustments on HU laboratory
and clinical response as compared to university-based patients.

\emph{Methods}

A one year retrospective chart reviewed was performed to evaluate HU
laboratory and clinical response based on clinic location and
socioeconomic status for patients with SCA. We identified the number of
clinic and acute care visits for one year and calculated the mean CBC
and HbF values for each patient.

\emph{Results}

We identified 107 academic center participants with SCA prescribed HU
and 65 satellite clinic participants. We identified no difference in
HbF, Hb, MCV, or ANC by clinic location. We also identified no
difference in hospital admissions based on clinic location. Finally,
mean socioeconomic indicators by zip code were lower in satellite clinic
patients but not associated with a difference in HbF response.

\emph{Conclusions}

The use of telehealth did not negatively impact laboratory response to
HU. Future studies should identify novel approaches to improve access to
HU among patients with SCA living in rural areas.

\textbf{Introduction}

Health disparities have been shown to exist in access to hematology care
for patients with sickle cell anemia (SCA) living in Alabama, especially
in rural areas of the state.\textsuperscript{1} To overcome the barrier
of transportation to the academic center in Birmingham, AL, the
University of Alabama at Birmingham (UAB) Pediatric Sickle Cell Program
developed satellite clinics throughout the state.\textsuperscript{2}With
the exception of transfusion therapy, patients living with sickle cell
can receive care at satellite clinics in Montgomery, Opelika, and
Tuscaloosa, AL. One clinical difference in available services at
satellite clinics, as compared to the UAB clinic, is that patients
receiving hydroxyurea (HU) therapy have their labs obtained on the day
of their clinic visit, but CBCs are performed in a local lab and faxed
back to the UAB Hematology office and fetal hemoglobin (HbF) levels are
processed in Birmingham when the medical team returns to the UAB campus.
Therefore, sickle cell providers do not have immediate access to HU
dosing labs during the satellite clinic visit. To address this barrier
of conducting HU monitoring clinic visits without immediate access to
labs, we developed a telehealth model in which a nurse receives the
faxed laboratory results, evaluates the laboratory values relevant to
our institutional HU dosing guidelines, confirms dosing changes to
achieve maximal tolerated dose with a sickle cell provider, and then
calls the patients to review laboratory results and educates on any
changes to the HU dosing plan.

Recent data identified that titrating HU to a maximal tolerated dose
leads to superior clinical outcomes as compared to lower dose
regimens.\textsuperscript{3} Therefore, sickle cell centers should
ensure that patients with SCA achieve their maximally tolerated dose of
HU. Novel techniques are being developed so that patients can be
initiated on a HU dose that is at or near their maximal tolerated
dose.\textsuperscript{4,5} Without this novel approach to initiate HU at
a maximal tolerated dose, clinical centers often achieve maximal
tolerated dosing and a high HbF level by titrating HU doses at each
visit based on CBC results, often targeting a specific neutrophil
count.\textsuperscript{6,7} Unique barriers may exist for programs
prescribing HU in satellite clinics and/or using telehealth or
telemedicine for dose adjustments if labs are not readily available.

Higher HbF levels and HU dosing have been achieved in other institutions
and during clinical trials as compared the mean levels at UAB;
therefore, our program identified a systematic need to improve HU
response to therapy among our patient
population.\textsuperscript{6,8}Prior to implementing any novel
approaches to improve adherence, we performed this study to determine if
systematic barriers exist in HU dosing adjustments based on our
telehealth plan for satellite clinics. We hypothesized that telemedicine
dosing, where the medical provider does not review laboratory results
and make in-person HU dose adjustment at the time of their medical
visit, would not result in lower HU response to therapy. To test this
hypothesis, we evaluated the HU dosing and adherence laboratory values
for patients cared for at both the UAB Pediatric Sickle Cell Clinic at
Childrens of Alabama and satellite clinics over a one year period. We
also evaluated the association between zipcode based socioeconomic
indicators on HU response outcomes.

\textbf{Methods}

We performed a one-year retrospective review of 172 HbSS and HbSb0
thalassemia patients prescribed HU during 2019 that were cared for in
either the academic center (Birmingham) or satellite clinics
(Montgomery, Tuscaloosa, Opelika). Patients prescribed HU older than age
18 at the beginning of 2019 were excluded. We excluded two patients with
HbSD, twenty-two patients with HbSC, and seven patients with Hb Sb+
thal. We excluded SCA patients on HU and a second sickle cell disease
modifying therapy, such as chronic transfusion therapy or an
investigational or novel SCA drug therapy. We abstracted from the EMR:
age, sex, clinic location, diagnosis, HU dose (mg/kg), white blood cell
count, hemoglobin, mean corpuscle volume, platelet count, absolute
reticulocyte count, hemoglobin F, and absolute neutrophil count from
each clinic visit. We recorded the total number of well-clinic visits
and categorized adherence to clinic visits/year as [?] 2 or
\textgreater{}2; satellite clinic visits are fixed either monthly to
every three months which limited our ability to reschedule patients with
missed visits. Well-clinic visits were limited to HU follow-up
appointments only. We recorded the number of ED visits and UAB pediatric
pain clinic visits and noted if the chief complaint included sickle cell
related pain. We also recorded the number of admissions to the hospital
for a) pain and b) all other sickle cell complications except for
scheduled procedures. We collected acute visit data from the EMR at the
academic center for Birmingham clinic participants and from patient
recall from satellite clinic participants. We evaluated dosing
adjustment as whether dosing was increased for ANC \textgreater{} 4000
per institutional standard of care. We categorized correct dosing
adjustments if \textgreater{} 65\% of visits had a dose adjustment per
institutional protocol; we categorized patients as a deviation from
protocol if the physician did not increase the dose based on ANC. We
defined non-adherence to HU as a HbF\% \textless{} 5. Socioeconomic
variables were assessed using the home address provided by the
participant and analyzing the information available for that geographic
location. Home address information was linked with the census track data
to determine the poverty level and the mean household income for the
census track of the patient's residence.

Our primary outcome for this study was percent fetal hemoglobin: our
primary predictors were clinic location, age, and socioeconomic status.
Our secondary outcomes were difference in hydroxyurea monitoring labs,
clinic visits, and acute care utilization. We performed descriptive
statistics including mean and standard deviation (s.d.), t-test for
continuous variables, chi-square for categorical variables, and
regression modelling using JMP Pro 14 (Cary, NC). P-values
\textless{}0.05 were considered statistically significant.

\textbf{Results}

\textbf{Study population}

We identified 107 participants prescribed HU at the academic center and
65 participants from satellite clinics. The mean age (\selectlanguage{ngerman}±s.d.) of the 172
participants was 11±5 years. Fifty two percent of participants were
female; we did not identify a mean difference in sex of participants by
clinic location (p=0.9). The mean (±s.d.) Hb was 8.5±1.1g/dL, MCV was
91.3±10.1 fL, HbF\% was 12.7±6.7, and ANC was 4.9±2.3
x10\textsuperscript{3}/L. The mean poverty level of all the communities
our participants live in was 18.1±4.2, the mean (±s.d.) median household
income was 50,119±8,298, the mean percent of adults with less than a
high school diploma was 13.5±3.9\%, and the mean percent of adults with
a high school diploma only was 29.1±5.0\% (Table 1).

\textbf{Laboratory and clinical outcomes by clinic location}

We identified no significant differences in HU monitoring laboratory
values for Hb (p=0.6), MCV (p=0.7), HbF (p=0.13), ANC (p=0.9) by clinic
location (Table 2). We did not identify a difference in all admissions
to the hospital (p=0.5) or pain admissions to the hospital (p=0.6)
between academic center vs. satellite clinic patients. However, academic
center patients did have a higher number of acute pain visits (p=0.03)
to either the ED or UAB pediatric pain clinic (Table 3). As expected,
among all participants, non-adherence to HU (HbF \textless{}5\%) was
associated with the highest number of admissions (p=0.02). Among 149
patients with more than one clinic visit, 97 (65\%) patients had more
than 65\% of clinic visits with a correct dose adjustment; we identified
no statistical difference in correct dosing adjustment among Birmingham
patients (67\%) and satellite clinic patients (62\%, p=0.5). Patients
cared for at the academic center had a statistically higher number of
clinic visits (p=0.01) and more patients that attended \textgreater{}2
clinic visits. HbF response was significantly associated with the number
of clinic visits (p=0.03). Finally, HbF response was significantly
inversely correlated with age (p=0.003). Adjusting for clinic location,
number of clinic visits, and age, HbF was associated with age (p=0.006)
and clinic visits (p=0.006), but not associated with clinic location.

\textbf{Difference by Socioeconomic Category}

We identified significantly worse socioeconomic indicators for patients
who attend our satellite clinics as compared to our UAB clinic for
poverty level (20.3±4.2 vs 16.8±3.6, p=0.0001), median household income
(\$45,704±7,048 vs \$52,841±7,853 p=0.0001) and the percent of adults in
the community with less than a high school diploma (15.6±3.5 vs
12.2±3.6, p=0.0001) (Table 4). When analyzing HbF by socioeconomic data,
we did not identify an association between HbF levels with poverty level
(p= 1.0), median household income (p=0.8) or percent of adults in the
community with less than a high school diploma (p=0.7). Finally, we
repeated our regression analysis to determine if community poverty level
or median household income impacted HbF value in addition to our prior
variables of clinic location, age, and number of clinic visits. Again,
only number of clinic visits (p=0.02) and age (p=0.003) significantly
impacted HbF but clinic location did not significantly impact HbF when
including socioeconomic data.

\textbf{Discussion}

It is important for patients with sickle cell anemia prescribed HU to
achieve a high HbF and maximal tolerated dose. A recent randomized
controlled trial demonstrated that titration to maximal tolerated dose
of 29.5mg/kg/day is clinically superior to fixed dose HU at
19.2mg/kg/day dosing and associated with an almost 50\% higher HbF
level.\textsuperscript{3} While our clinical program identified lower
levels of HU response than randomized clinical trial data, our data did
not demonstrate a systematic barrier to achieving a high HU dose and
high HbF response based on the use of telehealth dosing or for aggregate
socioeconomic data. However, we identified one potential systematic
barrier for our satellite clinics to implementing a strategy to achieve
a higher HU response. The total number of clinic visits a patient
completed in a year was associated with a better HU response. The
academic center has the ability to reschedule patients on a near daily
basis; however, we conduct satellite clinics monthly to every three
months depending on the satellite clinic location. Therefore, improving
HU response by targeting more frequent clinic visits may remain a
systematic barrier for institutions that conduct outreach sickle cell
clinics at scheduled intervals. Promising approaches for satellite
clinics would be to incorporate additional telemedicine videoconferences
to review HU adherence or apply novel pharmacokinetic technology that
can identify an initial maximal tolerated dose rather than dose
titration at interval clinic visits.

Patients that admit to poor adherence present a unique challenge to
dosing of HU at institutions that titrate to a maximal tolerated dose by
targeting mild myelosuppression. Clinicians can either increase a dose
of HU despite admitted poor adherence or promote adherence prior to
making dose adjustments for myelotoxicity. At our institution,
clinicians may defer dose adjustment aimed at mild myelosuppresion until
adherence improves. However, without a systematic approach to improve
adherence, our center likely maintains lower dosing and lower HbF
response as compared to other centers. Recent advances in technology
have been developed and tested in pilot studies to improve patient
adherence.\textsuperscript{9-12} These strategies present novel
opportunities to improve adherence in centers currently lacking a
standardized approach to improved adherence.

Literature has demonstrated the association of poverty, negative
socioeconomic factors and poor health outcomes in
children.\textsuperscript{13-15} Our data show that our sickle cell
patients cared for in our satellite clinics live in zipcodes with lower
socioeconomic indicators. This highlights the need to improve adherence
to HU at maximal tolerated dose in order to reduce disparities in acute
care for children living with sickle cell anemia in rural or lower
socioeconomic neighborhoods without immediate access to local pediatric
hematology experts. Our data shows similar HU dosing and response to
therapy utilizing a telehealth monitoring of laboratory values with
phone call dose adjustments by a nurse clinician. Therefore,
interventions to improve adherence to HU in Alabama can be developed and
tested in satellite clinics using telehealth HU dose adjustments.

While our data demonstrated that telehealth dosing allowed a similar
level of HU response among academic and satellite clinic patients, our
study has a few limitations worth noting. To determine hospitalizations
and ED visits, we abstracted data from patient recall in the clinic note
and our institutional EMR. Our data showed a similar number of
hospitalizations between academic center and satellite clinic patients
but a higher number of acute care visits among academic center patients.
This may represent recall bias of acute care visits among satellite
clinics as we do not confirm interval history of acute care visits with
local emergency care centers. However, we often receive records or
transfers to our hospital for patients admitted with a sickle cell
event. Second, we were unable to accurately determine from the medical
records whether a patient was continued at a HU dose despite a higher
ANC based on poor adherence. Therefore, we could only provide anecdotal
evidence that some clinicians in our practice do not aggressively
titrate HU in the setting of admitted poor adherence. Finally, we do not
collect patient specific socioeconomic indicators as standard of care
and therefore relied on zipcode to perform aggregate data analysis.

As acceptance and HU usage increases at academic centers, research must
continue to focus on ensuring dissemination of HU to patients with
sickle cell living in rural areas. This data suggests that telehealth or
telemedicine capacity can be implemented to monitor and titrate HU
therapy in rural populations. Clinicians should not be deterred from
implementing a telehealth strategy in rural areas or consider the lack
of immediate access to lab results a barrier to telehealth. Future data
can also evaluate outcomes of HU dosing response at academic centers
implementing telehealth during the COVID-19 pandemic.

\textbf{Conflict of Interest Statement}

The authors have no relevant conflicts of interest related to this
manuscript. Sarah Shaner MSIII received funding from a Physician
Scientist Development Short Term Institutional Research Training (NIH
T35 -- SHIRT) HLA007473.

\textbf{Acknowledgements}

The authors would like to thank the sickle cell clinical team for
providing excellent care and the patients living with sickle cell.

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\textbf{Legend}

TABLE 1: Overall patient population

TABLE 2: Birmingham vs satellite clinic hematologic outcomes

TABLE 3: Birmingham vs satellite clinic healthcare utilization

TABLE 4: Birmingham vs satellite clinic socioeconomic outcomes

\selectlanguage{english}
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\end{document}

