Keywords:
Sickle cell disease, comprehensive care, comprehensive center,
guideline-based care, implementation
Abstract
Sickle cell disease (SCD) requires coordinated, specialized medical care
for optimal outcomes. There are no United States (US) guidelines that
define a pediatric comprehensive SCD program. We report a modified
Delphi consensus-seeking process to determine essential, optimal, and
suggested elements of a comprehensive pediatric SCD center. Nineteen
pediatric SCD specialists participated from the US. Consensus was
predefined as 2/3 agreement on each element’s categorization. Twenty-six
elements were considered essential (required for guideline-based SCD
care), ten were optimal (recommended but not required), and five were
suggested. This work lays the foundation for a formal recognition
process of pediatric comprehensive SCD centers.
Introduction:
Sickle cell disease (SCD) affects approximately 100,000 Americans,
though exact numbers are not known due to lack of formal
tracking.1 Infants with SCD are identified through
newborn screening, but follow-up processes vary between states,
affecting care access. Unlike other childhood genetic diseases, namely
cystic fibrosis (CF) and hemophilia, there are no defined standards of
SCD care within the United States (US).2 While the
National Heart, Lung, and Blood Institute (NHLBI)’s 2014 “Evidence
Based Care for Sickle Cell Disease” guideline stipulates some pediatric
care elements, and the American Society of Hematology (ASH)’s care
guidelines fill some clinical gaps in the NHLBI document, implementation
is not monitored.3 Evidence from Medicaid claims and a
recent National Institutes of Health (NIH)-funded multicenter
implementation study show that many children do not receive indicated
penicillin prophylaxis4 or annual transcranial Doppler
ultrasound screening.5
Individuals with SCD require highly-knowledgeable, coordinated care
throughout their lifespan. Initiation of preventive therapies early in
life can minimize irreversible organ damage.6,7Pre-symptomatic hydroxyurea initiation, novel therapies, shared
decision-making, and comprehensive preventive care require expertise,
support staff, and time investment. Without mechanisms to monitor
outcomes throughout childhood, there is a lost opportunity to minimize
the lifelong burden of SCD. While >98% of children with
SCD survive into adulthood, the estimated median survival is in the
mid-40s and has not improved over the past 20 years due to limited care
access, few disease-specific therapies, and underinvestment in
SCD.8 The need for comprehensive care was recognized
in the National Sickle Cell Disease Control Act in
1972.9 However, the NIH-funded comprehensive sickle
cell centers were disbanded, and there is no current federal mechanism
supporting comprehensive SCD centers.
In 2019, SCD physicians identified essential, optimal, and suggested
elements of comprehensive SCD care for adults.10 Here,
we report a similar process in which pediatric SCD physicians reached
consensus on essential, optimal, and suggested elements of comprehensive
SCD care. This is the first step towards defining an accreditation
process for comprehensive pediatric SCD centers.
Methods:
We employed a modified Delphi process to establish consensus on SCD care
elements.11 The study initiators (MLH, DM, ERM, JK)
compiled center elements from guidelines, medical literature, and
clinical experience. Consensus was pre-specified as 66% agreement for
each element. Elements clustered in categories: center personnel,
treatments, screening/diagnostic tests, center processes, physical
spaces, and collaborations.
Twenty-one pediatric SCD specialists were invited to participate in the
process during 2021. All invitees were pediatric hematologists at
academic SCD centers, active in research, public health, and/or state
newborn screening programs. Participants of diverse ages, gender,
location, and ethnicity were invited. During the process, three
participants moved from academic practice to industry but continued on
the panel.
In the first questionnaire, participants rated each element as
essential, optimal, or suggested. Essential was defined as required for
comprehensive care, either embedded within the SCD team or via a defined
referral process. Essential elements have evidence-based support in
NHLBI, ASH, or other published guidelines. Optimal elements were defined
as beneficial but not required for guideline-based
care.10 Suggested elements were defined as likely to
enhance treatment but not required for guideline-based care.
Elements that did not reach consensus initially were re-queried in a
second email questionnaire. If one category received ≤3 votes, only the
remaining two options were provided (example: if an element had 7
essential votes, 9 optimal votes, and 3 suggested votes, the
“suggested” choice was removed). Finally, a virtual meeting was held
to categorize elements that had not yet reached consensus. During the
virtual meeting, panel participants nominated four additional elements.
Results:
Of 21 pediatric hematologists invited, 19 participated. The
participants’ SCD programs care for 150 to 1600 patients and are located
in all regions of the United States (Northeast: 2, Mid-Atlantic: 3,
Southeast/South: 6, Midwest: 6, West Coast: 2).
Initially, 37 elements were included. Twenty-four elements reached
consensus via email questionnaires. Fifteen participants attended the
virtual meeting to attain consensus on 13 remaining elements. Four new
elements (nutritionist, timely access to subspecialists, formal quality
improvement process, and formal mechanism for parent/family input) were
added and categorized during the virtual meeting.
Twenty-six elements were considered essential, encompassing center
staff, processes, diagnostic and treatment modalities, and necessary
collaborations outside the core SCD team (Table 1). Ten elements were
considered optimal, including staff, physical spaces, treatments, and
collaborations (Table 2). Five elements were considered suggested,
comprising staff and process elements (Table 2).
Essential elements:
A multidisciplinary team forms the core of the comprehensive pediatric
SCD center. The team must be directed by a physician expert in SCD who
oversees medical care and staff. This physician should have
post-residency training and experience in hydroxyurea, transfusion
therapy, and other SCD-modifying treatments. The multidisciplinary team
includes outpatient nursing staff with SCD experience and a care
coordinator/manager. A social worker dedicated to SCD helps
patients/families navigate the insurance environment and address social
determinants of health.12 Children with SCD experience
cognitive deficits and lower academic attainment, so an education
liaison (a social worker, neuropsychologist, teacher, or nurse) is
essential to support educational attainment.13 A
pediatric hematology team (attending physician, supervising advance
practice providers or residents/trainees, and nurses with hematology
experience) is essential for inpatient care (either by admission to a
pediatric hematology inpatient service or a pediatric hospitalist
service with a consulting pediatric hematologist).
Standardized processes are essential to uniform, guideline-based care.
Newborn screening follow-up ensures affected infants are immediately
engaged in SCD care to initiate penicillin prophylaxis and preventive
care.3,14 Standardized order sets and written
protocols for acute and chronic management, including in the ED, promote
adherence to care guidelines.15 A defined transition
process between pediatric and adult centers (or within a lifespan
center) prevents loss of hematology access, which is associated with
increased morbidity, greater acute care utilization, and early mortality
in young adulthood.16-18 A formal quality improvement
process is essential to evaluate and improve care delivery. Finally, a
formal patient/family input process is essential to ensure SCD care
meets families’ needs and is delivered with cultural sensitivity.
There are essential diagnostic tests and treatments supported by SCD
literature and guidelines. Transcranial Doppler ultrasonography
screening (also known as sickle stroke screening) for primary stroke
prevention in children with hemoglobin (Hb) SS/S-β0thalassemia should be performed in the SCD clinic or in the same
hospital to reduce barriers to care.13 Hydroxyurea
(HU) is recommended for all children with Hb SS/S-β0thalassemia starting at 9-12 months to prevent pain, acute chest
syndrome (ACS), strokes, transfusion needs, and
hospitalizations.3 HU is commercially available as
capsules or tablets, so a compounded liquid form is essential for young
children. Erythrocytapheresis for acute and chronic management is
essential; ASH’s transfusion management guidelines suggest
erythrocytapheresis when long-term transfusion therapy is employed,
including for stroke prevention, and for acute complications such as
severe ACS.19 Magnetic resonance imaging quantitation
of liver iron to assess transfusion-related iron overload is essential
for effective iron chelation.19 Finally, while most
children experience infrequent vaso-occlusive pain that is adequately
managed with standard weight-based dosing of opioids and non-opioid
medications, some benefit from specific pain medications or medication
combinations.15 Therefore, an annual review of each
patient’s pain management, with consideration of an individualized pain
plan, is essential.
Comprehensive care for SCD is multidisciplinary, and collaboration with
other medical teams is essential. Collaboration was defined as regular
communication and availability. Collaboration with a hematopoietic stem
cell transplant (HSCT) team is essential to offer curative therapy,
especially since early consideration of HSCT for children with Hb SS and
S-β0 thalassemia who have an unaffected human
leukocyte antigen-identical sibling was suggested by ASH in
2021.20 Since the goal of pediatric SCD care is
survival into adulthood and continued lifespan care, a partnership with
an adult SCD program is essential.16 Transition
requires not only a referral to an adult hematologist/center, but also
communication with the receiving team to convey essential knowledge
about the patient’s prior care and complications. Additional essential
collaborations included a transfusion medicine specialist to manage
erythrocyte alloimmunization; timely access to medical subspecialists
including surgeons, neurologists, pulmonologists, and nephrologists; a
pediatric neuropsychologist to perform educational and cognitive
assessments; a mental health care provider for children and young adults
with SCD; a gynecologist or other contraception prescriber; and
reproductive care for parents of children with SCD who wish to minimize
the risk of having another affected child.
Optimal elements:
Optimal elements are specific to SCD and likely to be beneficial but are
not required for guideline-based care. Optimal members of the
multidisciplinary team include advanced practice providers who expand
the SCD team’s capacity; dedicated inpatient nursing staff; and physical
therapy and expressive therapies (art, music, child life). A pain
management specialist is optimal; while opioid and non-opioid pain
medications are the mainstay of SCD pain management and can typically be
managed by a hematologist, newer treatments, such as ketamine and
regional anesthesia, are gaining support.15,21 Optimal
physical spaces include a dedicated outpatient clinic, dedicated
inpatient unit, and day hospital/infusion center. Children and adults
benefit from care for vaso-occlusive pain in an infusion center compared
to the ED, with more rapid analgesia administration and lower likelihood
of hospitalization.22,23 Clinical trial availability
is optimal, since enrollment may provide early access to new treatments;
in other diseases, patients receiving care at centers with active
clinical trials may have better outcomes, regardless of
enrollment.24 Partnership with a community-based
organization is optimal. Although some communities lack a local
organization, a community-based organization provides support for the
child, family, and SCD community.
Suggested elements:
Suggested elements are not required for guideline-based care and can be
provided outside the comprehensive SCD program. Suggested personnel
include a clinical pharmacist, primary care physician, genetic
counselor, and nutritionist/dietician. A written business plan detailing
center funding sources, financial impact, and organizational support is
a suggested process.
Discussion:
Although SCD is the most prevalent genetic disease of childhood in the
US, SCD treatment, care infrastructure, and research have been
underfunded compared to CF and hemophilia.22 The
funding disparity has produced limited treatments, few care guidelines
or standards, and inadequate reimbursement compared with other complex
pediatric diseases. Currently, there is no definition of a “pediatric
SCD center” or “SCD comprehensive care”. The components of an adult
SCD center were recently defined in a similar study identifying 19
elements, of which 8 were classified as essential.10Here we report a consensus set of elements required for recognition as a
comprehensive pediatric SCD center in the US.
Literature and guideline review identified most of the included
elements. SCD was historically a childhood condition due to early
mortality, so there are more guidelines for children than for adults,
resulting in a greater number of essential elements for pediatric
comprehensive care. Developmental stages of childhood from infancy
through young adulthood require age-specific elements that are not
needed for adults, such as newborn screening follow-up and transition
education plans. Importantly, as with the adult center study, the Delphi
method was used to identify elements of care as opposed to
defining actual quality outcome measures. The presence of necessary
elements does not guarantee appropriate utilization, so additional
quality improvement, implementation research, and outcomes monitoring
are necessary. Identifying the elements needed for quality care is a
crucial first step to ensuring guideline-based care.
Comprehensive care centers for other pediatric conditions are accredited
by disease-specific not-for-profit organizations, such as the Cystic
Fibrosis Foundation, or designated by public-private collaborations,
such as the partnership between the Centers for Disease Control and
Prevention, Health Resources and Services Administration, and the
National Hemophilia Foundation.2 The
accreditation/designation processes include private or federal funding
for centers and, for hemophilia, participation in the federal 340B drug
reimbursement program. In turn, participating centers have required
oversight and outcome tracking. The opportunity for accreditation of
comprehensive SCD centers, with accompanying funding, would incentivize
hospitals to provide resources necessary for high-quality,
guideline-based care. Center accreditation and tracking of
center-specific outcomes would allow patients and families to compare
care options and pursue the best available care in their region. In the
hemophilia and CF models, accreditation requires center engagement in
quality improvement. As evidence of the success of this approach,
individuals with hemophilia have lower mortality if their care is
managed in an HTC.25 In the Cystic Fibrosis Care
Center Network, collaborative quality improvement initiatives across
centers improve patient outcomes.26,27
Before SCD center accreditation can be implemented, the elements needed
for comprehensive care must be defined. Once pediatric SCD centers are
recognized for having the necessary elements, specific outcome targets
will be developed. Unfortunately, in 2019, the Centers for Medicare and
Medicaid Services declined to add any SCD-related outcomes to the
pediatric parameters reported by state Medicaid programs despite the
Pediatric Measure Application Partnership committee recommendation,
perpetuating a history of excluding SCD from specific
oversight.28 A recent publication urging inclusion of
SCD metrics in the US News and World Report’s “Best Hospitals” program
underscores the benefits of an accreditation process in securing
resources and improving care.29 The care disparities
between SCD and other childhood diseases have been driven by lack of
federal funding and heightened by structural racism, and a standardized
definition of comprehensive SCD care and center accreditation would be a
step towards mitigating these disparities.30
Many children with SCD live far from academic children’s hospitals.
Similar to proposed adult comprehensive care, a “hub and spoke” model
may be feasible, in which a larger accredited center serves as a hub for
smaller, often rural, programs.10 Additional
opportunities include expanding outreach clinics, tele-medicine, and
primary care-SCD partnerships, facilitating comprehensive care close to
home with referrals for complex management such as severe complications,
alloimmunization, or HSCT or gene therapy
treatments.31
The National Alliance of Sickle Cell Centers (NASCC) was founded in 2020
to address the need for SCD center recognition. The NASCC goals are to
support SCD center development, share improvement processes, and
increase access to guideline-based care. It is hoped that the NASCC will
have funding to support essential care implementation and quality
improvement. Currently, NASCC identifies SCD centers through a
recognition process. Eventually, NASCC plans to initiate an
accreditation process for centers meeting care standards. Process
improvement and quality assessment will be embedded in all NASCC centers
to ensure that all individuals receive consistent, equitable medical
treatment regardless of location or socio-economic status.
Limitations of this work are inherent in the Delphi process. This sample
of 19 leaders in pediatric SCD is biased toward urban tertiary-care
centers. A multidisciplinary team is critically important, but
non-physician SCD team members did not participate (e.g. nursing, social
worker, behavioral health). Primary care providers and patient
stakeholders were not involved in this stage. Elements of care will need
regular updates as the field adds new preventive strategies, treatments,
and curative approaches. Future studies will address these limitations,
but this consensus provides a significant foundation for further
development within NASCC.
A critical first step in ensuring high-quality SCD care is to define the
essential, optimal, and suggested components of a comprehensive
pediatric SCD center. With these necessary definitions, accreditation
and federal funding for recognized SCD centers should be pursued to
ensure access to care and quality of care for children living with SCD.
Disclosures:
MLH: consulting: bluebird bio; research funding to institution: Global
Blood Therapeutics, Forma Therapeutics; spouse employment: Pfizer, Inc.;
Scientific Executive Committee co-chair: Sickle Cell Transplant Advocacy
and Research Alliance
DM: consulting: Global Blood Therapeutics, Novartis, Pfizer
ERM: employment: Global Blood Therapeutics
OAA: Advisory board member: Global Blood Therapeutics, Novartis
RCB: Consulting: Global Blood Therapeutics, Imara, Novartis, and Novo
Nordisk; Research funding: Global Blood Therapeutics, Imara, Novartis,
FORMA Therapeutics, Pfizer
MUC: employment: Agios Pharmaceuticals
ADC: consulting: Agios Pharmaceuticals, Forma Therapeutics, Global Blood
Therapeutics, Novartis
TDC: Consulting: Vifor, Forma Therapeutics, Chiesi, Novartis, bluebird
bio, Agios Pharmaceuticals
MJF: none
MMH: Consulting: Vertex/CRISPR Therapeutics, Novartis, AstraZeneca,
FORMA Therapeutics, Pharmacosmos, ORIC Pharmaceuticals, bluebird bio
LLH: Consulting: DuPont/Nemours Children’s Hospital, Hilton Publishing
Co, Westat, Dispersol;
Research grants to institution: Global Blood Therapeutics, Forma
Therapeutics, Cyclerion, Imara; Data Safety Monitoring Board: Aruvant
JSH: Consulting: Global Blood Therapeutics, FORMA Therapeutics, CVS
Health
JDL: Consulting: Agios, Forma Therapeutics, Novartis, Bioproducts
Laboratory
CTQ: Research funding: Emmaus Medical, Merck, Aruvant
NS: Consulting: Global Blood Therapeutics, Novartis, FORMA Therapeutics,
Agios Pharmaceuticals, Emmaus; speaker: Global Blood Therapeutics,
Novartis, Emmaus, Alexion; Research: Global Blood Therapeutics
KSW: employment: Global Blood Therapeutics
CT: Data Safety Monitoring Board: bluebird bio
JK: Consulting: Novartis, Fulcrum Therapeutics, Graphite Bio, ORIC
Pharmaceuticals; Data Safety Monitoring Board: NovoNordisk, Magneta