Sickle Cell Disease in Childhood:

Standards and Recommendations

for Clinical Care

3rd edition
November 2019
This document was prepared on behalf of the Sickle Cell Society by:

Dr Moira Dick, Consultant Paediatric Haematologist (retired), King’s College

Hospital, London

Professor David Rees, Consultant Paediatric Haematologist, King’s College

Hospital, London.

With the assistance of the following advisory group members:

Dr Kofi Anie, Consultant Clinical Psychologist, Brent Sickle Cell and

Thalassaemia Centre, London

Dr Subarna Chakravorty, Consultant Paediatric Haematologist, King’s College

Hospital, London and member of the peer-review team
Susan Raybould, Specialist Nurse Haemoglobinopathy, Birmingham Sickle Cell
and Thalassaemia Service
Cathy Coppinger, NHS Sickle Cell & Thalassaemia Screening Programme,
Public Health England

Giselle Padmore Payne, Senior Clinical Nurse Specialist Haemoglobinopathy

Transition, King’s College Hospital, London
Iyamide Thomas, Sickle Cell Society NHS Engagement Lead, who coordinated
meetings, ran the parent/carer online surveys and conducted a focus group
consultation with parents in London

and additional specialist input from:

Dr Karl Atkin, Department of Health Sciences, University of York

Dr Mark Velangi, Consultant Paediatric Haematologist, Birmingham Children’s
Hospital and member of the peer-review team
Dr Jo Howard, Consultant Haematologist, Guy’s and St Thomas’ Hospital,
London and chair of the UK Forum on Haemoglobin Disorders (until September
2019)
Dr Kate Ryan, Consultant Haematologist, Manchester Royal Infirmary and chair
of the Clinical Reference Group for Haemoglobinopathy Specialist
Commissioning (until March 2019).

i
Acknowledgements
We would like to thank all those colleagues, parents and carers who kindly gave
their time to review this document prior to publication and provided constructive
criticism and helpful suggestions.
In addition, we acknowledge the assistance of:

Jamili Miah, Project Lead NHS Sickle cell & Thalassaemia Screening
Programme, Public Health England who provided help with the online
consultation surveys
Dr Jacky Wilson, Freelance Medical Writer who assisted with the writing and
formatting of this document.

Production

The publication of these standards is an initiative of the Sickle Cell Society and
Public Health England. The members of the advisory group and experts who
provided specialist input donated their time and expertise and received no
remuneration or benefits in kind for their contributions.

Clinical disclaimer
The content of this document is evidence based, as far as available evidence
allows, and reflects the experience and opinions of its authors. However, they,
the Sickle Cell Society, and Public Health England can take no responsibility for
clinical problems arising in individual patients managed in line with its content.
New evidence made available since publication should be taken into account
when using this document.

ii
 Contents

Foreword 1

Abbreviations 3

Introduction to the 3rd edition 4

Background to sickle cell disease in children 9

Overview of healthcare delivery for children with sickle cell disease 14

Standards and recommendations 18

Organisation of care 21

Pathway of care 32

Ongoing issues 48

Chronic complications 59

Acute complications 72

Elective surgery and perioperative care 81

Specific treatments 84

Standards 92

iii
 Foreword

Sickle cell disease is one of the most common serious genetic diseases in
England and, as such, it must be viewed as a mainstream issue for the National
Health Service (NHS). Since universal newborn screening using blood spot
samples was instituted in 2005, over 3000 children have been diagnosed with
the condition. Many of these children come from disadvantaged communities in
urban centres and require services at local hospital and community level, as well
as specialist services that match those available for other conditions (such as
cancer and cystic fibrosis) to foster health equalities and to provide a better
quality of life for both the child and their family.

There have been two previous editions of Clinical Recommendations and

Standards for Care of Children with Sickle Cell Disease. The first in 2006 was
intended to provide guidance for areas where sickle cell disease was not
prevalent and to support the roll out of universal newborn screening in England.
The second edition in 2010 highlighted areas where there was new guidance, for
example in providing transcranial Doppler screening for the recognition of those
children who might be at higher risk of stroke – a devastating consequence for
children and their families. This third edition reflects what has been learned from
peer reviews of hospital trusts across the country (2010–11 and 2014–16), which
looked at what services were being delivered measured against quality
indicators and standards, and also includes the recent guidance from NHS
England on specialist services and networks. It updates clinical
recommendations in several key areas and emphasises the importance of
collecting data and measuring outcomes against robust standards.

The All Party Parliamentary Group for Sickle Cell & Thalassaemia was set up in
response to the report A Sickle Crisis? by the National Confidential Enquiry into
Patient Outcome and Death (2008) and to concerns about inequity of access to
medication to control iron overload due to the need for regular transfusions. Its
stated purpose is to reduce health inequalities by improving standards of care
and by addressing other critical issues recommended by stakeholders. One
initiative has involved discussions with relevant Royal Colleges to increase
training on haemoglobinopathies for all healthcare workers.

Other initiatives to improve services include data collection and the development
of the National Haemoglobinopathy Registry (NHR) so that patient numbers and
outcomes can be accumulated over time, thereby offering a comprehensive
picture for commissioners to substantiate the need for clinical networks and
services across the country. An electronic system for notifying newborns with
sickle cell disease has been launched in 2019 to ensure that no infant is lost to
follow-up after screening at birth and that there will be easy links with the NHR

1
when parents have given consent for their child to be included. In addition, the
National Congenital Anomalies and Rare Diseases register (NCARDRS) in
Public Health England will be monitoring the incidence of haemoglobinopathies
and importantly looking at mortality data. This will provide the basis for a cohort
study and will give valuable information on outcomes, which is not currently
available in England.
We share a great sense of satisfaction in seeing this third edition of the Clinical
Recommendations and Standards published; in particular that it has once again
been the result of collaboration between clinicians, parents and carers, the
Sickle Cell Society and the UK Forum on Haemoglobin Disorders, together with
the NHS Sickle Cell and Thalassaemia Screening Programme and Public Health
England. However, we remain conscious that there is still work to do to ensure
the best possible healthcare is available for sickle cell patients wherever they
live.

Rt Hon Pat McFadden MP, Chair, Sickle Cell and

Thalassaemia All-Party Parliamentary Group

John James, OBE, Chief Executive,

Sickle Cell Society

Dr Farrukh Shah, Chair, UK Forum on

Haemoglobin Disorders

2
 Abbreviations

A&E Accident and emergency

CAMHS Child and adolescent mental health services

GP General practitioner

Hb Haemoglobin

HCC Haemoglobinopathy coordinating centre

HDU High dependency unit

HPFH Hereditary persistence of fetal haemoglobin

LHT Local haemoglobinopathy team

MDSAS Medical Data Services and Solutions

MRI Magnetic resonance imaging

NCARDRS National Congenital Anomaly & Rare Disease Registration Service

NHR National haemoglobinopathy register

NHS National Health Service

NICE National Institute for Health and Care Excellence

PHE Public Health England

PICU Paediatric intensive care unit

PPV Polysaccharide pneumococcal vaccine

RCPCH Royal College of Paediatrics and Child Health

SATs Standard attainment tests

SCD Sickle cell disease

SHT Specialist haemoglobinopathy team

TCD Transcranial Doppler

UKAS UK accreditation service

3
 Introduction

Introduction to the 3rd edition

Changes to this edition 5

Aims of this document 6

4
 Introduction

Sickle cell disease (SCD) is now the most common serious genetic disorder in
England, affecting over 1 in 2000 live births. The majority of cases occur in cities,
where expertise and resources tend to be concentrated 1. Nevertheless, with the
introduction of universal newborn screening for SCD in England through the
NHS Sickle Cell and Thalassaemia Screening Programme, implemented since
2006, affected infants have been identified in all parts of the country 2. SCD can
therefore be regarded as a mainstream health issue in England.
The original standards and guidelines document was published as an ‘executive
summary’ in September 2006; to support the introduction of universal newborn
screening in England. A 2nd edition was published in 2010 with updated
information and reference to other related documents and aimed to provide a more
comprehensive overview of care that might be useful for a wider readership and
not just clinicians. Since 2010 there have been two national peer reviews of
clinical services for children with SCD (2010–11 and 2014–16), carried out by
the West Midlands Quality Review Service, which were informed by the 2nd
edition3. There has also been a specialist commissioning review of services for
patients with haemoglobinopathies 4.

It is proposed that a clinical network should consist of local haemoglobinopathy

teams (LHTs) and specialist haemoglobinopathy teams (SHTs) who will work with
a specific haemoglobinopathy coordinating centre (HCC) to ensure that the roles
and responsibilities for its caseload of patients are clear. Note: in some areas,
the LHT and SHT may be the same. The SHTs and HCCs will be identified
through a compliance exercise and will be required to deliver services through
revised service specifications with contracts starting after 1 April 2019. HCCs will
receive funding to coordinate a support team with multidisciplinary specialists.

Changes to this edition

This 3rd edition has been revised to reflect research and guidance published in
the past 10 years. These include the guidance for preoperative transfusion5, the
long-term management of stroke and switching to hydroxycarbamide (previously
known as hydroxyurea) 6 and the recommendation to offer hydroxycarbamide to
all children from the age of 9 months regardless of their clinical status7. Most of
the clinical recommendations remain the same; however, it is expected that, over
the next 5 years, this will change as new medications come on the market and a
new edition will be needed at this juncture. As well as clinical updates, the
standards have been improved and extra ones incorporated to provide more
consistent and rigorous definitions, with the aim of collecting better data on
clinical outcomes.

Data collection is important to monitor the success of the newborn screening

programme and to measure clinical outcomes, such as the incidence of stroke
and early mortality in children. It is recognised that collection of data, although
understood to be important by clinicians, also adds extra work to busy

5
 Introduction

caseloads. To mitigate this, Public Health England (PHE) and Medical Data
Services and Solutions (MDSAS) has been developing an electronic system for
newborn screening results that will link in with the requirements of the National
Haemoglobinopathy Registry (NHR), the specialist commissioning dashboard
and the National Congenital Anomaly and Rare Disease Registration Service
(NCARDRS). NCARDRS has the responsibility for maintaining a register of all
children with SCD in England, and recording all who have died and whether the
death was directly related to the condition. This register does not require consent
and is not anonymised. It therefore provides an extremely valuable resource for
the future.

Specific revisions to be noted include:

• The standards are defined in line with PHE guidance and Metric Definition
Sets that inform the Specialised Services Quality Dashboard
commissioned by NHS England to aid consistent monitoring.
• Where relevant, standards conform or refer to other related standards e.g.
the newborn screening programme, transcranial Doppler (TCD) screening.
• New standards include the coverage of children offered hydroxycarbamide
therapy, coverage of children on the NHR and the number of children
having an annual review.
• Links have been provided for all other standards in order for the most up-
to-date version to be available at all times.
• The recommendations on cerebrovascular disease, preoperative
transfusion and hydroxycarbamide therapy have been updated.
• The section on delivery of healthcare has been expanded to acknowledge
the effect that socioeconomic determinants have on health.
• A new information technology system for referring infants from newborn
screening into treatment is introduced.

Aims of this document

These recommendations have been written to support clinicians and to ensure
that every infant has access to the same quality of care wherever they live. They
are written for paediatricians, haematologists, specialist nurses and
psychologists, and for those responsible for monitoring outcomes i.e. hospital
trusts, commissioning authorities and peer-review services.
The document is not intended to provide extensive clinical guidance for the
management of acute complications. Prior to 2010, clinical guidelines were
available mainly from the USA. Since the last edition, there have been clinical
guidelines produced by the British Society for Haematology on transfusion in
SCD8.9, acute chest syndrome10 and hydroxycarbamide therapy11. There has
been National Institute for Health and Care Excellence (NICE) guidance on the
management of pain in hospital12 and a NICE-accredited Royal College of
Paediatrics and Child Health (RCPCH) guideline on stroke13, updating the 2004

6
 Introduction

document. Most hospital trusts will now have their own clinical guidelines and
these are readily shared within and between networks and are available online.

This document outlines a model of care for children with SCD who have been
identified through the newborn screening programme. It extends from newborns
until transition into adult care – which is usually between 16 and 18 years. It will
also have relevance for the care of children who may have missed out on
newborn screening before the programme was introduced, or who have come
from abroad and been diagnosed after the newborn period. It is based on a
consensus of clinicians with experience in the UK, Jamaica and the USA.

Note: throughout this document, text that is underlined indicates a link either to a
relevant section within this document or to an external website that the reader may
wish to view; Ctrl + Click will allow the reader to follow the link.

References
1 Streetly A, Latinovic R, Henthorn J. Positive screening and carrier results for
the England-wide universal newborn sickle cell screening programme by
ethnicity and area for 2005–07. J Clin Pathol 2010; 63: 626–9.
2 NHS Sickle Cell and Thalassaemia Screening Programme. Laboratory data
report 2007–2008: Development towards a quality report. Published: 2009.
3 NHS Sickle Cell and Thalassaemia Screening Programme. Sickle Cell
Disease in Childhood: Standards and Guidelines for Clinical Care. 2nd
edition. Published: October 2010.
https://assets.publishing.service.gov.uk/government/uploads/system/upload
s/attachment_data/file/408961/1332-SC-Clinical-Standards-WEB.pdf.
Accessed: 29 August 2019.
4 NHS England. Specialist Haemoglobinopathy Services. Published: 11 July
2019. https://www.england.nhs.uk/publication/specialist-
haemoglobinopathy-services-specialist-haemoglobinopathy-teams/.
Accessed: 29 August 2019.
5 Howard J, Malfroy M, Llewelyn C, et al. The Transfusion Alternatives
Preoperatively in Sickle Cell Disease (TAPS) study: a randomised,
controlled, multicentre clinical trial. Lancet 2013; 381: 930–8.
6 Ware RE, Davis BR, Schultz WH, et al. Hydroxycarbamide versus chronic
transfusion for maintenance of transcranial doppler flow velocities in children
with sickle cell anaemia—TCD With Transfusions Changing to Hydroxyurea
(TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet
2016; 387: 661–70.
7 Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell
disease: summary of the 2014 evidence-based report by expert panel
members. JAMA 2014; 312: 1033–4.

7
 Introduction

8 Davis BA, Allard S, Qureshi A et al. Guidelines on red cell transfusion in

sickle cell disease. Part I: principles and laboratory aspects. B J Haem
2017; 176: 179–91.
9 Davis BA, Allard S, Qureshi A, et al. Guidelines on red cell transfusion in
sickle cell disease. Part II: indications for transfusion. B J Haem 2017; 176:
192–209.
10 Howard J, Hart N, Roberts‐Harewood M, et al. Guideline on the
management of acute chest syndrome in sickle cell disease. B J Haem
2015; 169: 492−505.
11 Qureshi A, Kaya B, Pancham S, et al. Guidelines for the use of
hydroxycarbamide in children and adults with sickle cell disease. B J Haem
2018; 181: 460–75.
12 NICE. Sickle cell disease: managing acute painful episodes in hospital.
CG143. Published: June 2012. https://www.nice.org.uk/guidance/CG143.
Accessed: 2 April 2019.
13 Stroke in Childhood: Clinical guideline for diagnosis, management and
rehabilitation. Published: May 2017.
https://www.rcpch.ac.uk/resources/stroke-childhood-clinical-guideline-
diagnosis-management-rehabilitation. Accessed: 2 April 2019.

8
 Background

Background to sickle cell disease in children

Conditions to be treated 10

Incidence, prevalence and survival 10

Pathophysiology 11

Presentation 11

Variability 12

9
 Background

Conditions to be treated
SCD denotes all genotypes containing at least one sickle gene in which HbS
makes up at least half the haemoglobin (Hb) present. In addition to sickle cell
anaemia (this will be referred to as HbSS in future in this document), there are
other compound heterozygous conditions that occur in the UK. Conditions to be
treated include:
• Haemoglobin SS (sickle cell anaemia)
• Haemoglobin SC*
• Haemoglobin SDPunjab
• Haemoglobin SE
• Haemoglobin S/β thalassaemia (β+, β0, δβ and Lepore)
• Haemoglobin SOArab.
* Note: areas where the management of HbSC differs from HbSS will be shown in this
document in green.

Haemoglobin S/HPFH (hereditary persistence of fetal haemoglobin) is

indistinguishable on neonatal screening from HbSS and HbS/β0 thalassaemia.
Family studies and DNA testing may clarify the diagnosis. HbS/HPFH is not
thought to cause clinical complications and there is no evidence as to whether
children with this should be followed up regularly. There is no evidence that
HbS/HPFH leads to splenic hypofunction and prophylactic penicillin is not
recommended. However, in the absence of both parental phenotypes, it is best
to start penicillin prophylaxis until such time that the diagnosis is confirmed.
HbS/HPFH should not be confused with the more common HbSS where the
child continues to produce relatively large amounts of fetal haemoglobin (HbF)
beyond early childhood.

Incidence, prevalence and survival

SCD is one of the commonest serious genetic conditions in England, affecting
approximately 1 in 2436 live births (2016–17 annual data report). The birth
prevalence in some urban areas may be as high as 1 in 3001. It is found at a low
frequency in all populations, the highest prevalence occurring in people of
African and African-Caribbean origin. Cases also occur in families originating
from the Middle East, India and the eastern Mediterranean, with increasing
numbers of cases in mixed-race families. A recent analysis of multiple databases
concluded there are 14,000 people with a diagnosis of SCD living in the UK2.
Considered a disease of childhood 30 years ago, at least 99% of children in
London are now expected to survive until adulthood 3. Life expectancy has
improved owing to newborn screening and early administration of antibiotic
prophylaxis, improved recognition and better management of acute episodes and
screening for children at high risk of stroke. The introduction of neonatal screening
programmes in parts of the USA dramatically improved healthcare, and childhood
mortality is now about 1–2% in some areas4.

10
 Background

However, in the USA there is a marked geographic difference in the mortality of

young children with SCD, which greatly exceeds the mortality of black children
without the disease5,6. This highlights the importance of having a robust clinical
programme with clear guidelines, evidence-based standards of care and access
to high-quality clinical care wherever a child with SCD lives. Studies in London
suggest that the survival of children with SCD is very similar to that in the non-
sickle population2.
A US multicentre study in 1994 reported a median survival in people with HbSS
of 42 years for men and 48 years for women; in those with HbSC disease of
60 years and 68 years, respectively7. Survival estimates for HbSS in Jamaica,
based on a clinic population, suggested median survival for men of 53 years and
for women of 58.5 years8. A recent study in the UK suggested a median survival of
67 years for adults with HbSS/HbSβ 0 thalassaemia9 probably reflecting that the
NHS is available to all residents, free at the point of use.

Pathophysiology
A single nucleotide substitution in the seventh codon of the β globin gene results
in the substitution of valine for glutamic acid on the surface of the variant β globin
chain. This change causes HbS to polymerise when deoxygenated, the primary
event in sickle cell pathology. Polymerisation is dependent on intra-erythrocytic
HbS concentration, the degree of haemoglobin deoxygenation, pH and the
intracellular concentration of HbF. The polymer is a rope-like fibre that aligns with
others to form a bundle, distorting the red cell into the characteristic sickled
forms.

These deformed sickle red cells can occlude the microvascular circulation
producing vascular damage, organ infarcts, painful episodes and other
symptoms associated with SCD. HbS polymerisation and vaso-occlusion lead to a
cascade of inter-related pathological processes, including anaemia, haemolysis,
disturbed nitric oxide metabolism, inflammation, hypercoagulability, oxidative
stress, hypoxia and vascular-endothelial dysfunction.

A recent review gives a comprehensive account of the current understanding of

the pathophysiology in SCD10.

Presentation
There is a wide range of clinical presentations and severity. In the unscreened
population, infants may present with sudden death from pneumococcal sepsis
due to splenic hypofunction or with acute splenic sequestration, before a
diagnosis is made. Dactylitis is a common presenting symptom in infants
between 9 and 18 months, but many children do not experience this and may
only present later with vaso-occlusion affecting the long bones.

11
 Background

Possible complications may include:

• Painful episodes due to vaso-occlusion – the most common complication,
accounting for the majority of hospital admissions
• Stroke:
− silent strokes (with changes seen on magnetic resonance imaging
[MRI]) occur in up to 20% before the age of 20 years, and may
cause cognitive or psychological problems
− overt strokes are less common since the introduction of routine
transcranial Doppler (TCD) but previously affected 5–10% of the
paediatric population
• Acute chest syndrome – a serious and common cause of morbidity and
mortality, which may be precipitated by infection, infarction or a combination
of the two
• Other complications:
− lung damage
− hepatobiliary disease
− renal disease
− osteomyelitis
− avascular necrosis
− eye complications
− hearing impairment
− priapism
− leg ulcers.

Variability
Some children with SCD are severely affected, while others remain largely
symptom-free in terms of painful episodes. However, many children who do not
experience pain go on to suffer other complications, including progressive organ
damage and vasculopathy.
This variability is not completely understood but may be due to inheritance of
other genes that either affect the types and levels of Hb produced along with
HbS or affect vaso-occlusive events:
• HbSC – co-inheritance of HbC with HbS results in a generally milder
condition (typically half the number of acute painful episodes, less risk of
splenic hypofunction and low risk of stroke)
• HbF level – once the level has stabilised during infancy, it is constant
through life and a relatively good predictor of disease severity 11
• concurrent α thalassaemia carrier status – episodes of acute pain are
more common, but severe, life-threatening complications are less
common.
In addition, a number of socioeconomic factors can affect variability.

12
 Background

References
1 Public Health England. Data report 2016 to 2017: trends and performance
analysis. PHE publications gateway number 2018025.
2 Dormandy E, James J, Inusa B, Rees D. How many people have sickle cell
disease in the UK? J Public Health (Oxf) 2018; 40: e291–5.
3 Telfer P, Coen P, Chakravorty S, et al. Clinical outcomes in children with
sickle cell disease living in England: a neonatal cohort in East London.
Haematologica 2007; 92: 905–12.
4 Centers for Disease Control and Prevention (CDC). Mortality among
children with sickle cell disease identified by newborn screening during
1990–4 -- California, Illinois, and New York. Mort Morb Wkly Rep 1998; 47:
169–72.
5 Davis H, Schoendorf KC, Gergen PJ, et al. National trends in the mortality of
children with sickle cell disease,1968 through 1992. Am J Public Health
1997; 87: 1317–22.
6 Davis H, Gergen PJ, Moore RM, Jr. Geographic differences in mortality of
young children with sickle cell disease in the United States. Public Health
Rep 1997; 112: 52–8.
7 Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life
expectancy and risk factors for early death. N Engl J Med 1994; 330: 1639–
44.
8 Wierenga KJ, Hambleton IR, Lewis NA. Survival estimates for patients with
homozygous sickle-cell disease in Jamaica: a clinic-based population study.
Lancet 2001; 357: 680–3.
9 Gardner K, Douiri A, Drasar E, et al. Survival in adults with sickle cell
disease in a high-income setting. Blood 2016; 128: 1436–8.
10 Piel FB, Steinberg MH, Rees DC. Sickle Cell Disease. N Engl J Med 2017;
376: 1561–73.
11 Platt OS, Thorington BD, Brambila D, et al. Pain in sickle cell disease; Rates
and risk factors. N Engl J Med 1991; 325: 11–16.

13
 Healthcare delivery

Overview of healthcare delivery for children with SCD

Challenges and requirements 15

Health and wellbeing 15

Non-clinical care interventions 16

14
 Healthcare delivery

Challenges and requirements

The provision of equitable and comprehensive care for children with SCD is
uniquely challenging, given the wide geographical variation in prevalence and
known variability in the severity. Care must be delivered at an optimal level both
close to the patient’s home and via access to an SHT. In addition, services
should support young people, parents and family carers to manage the condition
at home where appropriate.
As SCD becomes more common across the UK, every hospital should be able to
provide basic inpatient and outpatient care for local patients. All hospitals with an
emergency department and/or acute paediatric unit should be able to provide
emergency care of acute sickle problems, most commonly severe pain. Units
need to have guidelines to manage acute anaemia that is getting worse,
respiratory problems and more infrequent sickle cell complications, along with
protocols for when these children need to be transferred to a specialist unit.

Health and wellbeing

SCD should be considered as a chronic long-term, life-limiting condition with
acute exacerbations that have far-reaching disabling consequences for
education, family life, social integration and the emotional wellbeing of the child
and family. This requires those working in secondary and tertiary care to work
with those in primary care, social care, education and public health, in addition to
third-sector, voluntary organisations. Care therefore needs to be provided by a
multidisciplinary team, working across sectors and different agency boundaries,
with consistent clear communication being vital. An effective team has a clear
strategy for sharing information, plus sharing and agreement of common goals,
alongside an understanding of each other’s respective responsibilities,
experience, skills and knowledge.
The model of local and specialised centres is well established for the treatment of
such conditions as cystic fibrosis, cancer and haemophilia. The value of
haemoglobinopathy centres has been well documented in the USA1.
The specialist haemoglobinopathy services specification2 has proposed that
there should be a number of HCCs across the country to provide a coordinated
leadership function within their area, supporting SHTs and LHTs in the delivery
of clinical care, and strengthening the network concept. All children with SCD
should have access to those with specialist knowledge and an annual review in
conjunction with an SHT is recommended, along with a transition policy for
transfer to adult care when appropriate. Shared care arrangements will vary
according to local needs and circumstances. It may be appropriate in some areas
for the SHT to visit the local unit and in others for children and their families to
travel to the centre in which the SHT is based.

15
 Healthcare delivery

When organising care, it is important to take into account local community

support and health provision, including child and adolescent mental health
services (CAMHS), education, social services and self-management, as well as
hospital care. Training for general practitioners (GPs), community nursing and
local authority employees will be needed, along with inter-agency agreement on
criteria for referral to social services and education services for additional
support. The voluntary sector (e.g. the Sickle Cell Society) plays an important
part.
Parents should be encouraged to know and use their community teams and to
make use of primary care. Parents who are knowledgeable about their child’s
condition will however often know when home treatments are not working or
when an emergency necessitates them taking their child straight to hospital.
Young people are also increasingly empowered to make choices about their care
options.
Children, young people and their families who have a clear understanding of
their condition are more likely to manage their disease optimally 3. An emphasis
on family education and independent self-care is therefore fundamental to
successful outcomes, particularly given the uncertainties associated with SCD 4.

Non-clinical care interventions

In addition to clinical interventions, there are a number of other important non-
clinical interventions that can help towards improved patient wellbeing5.

Interventions that promote public health, improve outcomes in primary and social
care, and facilitate successful education have the potential to transform lives,
particularly for those with longstanding conditions6. People with SCD are more
likely to be exposed to social factors that contribute to health inequalities, which
can become disabling and create barriers to social inclusion5. These risks factors
include lack of physical activity, social isolation and poor diet, alongside issues
associated with education and employment opportunities, poverty and poor
housing, and inequitable access to health and social care7. Tackling inequalities,
which may cause enduring lifelong effects, is especially important for children8.
Although sometimes neglected, primary care, public health and more socially
orientated provision have important roles to play in supporting those with SCD.
The scope of primary and community provision is necessarily broad. This
highlights the importance of coordination, communication and team-working
between the different stakeholders.

16
 Healthcare delivery

References
1 American Academy of Pediatrics. Health Supervision for Children with Sickle
Cell Disease. Pediatrics 2002; 109: 526–35.
2 NHS England. Specialist Haemoglobinopathy Services. Published: 11 July
2019. https://www.england.nhs.uk/publication/specialist-
haemoglobinopathy-services-specialist-haemoglobinopathy-teams/.
Accessed: 29 August 2019.
3 Taylor D, Bury M. Chronic illness, expert patients and care transition. Sociol
Health Illn 2007; 29: 27–45.
4 Campbell AD, Ross PT, Kumagai AK, et al. Coming of age with sickle cell
disease and the role of patient as teacher. J Nat Med Assoc 2010; 102:
1073–8.
5 World Health Organization. World report on disability. 2011. Available from:
https://www.who.int/disabilities/world_report/2011/en/. Accessed: 24 April
2019.
6 Marmot M, Bell R. Fair society, healthy lives. Public Health 2012; 126: S4–
10.
7 Marmot M, Friel S, Bell R, et al. Closing the gap in a generation: health
equity through action on the social determinants of health. Lancet 2008;
372: 1661–9.
8 Berghs MJ, Atkin KM, Graham HM, et al. Implications for public health
research of models and theories of disability: a scoping study and evidence
synthesis. Public Health Res 2016; 4. Available from:
https://doi.org/10.3310/phr04080. Accessed: 2 April 2019.

17
 Standards and recommendations

Standards and recommendations

Basis of recommendations 19

Grading of recommendations 19

Standards 19

Target thresholds 20

Grouping of recommendations 20

18
 Standards and recommendations

Basis of recommendations
Recommendations are based on evidence, which may have been obtained by:
• randomised controlled trials
• good clinical studies
• clinical opinion based on expertise.

Examples of a strong evidence base in the management of HbSS and

HbS/β0thalassaemia include the use of prophylactic penicillin in children, routine
TCD screening to identify children who might be at risk of stroke and prescription
of hydroxycarbamide to reduce the frequency of painful episodes and acute
chest syndrome.

Grading of recommendations
For the recommendations, the letter in brackets following the recommendation
refers to its grading, as based on the US Agency for Health Care Research and
Quality recommendations.

A Requires at least one randomised trial as part of the body of literature

of overall good quality and consistency addressing the specific
recommendations
B Requires availability of well-conducted clinical studies, but no
randomised clinical trials, on the topic of the recommendations
C Requires evidence from expert committee reports or opinions and/or
clinical experience of respected authorities. Indicates absence of
directly applicable studies of good quality

Standards
The standards are linked to the strong recommendations and provide a
mechanism by which laboratory, nursing and medical care can be assessed
across the country. Some standards are already in use through the NHS Sickle
Cell and Thalassaemia screening programme or have been agreed by NHS
England in the specialist commissioning dashboard. Some are already part of
the quality standards agreed by the UK Forum for Haemoglobin Disorders in
collaboration with the West Midlands Quality Review Service. The screening
programme, after much consultation and several re-iterations, include in their
standards a description of the standard, the rationale behind the standard, a
definition, up to two performance thresholds and appropriate reporting
mechanisms. The value of this approach has been to ensure a clear pathway for
monitoring and recording, thereby allowing for ease of comparison across
different units. For this reason, the same format has been adopted for the
standards in this document.

19
 Standards and recommendations

Target thresholds
All centres should aspire towards attaining and maintaining performance at the
achievable threshold. All centres are expected to exceed the acceptable
threshold. Centres not meeting the acceptable threshold are expected to
implement changes to ensure sustained improvement. For some of the
standards, it has not been possible to set an acceptable or achievable standard
e.g. the coverage of hydroxycarbamide. These will be suggested once the peer-
review process gives feedback on current practice.

Grouping of recommendations
The recommendations have been divided into the following sections:
• Organisation of care (community- and hospital-based care)
• Pathway of care (from newborn screening to transition to adult care)
• Ongoing issues (often managed at home/in the community)
• Chronic complications (usually requiring hospital care)
• Acute complications (usually requiring urgent inpatient care)
• Elective surgery and perioperative care
• Specific treatments.
These are followed by the eight standards, which cover:
• reporting of newborn screen-positive results to parents
• timely follow-up, diagnosis and treatment of newborn infants with a
positive screening result
• timeliness of penicillin prophylaxis
• coverage of pneumococcal immunisation
• coverage of TCD scanning
• offer of/treatment with hydroxycarbamide
• registration on the NHR
• performance of an annual review.

20
 Organisation of care

Organisation of care

Community-based services/individuals involved in the care of

children with SCD 22

Primary care 22

Sickle cell and thalassaemia community centres 22

Community specialist nursing and counselling 22

Local authorities 23

Welfare benefits 23

Education 24

Community paediatrics 24

CAMHS and other psychological interventions 25

Roles and responsibilities of those providing community services 25

Hospital-based care for children with sickle cell disease 27

Role of the haemoglobinopathy coordinating centre 27

Definition of specialist haemoglobinopathy team 27

Role of specialist haemoglobinopathy team 27

Role of the local haemoglobinopathy team 28

21
 Organisation of care

Community-based services/individuals involved in the care of children with

SCD
Primary care
With improved staff knowledge and training, primary care is increasingly
important in the management of SCD, although its potential is not always
realised1,2. The primary care team may be involved in:
• genetic screening
• offering reproductive and health advice
• providing routine screening and testing
• preventive care such as immunisation
• follow-up after emergency admission
• coordination of care, including for patients who may have multiple co-
morbidities and unrelated health issues alongside SCD – liaison with the
sickle cell team is important before referring for any potentially SCD-
related problem (e.g. hip pain).
Practical information that needs to be given by the acute hospital to the general
practitioner includes:
• steady state values
• the information that has been given to parents
• dosages of medications
• when children can be managed at home or need to be seen in hospital.

Sickle cell and thalassaemia community centres

In areas of high prevalence, there may be sickle cell and thalassaemia
community centres that provide an information resource, support and advice to
families, training for health and other professionals, as well as genetic
counselling and specialist nursing. A list of centres is available from the Sickle
Cell Society. Where possible, parents should be put in touch with their local
centre.

Community specialist nursing and counselling

Models of community specialist nursing for sickle cell care vary across the
country and there are no nationally agreed models of nursing care. Community
nursing teams make an important contribution to care. This may include social,
psychological support, genetic counselling and more practical nursing support
(such as review of medications and pain management).
Community nursing may be provided as a standalone community service, often
as part of a community sickle cell and thalassaemia community centre or as part
of a wider community NHS directive. They may also be integrated with the acute
haemoglobinopathy team.

22
 Organisation of care

Local authorities
Local authorities are now responsible for commissioning health visiting and
school nursing services. Since the 2012 Health and Social Care Act, local
authorities have set up health and wellbeing boards that bring together the NHS,
public health, adult social care and children's services, including elected
representatives and Local Healthwatch, to plan how best to meet the needs of
their local population and tackle local inequalities in health.
Every local authority must protect and promote the welfare of children in need in
its area. To do this, it must work with the family to provide support services that
will enable children to be brought up within their own families.
Children in need are defined in law as children who are aged under 18 and:
• need local authority services to achieve or maintain a reasonable standard
of health or development
• need local authority services to prevent significant or further harm to
health or development
• are disabled.

The local authority must keep a register of children with disabilities in its area but
does not have to keep a register of all children in need.

Local authorities provide for children with SCD as they do for other children who
may be ‘in need’ or experience an ongoing disability. Children with SCD, unless
they have a chronic disability such as stroke, do not fulfil the criteria for
acceptance onto the disability register for social services departments. This is
despite the fact that frequent acute exacerbations disrupt normal life and may be
as disabling as other chronic conditions.

Unfortunately, with no clear guidelines on what services should be available to

them, it can be difficult for families to negotiate social care provision.

Welfare benefits
While children and their families may not be able to access a social worker, there
may be welfare benefits that can mitigate some of the problems they face. In
some areas, a welfare benefits adviser is an integral part of the community sickle
cell centre. In other areas, it should still be possible to refer parents to their local
welfare benefits advisor. However, it may still not be easy to claim benefits,
especially as SCD can cause intermittent problems, meaning needs can
fluctuate. Because information on benefits can change frequently, details of
benefits that it may be possible to claim will not be listed in this document.

Provision of suitable housing is also key as cold damp conditions can precipitate
painful episodes. Ease of access with the minimum of stairs may also be
important for some.

23
 Organisation of care

Education
Education can mitigate against the impact of longstanding conditions, having an
important long-term role in improving quality of life3. Educational qualifications
can protect against socioeconomic disadvantage, but education providers can
struggle to accommodate the needs of children with SCD 4. For example, children
with SCD are only monitored if they have been found to have a learning disability
and defined special educational needs 5. Even then, most special needs resource
has been devolved to the local school, who provide only as much extra support
as they can afford. Most children, when well, should however be able to attend
school regularly and take part in all school activities.

There is a particular need to inform school teachers that overt or silent stroke
can cause cognitive impairment that leads to learning difficulties6, occurring in
about 20% of those with SCD under 20 years. These acquired impairments may
be missed in children who when they started school had no difficulties. It is vital
that teachers liaise with the clinical nurse specialist if they become aware of any
decrease in cognitive functioning. A formal neuropsychology assessment, which
can be performed either by a neuropsychologist or an educational psychologist,
is likely to be required.
Many children can attend school, despite having mild-to-moderate pain, if there
is a care plan in place. It is of great concern that some children have a very low
school attendance because of parental concerns that they will not be managed
appropriately4. There is Department of Health policy for managing medical
conditions in schools7 and parents and clinicians should be aware of this and
work closely with the school nursing service and the school to ensure its
implementation.
Most children should be encouraged to take part in all school activities. Children
who need additional and specialist help in school to access learning should be
able to achieve this through the special educational needs process 8. Helpful
information is available in the leaflet Sickle Cell and Thalassaemia: Education,
Health and Care. A guide to School Policy and the booklet A parent’s guide to
managing sickle cell disease.

Community paediatrics
Community paediatricians already have extensive experience in coordinating
community services and liaising with education, social services, the voluntary
sector, CAMHS and the acute sector. They can therefore be a valuable
resource.

24
 Organisation of care

CAMHS and other psychological interventions

CAMHS are available in every borough, although they have limited resources to
manage children who do not have a mental health diagnosis. Counselling
services can be accessed in some schools. These community services need to
link to those in hospital departments where there is specialist sickle cell
psychology provision.
Psychological interventions can be especially valuable in helping children and
families build resilience1. SCD can pose multiple and severe psychological
challenges to children, young people and their families, although health and
social care agencies can sometimes struggle to accommodate these
challenges2. Psychosocial issues for people with SCD and their families can
result from the impact and disruption due to pain and other symptoms on their
daily lives. For example, stress, depression, fear or anxiety may affect the
experience of pain. Psychological therapies with children and young people have
been shown to be effective in reducing pain and, therefore, hospital admission3.
While group psychoeducation for families of children and adolescents with SCD
has shown improvements in understanding1.

Roles and responsibilities of those providing community services

The roles and interlinkages of those providing care to children with SCD in the
community are shown in the flowchart on the following page.

Recommendations
• There should be a network of care based on local community care, including
GPs, the local sickle cell and thalassaemia centre (if available), health visitors,
voluntary sector and school nurses, with links to the relevant
haemoglobinopathy teams. (C)
• Parents should be put in touch with local and national voluntary
organisations and local sickle cell and thalassaemia centres. (C)
• GP and community nurses should be kept informed about patients on a
regular basis. (C)
• There should be community paediatric services to coordinate the
community needs of the child and to liaise with CAMHS, local authority
services and the voluntary sector as needed. (C)
• Local authority services (including education and social services) should
be aware of the specific needs of children with SCD and their families. (C)
• Any child with a deterioration in cognitive functioning should be assessed
by an educational psychologist or clinical/neuropsychologist. (C)
• CAMHS should be aware of the specific emotional and learning needs of
children with SCD and their families. (C)
• Parents need to know how to access welfare benefits. (C)

25
 Organisation of care

LOCAL AUTHORITY
Welfare benefits advisor Social services Education
Advice on range of welfare Recognition of a child as Regular awareness training for school staff
benefits ‘child in need’
Early recognition of child with acquired learning
Support in completing forms Registration on children’s difficulties e.g. from silent or overt stroke
disability register as
appropriate Support of child with identified learning disability or with
chronic health problems impacting on education
Respite where appropriate
Voluntary sector Assessment by educational psychologist
Provision of information about
condition and local resources
Support and respite for families
Advice re. signs Care plan for
Provision of advocacy services and symptoms
Liaison re. use in school
Facilitation of service user needs of child
feedback and engagement

School nurse
Health-promotion
advice and screening
Community paediatrician
Assessment of children with
developmental delay and learning
disabilities Health visitor
Health-promotion advice and
Coordination of community
screening
services in cases of chronic
disability e.g. stroke Training Targeted visits (following local
and guidance for child in need)
support

Specialist GP
nurse/counsellor Training NHS
Register details of child’s condition
Antenatal screening and and
support Start penicillin prophylaxis for an
genetic counselling
eligible child by age 90 days
Specialist support to child Maintain
close Provide immunisations (universal and
and family following
liaison additional for SCD)
diagnosis
Provide primary care for common
Ongoing advice throughout
childhood ailments
childhood and into adult life
Manage straightforward SCD
Specialist nursing input on
complications e.g. mild-to-moderate
pain management and
pain
medication
Be aware of:
Social and psychological
– co-morbidities Practice nurse
support
– when a child needs to be seen in
Give immunisations
hospital
Provide treatments
CAMHS e.g. dressings for
Assessment and management leg ulcers
of children with emotional and
behavioural challenges (clinical
psychology services)
Assessment of learning abilities
e.g. following a stroke
(neuropsychology services) Local and specialist haemoglobinopathy teams
(overseen by haemoglobinopathy coordinating centre)

26
 Organisation of care

Hospital-based care for children with SCD

Role of the haemoglobinopathy coordinating centre (HCC)
Responsibilities include:
• supporting local providers to ensure all patients are registered on the NHR
• ensuring local and national guidelines are in place
• identification of a TCD screening lead
• ensuring NICE guidance is followed for automated red cell transfusions.

Full details and a list of indicators are available in the HCC service specification
(https://www.england.nhs.uk/wp-content/uploads/2019/07/Haemoglobinopathy-
Coordinating-Centres-Service-Specification.pdf).

Definition of specialist haemoglobinopathy team (SHT)

SHTs should fulfil the following criteria:
• have a designated paediatrician/paediatric haematologist/haematologist
with a specific interest in paediatric haemoglobinopathy
• have a lead nurse
• have a designated paediatric haemoglobinopathy clinic (which may be part
of a larger clinic)
• provide paediatric high dependency and intensive care, or have
established protocols for the referral of patients to a hospital with a
paediatric high dependency or intensive care unit (HDU/PICU) with
experience and protocols for the management of SCD in children
• have clinical pathology (CPA)-accredited laboratory facilities for accurate
haemoglobinopathy diagnosis
• have established links with local neonatal screening programme and sickle
cell counsellors
• have access to TCD scanning
• have links with clinical psychology for specialised treatment and
neuropsychological assessment or cognitive testing
• participate in the peer-review process.

Role of SHT
The SHT will:
• work with a specific HCC to ensure the roles and responsibilities for its
caseload of patients is clear
• agree and monitor compliance with network care pathways and treatment
protocols
• support the provision of coordinated expert care and advice within the
network

27
 Organisation of care

• provide 24/7 advice for other clinical teams both within the hospital and at
other local hospitals
• support the provision of routine non-complex care for its local population
and be responsible for ensuring all of their patients have an annual review
• ensure all consented patients in their network are registered on the NHR.

All SHTs should provide:

• paediatric and adult outpatient review and care; annual reviews; referral
for specialist diagnostic investigations; discussion of disease modifying
treatments; discussion of new treatments and new trials; and
neurocognitive assessment and review (see Standard 8)
• nursing care by staff with experience in haemoglobinopathies
• transition care from paediatric to adult services
• support from a psychologist with a specialist interest in
haemoglobinopathies
• specialist support and advice on conditions such as transfusion reactions,
severe or recurrent painful vaso-occlusive episodes, acute sickle chest
syndrome and aplastic crisis
• advice on complex care surgery
• initiation of hydroxycarbamide treatment, blood monitoring and dose
escalation as appropriate
• advice on acute organ failure
• transfusion management including decisions regarding initiation and
cessation of elective transfusion programmes
• prescription and routine monitoring of iron chelating drugs.
They should also provide or have clear referral pathways within their network to
provide the following:
• neurocognitive assessment and review
• MRI assessment of liver and cardiac iron
• management of complications related to iron overload, endocrine and
growth issues
• management of complex patients and those with co-morbidities
• advice and referral for stem cell transplant, novel and curative therapies
• specialist advice for the management of pregnancy in conjunction with
expert obstetric teams.
Further details are available in the SHT service specification
(https://www.england.nhs.uk/wp-content/uploads/2019/07/Specialist-
Haemoglobinopathy-Teams-Service-Specification.pdf).

28
 Organisation of care

Role of the local haemoglobinopathy team (LHT)

The LHT, which in some places is the same as the SHT, should:
• have a named paediatrician to link in with the SHT and neonatal screening
laboratory
• arrange initial contact with the family and provide a paediatric clinic for
routine outpatient management
• promote and support management at home by the parents, GP and
community sickle cell and thalassaemia centre (if available)
• manage severe acute pain and acute anaemia, and provide initial care for
other complications before transfer to the SHT according to shared
guidelines and protocols
• liaise with the SHT for annual review
• follow-up children who fail to attend, reporting to the SHT on annual
activity as part of a network review meeting
• liaise with local authorities e.g. education and social services
• manage transition to the adult service
• provide accurate, comprehensive and timely data to the Newborn
Outcomes system to enable the outcomes of newborn screening to be
evaluated
• complete and update entries into the NHR (when consent has been given).

Recent peer reviews reveal very wide discrepancies in staff resources across
different units. The areas most affected are medical and specialist nursing provision
together with psychology support. Some variation in staffing is inevitable as it will
depend on other factors such as number of available supporting staff and case mix.
However, an expected minimum requirement might be: one whole-time equivalent
(WTE) consultant paediatric haematologist (or paediatrician with expertise in
haemoglobinopathy disorders) and one WTE specialist nurse for every 200
patients with a major haemoglobin disorder based at any centre, with one WTE
psychologist recommended by the British Psychological Society (BPS) for every
300 patients. In addition, the following was suggested after a survey of medical
specialists treating haemoglobinopathy patients in England1:
• 0.25 programmed activities (PAs) for continuing professional development
(CPD) per consultant
• 1.5 PAs for every 50 patients for direct clinical duties
• 1 PA for the geographical area clinical lead
• Additional PAs as required (e.g. for specialist training, laboratory work,
research, outreach clinics).

Recommendations
• Organisation of care at the LHT and SHT levels should be in line with the
findings of the specialist review. (C)
• The LHT and SHT should work closely with the HCC. (C)

29
 Organisation of care

• There should be a named paediatrician responsible for follow-up in the

LHT. (C)
• There should be a named paediatrician and/or paediatric haematologist in
the SHT. (C)
• There should be access to nurses experienced in caring for children with
SCD. (C)
• There should be access to clinical psychology services. (C)

References

Community-based services
1 Al Juburi G, Okoye O, Majeed A, et al. Views of patients about sickle cell
disease management in primary care: A questionnaire-based pilot study.
JRSM Short Rep 2012; 3: 1–5.
2 Jacob E, Childress C, Nathanson JD. Barriers to care and quality of primary
care services in children with sickle cell disease. J Adv Nurs 2016; 72:
1417–29.
3 Berghs MJ, Atkin KM, Graham HM, et al. Implications for public health
research of models and theories of disability: a scoping study and evidence
synthesis. Public Health Res 2016; 4. https://doi.org/10.3310/phr04080.
Accessed: 2 April 2019.
4 Dyson SM, Abuateya H, Atkin K, et al. Reported school experiences of
young people living with sickle cell disorder in England. Br Educ Res J
2010; 36, 125–42. https://doi.org/10.1080/01411920902878941. Accessed:
2 April 2019.
5 Dyson SM, Atkin K, Culley LA, et al. Disclosure and sickle cell disorder: A
mixed methods study of the young person with sickle cell at school. Soc Sci
Med 2010; 70: 2036–44.
6 Dyson S. Sickle cell and thalassaemia: A guide to school policy v2. Open
Education Resource 2016. http://sicklecellanaemia.org/policy/version-2-
guide-to-school-policy-for-young-people-with-sickle-cell-disease/. Accessed:
2 April 2019.
7 Department for Education. Supporting pupils at school with medical
conditions. Statutory guidance for governing bodies of maintained schools
and proprietors of academies in England. Published: December 2015.
Available from: https://www.gov.uk/government/publications/supporting-
pupils-at-school-with-medical-conditions--3. Accessed: 26 April 2019.
8 Department for Education. Special educational needs and disability. A guide
for parents and carers. Published: August 2014. Available from:
https://www.gov.uk/government/publications/send-guide-for-parents-and-
carers. Accessed: 26 April 2019.

30
 Organisation of care

CAMHS
1 Anie KA, Green J. Psychological therapies for sickle cell disease and pain.
Cochrane Database Syst Rev 2015; 5: CD001916.
2 McClish DK, Penberthy LT, Bovbjerg VE, et al. Health related quality of life
in sickle cell patients: The PiSCES project. Health Qual Life Outcomes
2005; 3: 50.
3 Eccleston C, Palermo TM, Williams A, et al. Psychological therapies for the
management of chronic and recurrent pain in children and adolescents.
Cochrane Database Syst Rev 2014; 5: CD003968.

Hospital-based care
Ryan K. Caring for haemoglobinopathy patients: Report of a national
workforce survey. Available from: https://www.haemoglobin.org.uk/wp-
content/uploads/2017/07/workforce-survey-2782015.pdf. Accessed: 23 May
2019.

31
 Pathway of care

Pathway of care

Initial identification of disease 33

Communication of initial screening result 33

Informing parents 33

Confirmation of diagnosis 35

Outpatient care 35

Organisation of follow-up 35

The consultation 38

Provision of transcranial Doppler ultrasonography 39

Education about sickle cell disease 39

The annual review 40

Inpatient care 41

Provision of PICU/HDU 42

Provision of stem cell/bone marrow transplantation 42

Transition to adult service 43

32
 Pathway of care

Initial identification of disease

Parents of all babies born in England, Wales, Scotland and Northern Ireland are
offered screening for SCD as part of the newborn bloodspot screening
programme.
National blood spot laboratories are assessed by the UK Accreditation Service
(UKAS) and must meet ISO 15189. The newborn screening programme set
standards for the initial contact with the parent and registration in paediatric
follow-up.

Communication of initial screening result

Bloodspots samples are sent to one of 13 newborn screening laboratories and
the results of all infants who may have a type of SCD are sent as a matter of
urgency to the nominated coordinating centre and the named individual. The centre
confirms receipt.
Data is shared with NCARDRS who have permission from the National
Information Governance Board under section 251 the NHS Health Act 2006 and
the authority of the Health Service (Control of Patient Information) Regulations
2002 to collect patient-identifiable data without the need for individual informed
consent for the purposes of congenital anomaly and rare disease registration. As
from 2019 this system will be automated by the Newborn Outcomes System,
improving the effectiveness of the whole system.

The NHR is commissioned by NHS England, with data collected from clinicians
in haemoglobinopathy teams. It is a database of patients with haemoglobino-
pathies living in England, its central aim being to improve patient care – initially it
was set up to aid the planning of service delivery but recently it has become
more of a clinical register. NHR users are able to view and use the Newborn
Outcomes System but the NHR is a consented register and no data crosses into
it until consent has been explicitly recorded. Additional data items recorded on
the NHR are not shared back to the Newborn Outcomes system.
Information about what personally identifiable information is used by the
screening programmes and why it is required is provided in Screening tests for
you and your baby, a booklet issued to all pregnant women in England, with
more detailed information on the Gov.UK website. This includes the parent’s
right to opt out of their data being held in NCARDRS under Section 251
approval.
More information on the NHR can be found on their website and includes a
patient information leaflet.

33
 Pathway of care

Informing parents
The parents of every child found to have a probable significant haemoglobino-
pathy should be informed by personal contact from the designated healthcare
professional by 28 days after the birth of the child (see Standard 1). Every area
has a named healthcare professional, who may be a paediatrician or a nurse. In
some high prevalence areas, the nurse will be a specialist in SCD.
Although women and their partners should have been offered antenatal screening
and counselling, and should have been fully informed of their risk, this may not
always be the case in reality. It may still come as a shock to learn the diagnosis1.
Early communication from the local named healthcare professional, in a
culturally sensitive way2, is important to provide accurate information and to
ensure that the infant has timely access to prophylactic treatment. There are a
number of leaflets that parents may find useful including Information for mums
and dads: your baby carries a gene for sickle cell and A parent's guide to
managing sickle cell disease.

The primary care team needs to know the diagnosis as soon as possible to provide
ongoing medical and emotional support, and to begin penicillin treatment and
appropriate immunisations. Arrangements for outpatient follow-up should be made
so that the infant is seen by 90 days of age.

Recommendations
• Newborn screening laboratory scientists and clinicians responsible for the
care of screen-positive infants must use PHE’s Newborn Outcomes
System to refer screen-positive infants from screening into treatment
services. (C)
• All parents/carers of infants where SCD is suspected via the newborn
screening programme should be given the result by the time the child has
reached 28 days (see Standard 1). This should be done in a culturally
sensitive manner, respecting the parents’ dignity and individuality. An
interpreter should be provided where necessary. (C)
• The result should be communicated to the family GP and health visitor as
soon as it is received by the specialist nurse counsellor, or named
healthcare professional. (C)
• Newborn infants with a positive screening result should be seen at
paediatric clinic to confirm the screening result or be discharged having
been found to have a clinically insignificant result by ≤90 days of age. (C)
• Penicillin prophylaxis should be offered to all children with SCD (A) and
should be initiated by 90 days of age. (C)
• Appropriate written information about the condition should be provided for
carers. (C)
• Parents should be given the opportunity to have genetic counselling,
especially if they did not take up this option before their child was born. (C)

34
 Pathway of care

Confirmation of diagnosis
Screen-positive infants must have a second sample taken by 90 days so that the
screening test can be confirmed. This is usually done at the first sickle cell clinic
visit, but in some areas may be requested before the child attends clinic. A
confirmatory test is important in case of laboratory or administrative error.
Samples for diagnostic testing should be sent to a laboratory that is UKAS-
accredited and takes part in quality control schemes for haemoglobinopathy
testing. There should be organised links with the neonatal screening laboratory
to feedback about cases identified by the newborn screening programme.
In the absence of the father’s haemoglobin phenotype, it may be difficult to get a
definitive diagnosis, as HbSS, HbS/β0 thalassaemia and HbS/HPFH all have an FS
phenotype on screening. If there is any doubt, DNA analysis should be requested
from a specialist unit.

Penicillin prophylaxis should be instituted for all children whilst waiting for the
diagnosis to be confirmed. There is no evidence that infants with HbS/HPFH
need ongoing care and prophylactic treatment. This diagnosis must however not
be confused with HbSS and a persisting high level of HbF, which is a relatively
common finding, as these children require antibiotic prophylaxis. If there is doubt,
the child should be treated having HbSS until confirmatory testing is complete.

Recommendations
• A blood sample to confirm the screening result should be taken at or before
the first sickle cell clinic visit and sent to a laboratory accredited by UKAS
to carry out haemoglobinopathy testing. (C)
• DNA analysis should be requested in cases where the diagnosis is unclear.
(C)
• Penicillin prophylaxis should be started while waiting for confirmation of
the final diagnosis. (C)

Outpatient care
Organisation of follow-up
The majority of a child’s care will take place at home, in an outpatient department
or in a GP surgery. Many children require hospital admission at some point, but
only a minority will require frequent admissions. As SCD is a lifelong condition, it
is important to engage with the family early, not only to establish the diagnosis
and start treatment, but also to provide advice, education and support.
The US Department of Health and Human Services’ clinical practice guideline1
outlines the importance of early entry into care for pneumococcal prophylaxis and
the parents’ ability to recognise and manage the signs and symptoms of illness.
In a Jamaican cohort study, parents were able to accurately define spleen size in

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 Pathway of care

cases of acute splenic sequestration, a potentially fatal complication if

presentation is late2.

It is generally accepted that penicillin prophylaxis should start by 90 days of age,

as the level of HbF starts to decline and the risk of splenic hypofunction
increases. The Cooperative Study of Sickle Cell Disease, initiated in the USA in
1978, showed a significant number of acute events, including bacterial
meningitis and sepsis, before the age of 6 months3. Although there is no
evidence for early splenic hypofunction in HbSC and HbS/β+ thalassaemia, the
Cooperative Study showed a significant incidence of pneumococcal infections in
HbSC in the first years of life, indicating that these children should receive the
same treatment and education as children with HbSS. In order to ensure this is
achieved, children should be registered for follow-up in the sickle cell clinic by
90 days of age.
The value of specific follow-up programmes for SCD, particularly after
identification by neonatal screening, has been confirmed over the past 30 years.
A cohort study in Jamaica showed improved survival rates4 and enlistment in
follow-up programmes following neonatal screening in the USA was found to
reduce morbidity and mortality to about 1%5. More recently, a review of children
with SCD identified by universal birth screening in East London showed that a
program of hospital- and community-based care, which included penicillin V
prophylaxis and appropriate vaccinations against pneumococcal infection, was
able to virtually eliminate childhood mortality due to SCD6.

An evaluation of the newborn sickle cell screening programme in England from

2010 to 2016 confirmed that the programme identified all infants and those resident
in England were all in follow-up7. A further benefit of screening is the offer of
regular TCD scans to identify those children at risk of cerebrovascular disease,
with the aim of preventing stroke8.

The aims of regular attendance at a designated sickle cell clinic should be to:
1 encourage adherence to treatment – particularly penicillin prophylaxis and
immunisation programmes
2 continue education on the recognition of signs and symptoms to ensure early
access to medical care when appropriate
3 offer screening tests for other complications of SCD
4 monitor general health, nutrition and growth
5 discuss treatment options, including hydroxycarbamide and stem cell
transplantation.
Treatment options can be offered depending on the nature of complications and
transition to the adult clinic can be organised in a timely fashion. A policy for the
frequency of attendance at the specialist sickle cell clinic can be helpful e.g. a
minimum of 3 monthly during the first 2 years; 6 monthly until the age of 5 years;
and annually thereafter.

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 Pathway of care

Every child with SCD, regardless of where they live, should be offered annual
access to a full range of specialist professionals within the SHT and services to
ensure that their care is optimised. Every network should determine how this
should be organised. In some areas, shared care works well, with an annual visit
to the specialist centre. In others, outreach clinics are much more readily
accessed by parents and carers and the visit can be coordinated with the annual
TCD. Communication between centres is key to effective shared care.
It is important that all families feel supported and have access to specialist advice
and treatment. A qualitative study of pain management 9 showed that where
families were supported and able to cope with their child’s condition, the young
adult was more likely to be able to manage their condition.
There should be regular communication with primary care and, where
appropriate, the wider multidisciplinary team; the parent-held book (provided to
all newborns) should be completed at every visit. Arrangements for follow-up and
shared care should be made explicit. A policy for tracking children who do not
attend should be in place.

The benefits of entering their child’s details onto the National Haemoglobino-
pathy registry should be explained to parents as soon as the child’s screening
test is confirmed. Verbal consent should always be sought from parents.

Recommendations
• An infant screened as having a possible significant haemoglobinopathy
through the newborn screening programme should be seen in a
designated sickle cell clinic by 90 days of age. (C) See Standard 2.
• At the first visit, the family should meet with a doctor and/or nurse
experienced in the management of SCD who can give them accurate
information and advice. (C)
• The parents should be encouraged to consent to their child being entered
on to the National Haemoglobinopathy Registry. (C) See Standard 7.
• Confirmation of the diagnosis, date of first clinic attendance and date of
starting prophylactic penicillin should be returned to MDSAS electronically.
(C)
• There should be regular communication between the SHT, the LHT,
primary care and the community nursing teams. (C)
• There should be a policy for monitoring attendance in clinic and for
following up those families who fail to attend. This should include
documentation of children who have moved to another area. (C)
• There should be ongoing support for the family and promotion of
management of straightforward illness, including uncomplicated pain, at
home. (C)

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 Pathway of care

• There should be access to specialist assessment and treatment when

required. (C)
• Every child should be reviewed at least once a year by the SHT; this may be
by direct consultation, in an outreach clinic or within a multidisciplinary team
setting as appropriate. (C)

The consultation
The following gives a guide as to what should be included in each consultation.
The list is not comprehensive.
The history should include:
• current symptoms and a review of painful episodes, illnesses, any accident
and emergency attendances or hospital admissions since the last
consultation
• a focused enquiry about symptoms e.g. abdominal pain, pica, enuresis,
priapism, headaches, snoring, other neurological symptoms suggestive of
ischaemia
• adherence to penicillin prophylaxis
• adherence to vaccination programme
• a review of how pain and fever is managed at home
• regularity of school attendance and reasons for absence
• outcome of developmental screening tests, school progress and
achievement in national tests (e.g. standard attainment tests [SATs], GCSEs)
• travel plans, in particular if involving air travel, which is associated with
increased risk of complications10. Airlines will have their own regulations
and the need for in-flight oxygen should be discussed with the SHT in
advance.
The examination should include:
• an assessment of growth and development
• a general physical examination, taking particular note of pallor, jaundice,
spleen size, presence of a heart murmur
• blood pressure.

At the first consultation, investigations should include:

• full blood count
• haemoglobin electrophoresis
• reticulocyte count
• blood group and extended red cell phenotype (and genotype where
possible).
As glucose-6 phosphate dehydrogenase (G6PD) deficiency is common in the
same ethnic groups and also induces haemolysis, it is advisable to test for G6PD

38
 Pathway of care

at the first newborn visit when the degree of reticulocytosis is unlikely to produce
falsely elevated results.

Subsequent consultations: it is not necessary to take blood and urine tests at

every visit. It is usually advised that steady state investigations (full blood count,
renal and liver function tests) are carried out at 1 year of age to give a baseline. It
is then possible to assess the severity of any subsequent acute problem.
The frequency of further investigations will depend on the clinical picture but they
would not be routinely performed more than once a year. Blood and urine tests
and other screening tests are performed in well children to provide a baseline
should the child become unwell, and to screen for conditions that may benefit
from treatment. Steady-state oxygen saturations should also be recorded.
TCD scans should be carried out annually from age 2 years (or earlier at the
discretion of the clinic).

Provision of transcranial Doppler ultrasonography

Annual TCD ultrasound assessment of children with SCD from the age of 2 years is
recommended. This is based on the findings of a randomised controlled trial on the
benefits of transfusion in children with raised cerebral blood-flow velocities11.

The NHS Sickle Cell and Thalassaemia Screening Programme has published
Standards and Guidelines for Transcranial Doppler scanning in Children with
SCD. Most of the proposed SHT centres have now developed TCD scanning for
children with SCD or have strong links and referral systems to other specialist
centres. Supervision of this TCD programme is the responsibility of the SHT.

Education about SCD

Certain topics should be emphasised at every clinic visit or contact with the team.
The aim being to:
• educate parents (and then the children themselves) to manage
uncomplicated problems at home
• teach them to recognise the onset of serious complications so that the
child is brought promptly for hospital treatment when indicated.
Where possible, this information should be backed up by written material in the
first language of the parents, and interpreters should be available during
discussions as required.
Topics covered should include (the following list is not comprehensive):
• a simple understanding of the condition
• the importance of penicillin
• the importance of staying up to date with all vaccinations
• management of pain at home

39
 Pathway of care

• the need to seek early advice, along with how to access that advice and
seek admission if necessary, for
− fevers
− respiratory symptoms or other signs of infection
− priapism
− unusual pallor
− weakness (without pain), tingling, loss of speech, or any
neurological complications
• how to detect an enlarged spleen by palpation
• how to recognise dactylitis and other painful episodes
• symptoms and signs of priapism
• when to consult the GP
• when to come to hospital in an emergency
• the need to report any visual symptoms immediately, especially in children
with HbSC
• the need to report any developmental concerns or falling-off in school
achievement
• general advice regarding not getting cold, care when swimming,
maintaining a good fluid intake
• information that should be shared with the child’s school
• the need for any planned surgery to be managed jointly with the surgeon,
anaesthetist and the SHT +/− LHT
• travel advice, including the need to:
− discuss plans with the team in advance
− inform travel companies of the child’s diagnosis
− take out appropriate travel insurance
− for long journeys (e.g. on a plane), keep warm, drink plenty of
fluids and move around when possible
• genetic counselling, contraception
• advice on avoidance of smoking and alcohol.

Recommendations
• Every outpatient visit should provide an opportunity for ongoing education
of the child and family. (C)
• There should be a systematic approach to education, which will vary at
different ages. (C)

The annual review

This should include assessment of progress in general and a review of the
patient’s and family’s knowledge of the condition by an experienced doctor, clinical
nurse specialist or nurse counsellor from the SHT. If possible, a clinical
psychologist should be available at the same visit.

40
 Pathway of care

The annual review can take place at either the SHT or LHT site, depending on
local circumstances. In practice, with the advent of electronic patient records, it is
possible to keep a running assessment of many of the issues outlined below.
The annual review does however give a chance for the annual TCD to be
performed and for updating of the NHR. There should be a written policy on
annual review devised by the SHT.
Issues covered should include:
• review of information provided by the LHT including any investigations
undertaken and treatment given
• clinical review:
− number of hospital admissions
− number and severity of painful episodes (including days off school)
− other complications e.g. splenic sequestration, aplastic crisis,
priapism, gallstones, chest syndrome, stroke
− nocturnal enuresis in children aged >6 years
− assessment of child development
− (for children on regular transfusions) blood volume transfused in
past year
• review of infection prevention:
− penicillin V dosage and compliance
− immunisation record
− (for children on regular transfusions) hepatitis A, B and C serology,
including Hep B surface antibody titre, and CMV serology
• clinical tests (undertaken at visit or performed since last review):
− clinical examination of heart, lungs, liver and spleen
− assessment of growth and development
− blood pressure
− oxygen saturation
− urinalysis, including urine albumin:creatinine ratio
− ferritin
− (for children on regular transfusions) pretransfusion HbS
percentage
− TCD screening and risk of stroke
− (for children on regular transfusions for cerebrovascular disease)
MRI/magnetic resonance angiogram (MRA) of brain
− (for children on regular transfusions) T2*MRI heart and ferriscan of
liver
• consideration and discussion of other treatments e.g. hydroxycarbamide,
stem cell transplantation.
The annual review also provides an opportunity for collection of data as
suggested by the NHR.

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 Pathway of care

Inpatient care
SCD is characterised by both acute and chronic complications. Acute
complications will usually present initially to local hospitals and may be associated
with significant mortality in childhood. Mortality rates have however been reduced
through effective antimicrobial prophylaxis, parental education and appropriate
acute intervention coordinated in dedicated sickle centres employing experienced
and well-trained staff1,2. Protocols should be in place to manage worsening
anaemia, febrile episodes, severe acute pain, acute neurological complications,
acute chest syndrome and priapism.

Every LHT and SHT should have a designated consultant paediatrician and/or
paediatric haematologist responsible for the management of children with SCD.
There should also be a named deputy. Junior doctors involved in the assessment
and treatment of children with acute sickle complications should be made aware
of the possible conditions and their local treatment protocols through regular
education/training sessions.

Provision of PICU/HDU
Some of the proposed SHT centres and many of the LHTs do not have provision
for PICU/HDU or MRI scanning. Arrangements will need to be made to develop
shared protocols with regional paediatric and PICU units where required e.g. for
the assessment and management of acute neurological complications, for
exchange transfusions in an acutely unwell child and for children needing
ventilatory support.

Provision of stem cell/bone marrow transplantation

There are a limited number of units in England that are accredited to provide
haemopoietic stem cell (or bone marrow) transplantation for children. Clinicians
in both LHTs and SHTs should have patient information available on the
eligibility criteria for referral for haemopoietic stem cell transplantation and
information regarding the process. There should be good links between the
referring hospital and the specialist stem cell transplant unit, with agreement in
particular about follow-up arrangements.

Recommendations
• Parents and carers should be made aware of the symptoms and signs
associated with severe and life-threatening complications and know where
to take their child if these occur. (C)
• A care pathway should be in place in the LHT for assessment of the child
in accident and emergency (A&E) and for transfer to a designated ward if
admission is necessary. (C)

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 Pathway of care

• Protocols should be available to cover the management of all acute sickle

cell complications. These should include worsening anaemia, febrile
episodes, severe acute pain, acute neurological complications, acute
chest syndrome and priapism. (C)
• A designated consultant paediatrician and/or paediatric haematologist,
with a named deputy, should be responsible for the management of all
children in the LHT and SHT. Junior doctors involved in assessment and
treatment of acute sickle admissions should be made aware of acute
complications and the local treatment protocols through regular
education/training sessions. (C)
• Communication and transfer to a specified PICU should be readily available
according to an agreed procedure. (C)

Transition to adult service

Transition is ‘the purposeful planned movement of adolescents and young adults
with chronic physical and medical conditions from child-centred to adult-oriented
healthcare systems’1.

The importance of transitional care has been highlighted in the Children’s National
Service Framework Hospital Standards2, Improving the transition of young
people with long-term conditions from children’s to adult health services3 and the
intercollegiate report Bridging the gaps: health care for adolescents4. This
includes a requirement for children and adult services to take the needs of this
group of patients into consideration when planning and developing services.

The 2004 National Service Framework for Children who are ill5 emphasises the
importance of transition and states that ideally within 10 years: ‘Transition to adult
services for young people is planned and coordinated around the needs of each
young person to maximise health outcomes, their life chance opportunities and
their ability to live independently.’

There is a need to involve the GP and community services early in the process,
as they may be expected to take on a wider role as children leave the holistic
care of paediatric outpatients.
In paediatric care, services place very few medical management expectations on
the adolescent (these being placed instead on their parents) and clinicians are
generally knowledgeable about the patient’s condition. In contrast, adult
healthcare services may know less about their patients and/or how their condition
affects them, but generally have higher expectations for medical self-
management. In addition, young adults/adolescents, by definition, have to cope
with numerous changes as they develop their individual identity and deal with
personal priorities of school, work, friends, family, social relationships and
independent living.

43
 Pathway of care

Perhaps the biggest fear for adolescents is how their painful episodes are going
to be managed when they need to be admitted to an adult ward.

Likely differences include:

• significantly lower supervision and direct nursing care on the adult ward
• a reasonable expectation that the adolescent will take a more active role in
managing painful episodes
• fewer visits from doctors
• less structured activity, including school or work supervision
• medical staff, at least initially, being unfamiliar with the individual
• the ‘adult’ analgesic regimen possibly being different from the paediatric
one
• a different visiting schedule, usually more limited and with specific visiting
times, whereas a parent is often allowed to stay at all times on a paediatric
ward.

This all occurs at a time when young people become more at risk of major
complications.
Research indicates that adolescents with SCD have concerns, opinions and
expectations about their future healthcare and medical management. They need
guidance, support and information about available services to help meet daily
challenges6. Adolescents with SCD may have problems of adjustment during a
transition phase and it is important to identify factors that would guide
appropriate interventions7.

Transition care is particularly important as studies have indicated that a risk of

increased mortality and morbidity occurs among young people with SCD if a
robust care pathway is not in place8. In an ideal world, where numbers of
adolescents with SCD are appropriate, there should be:
• an adolescent clinic with both paediatric and adult consultants and
multidisciplinary team members, ‘the joint approach’
• a transition clinic, run in the adult outpatient department, preferably in the
evening as this reduces failure to attend rates; this clinic allows familiarity
with teams and enables young people to conduct their own clinic
appointments in a supportive environment
• a transition nurse specialist/key support worker who will follow these
patients through to their early 20s, ensuring that the vital period between
formal discharge from paediatrics and beginning adult services is
supported, and that the risk of falling between these two services are
minimised
• regular patient meetings, transition workshops/‘adolescent days’ and other
engagement meetings held throughout the year.

44
 Pathway of care

Arrangements need to be flexible9, as children reach maturity at different ages

and puberty is often delayed in children with SCD. Hospital policy may demand
that all children are admitted to adult wards at the age of 16 years, even when
they are emotionally immature.

The National Children’s survey 2014 found that older children were often not
involved in decisions about their care, which was particularly worrying for
children with long-term conditions who were preparing to make the transition into
the adult service6. Evidence to support the transition process in improving patient
outcome is lacking and requires prospective well-designed qualitative studies.
However, patient and clinician experience clearly highlight the need for a well-
structured and supportive transition process. The recommendations made in this
document are based on experience from existing transition clinics in certain
SHTs.

Recommendations
• There should be an accessible hospital transition policy in place and the
introduction of a key support worker, with the aim to start preparation and
planning at an early age e.g. 13–14 years. (C)
• A detailed review should be carried out at 15–16 years to assess the
patient’s knowledge of their condition and treatment concordance,
understanding about SCD management, concerns about healthcare in an
adult setting, emotional readiness for transition, self-efficacy and general
readiness to transfer. (C)
• A transition or adolescent clinic should be available to allow the adolescent
to meet the adult sickle cell team and for a formal review and handover to
take place. (C)
• Adult and paediatric protocols for managing complications, in particular
painful episodes, should correspond as much as possible. (C)

References

Identification of disease
1 Brewin TB. The three ways of giving bad news. Lancet 1991; 337: 1207–10.
2 D’Ardene P, Mahtani A, eds. Transcultural counselling in action. London:
SAGE Publications; 1990.

Organisation of follow-up
1 Department of Health and Human Sciences. Clinical practice guideline for
the management of sickle cell disease. Washington, DC: DHHS; 1993.

45
 Pathway of care

2 Emond AM, Collis R, Darvill D, et al. Acute splenic sequestration in

homozygous sickle cell disease: natural history and management. J Pediatr
1985; 107: 201–6.
3 Gill FM, Brown A, Gallagher D, et al. Newborn experience in the Cooperative
Study of Sickle Cell Disease. Pediatrics 1989; 83: 827–9.
4 Lee A, Thomas P, Cupidore L, et al. Improved survival in homozygous sickle
cell disease: lessons from a cohort study. BMJ 1995; 311: 1600–2.
5 Centers for Disease Control and Prevention (CDC). Mortality among
children with sickle cell disease identified by newborn screening during
1990–4 – California, Illinois, and New York. Mort Morb Wkly Rep 1998; 47:
169–72.
6 Telfer P, Coen P, Chakravorty S, et al. Clinical outcomes in children with
sickle cell disease living in England: a neonatal cohort in East London.
Haematologica 2007; 92: 905–12.
7 Streetly A, Sisodia R, Dick M, et al. Evaluation of newborn sickle cell
screening programme in England 2010–16. Arch Dis Child 2018; 103: 648–
53.
8 Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusion
in children with sickle cell anaemia and abnormal results on transcranial
Doppler ultrasonography. N Engl J Med 1988; 339: 5–11.
9 Maxwell K, Streetly A, Bevan D. Experiences of hospital care and treatment-
seeking for pain from sickle cell disease: a qualitative study. BMJ 1993; 306:
1491–2.
10 Bossley C, Balfour-Lynn IM. Taking young children on aeroplanes: what are
the risks? Arch Dis Child 2007; 93: 528–33.
11 Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by
transfusions in children with sickle cell anemia and abnormal results on
transcranial Doppler ultrasonography. N Engl J Med 1998; 339: 5–11.

Inpatient care
1 Gill FM, Sleeper LA, Weiner SJ, et al. Clinical events in the first decade in a
cohort of infants with sickle cell disease: the Cooperative Study of Sickle Cell
Disease. Blood 1995; 88: 776–83.
2 Lee A, Thomas P, Cupidore L, et al. Improved survival in homozygous sickle
cell disease: lessons from a cohort study. BMJ 1995; 311: 1600–2.

Transition to adult care

1 Blum RWM, Garell D, Hodgman CH, et al. Transition from child-centred to
adult health-care systems for adolescents with chronic conditions. A position
paper of the Society for Adolescent Health and Medicine. J Adolesc Health
1993; 14: 570–6.

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 Pathway of care

2 Department of Health. Getting the right start: National Service Framework

for Children, Young People and Maternity Services: Standard for hospital
services. 2003. Available at:
https://assets.publishing.service.gov.uk/government/uploads/system/upload
s/attachment_data/file/199953/Getting_the_right_start_-
_National_Service_Framework_for_Children_Standard_for_Hospital_Servic
es.pdf. Accessed: 9 April 2019.
3 Department of Health. Improving the transition of young people with long-
term conditions from children’s to adult health services. 2006. Available at:
https://webarchive.nationalarchives.gov.uk/20130124072700/http://www.dh.
gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@en/documents/digi
talasset/dh_4132149.pdf. Accessed: 23 May 2019.
4 Royal College of Paediatrics and Child Health. Bridging the gaps: health
care for adolescents. London: RCPCH; 2003.
http://rcpch.adlibhosting.com/files/Bridging%20the%20Gaps%20-
%20Health%20Care%20for%20Adolescents%202003-06.pdf. Accessed: 23
May 2010.
5 Department of Health. National service framework for children, young
people and maternity services: Children and young people who are ill. 2004.
https://assets.publishing.service.gov.uk/government/uploads/system/upload
s/attachment_data/file/199954/National_Service_Framework_for_Children_
Young_People_and_Maternity_Services_-
_Children_and_Young_People_who_are_Ill.pdf. Accessed: 23 May 2019.
6 Telfair J, Ehiri J, Loosier P, et al. Transition to adult care for adolescents with
sickle cell disease: results. Adolesc Med Health 2004; 16: 47–64.
7 Burlew AK, Telfair J, Colangelo L, et al. Factors that influence psychosocial
functioning in adolescents with sickle cell disease. J Pediatr Psychol 2000;
25: 287–99.
8 Sawicki GS, Garvey KC, Toomey SL, et al. Development and validation of
the adolescent assessment of preparation for transition: a novel patient
experience measure. J Adolesc Health 2015; 57: 282–7.
9 Rosen DS, Blum RW, Britto M. Transition to adult health care for
adolescents and young adults with chronic conditions: position paper of the
Society for Adolescent Medicine. J Adolesc Health 2003;33: 309–11.

47
 Ongoing issues

Ongoing issues

Prevention of infection 49

Antibiotic prophylaxis 49

Immunisations 50

Travel requirements 50

Management of pain at home 51

Nutrition and growth 52

Nocturnal enuresis 54

Dental health 55

Psychological issues 55

Psycho-education 55

Cognitive behavioural therapy 56

48
 Ongoing issues

Prevention of infection
A major aim of neonatal screening and follow-up care is to reduce the morbidity
and mortality from preventable disease by antibiotic prophylaxis and
immunisations.
Splenic hypofunction resulting from splenic infarction, usually from the first
6 months of life, means that children are at a greatly increased risk of infection by
organisms expressing polysaccharide antigen, such as Streptococcus
pneumoniae (pneumococcus) and Haemophilus influenzae. A national
observational cohort study (2010–15) in England showed that children with
HbSS had a 49-fold higher risk of invasive pneumococcal disease compared
with their peers without SCD1.
Children with SCD are more likely than the general population to be transfused
for complications such as acute splenic sequestration or aplastic crisis; some 5–
10% may be enrolled on a chronic transfusion programme at some time in their
life. All neonates in the UK have been vaccinated against hepatitis B since
August 2017. Older children with SCD should be offered vaccination against
hepatitis B if not already vaccinated.
Meningitis ACWY is now advised for all children with SCD in infancy. This should
be offered to older children, especially those travelling to parts of the world
where these serotypes are prevalent.
Malaria is likely to be a serious issue due to splenic hypofunction and
appropriate prophylaxis for the area of travel should be offered. Families should
be aware that having SCD or sickle cell trait does not make a person immune to
malaria.

Antibiotic prophylaxis
Penicillin prophylaxis has been shown in a randomised controlled trial to be
effective in reducing mortality from pneumococcal sepsis2. Published guidelines
recommend that penicillin prophylaxis is lifelong. As compliance is likely to
decline and the incidence of pneumococcal infection in the community reduces
significantly after the age of 5 years3, the emphasis should be on excellent
adherence in early childhood.

Penicillin V should be offered to all children according to the following dosage

schedule:
• 62.5 mg per orally twice daily for those <1 year
• 125 mg per orally twice daily for those 1–5 years
• 250 mg per orally twice daily for those >5 years.

Erythromycin is a suitable alternative if penicillin allergy is documented.

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 Ongoing issues

Immunisations
Children with SCD should follow the UK schedule of routine immunisations,
which is updated regularly in the ‘Green Book’. Children arriving in the UK after
the newborn period who have not received the complete vaccination schedule
should follow the guidance provided in the document Vaccination of individuals
with uncertain or incomplete immunisation status.
Children with SCD are also recommended to receive the following additional
vaccinations:
• for a child diagnosed in the first year of life, two doses of MenACWY
1 month apart (in practice this probably means giving two doses of
MenACWY in the second year of life)
• for children not given Prevenar 13 (a pneumococcal conjugate vaccine,
also sometimes called PCV) during the first year of life, two doses of
Prevenar 2 months apart in the second year
• for all children aged 6 months to 2 years, the intramuscular flu vaccine
• for all children aged 2 years to 17 years (the licensed age groups), Fluenz
tetra nasal spray (a live attenuated vaccine), given annually – increasing
numbers of children will receive this vaccination in school as the
programme is gradually rolled out to children without specific conditions
• polysaccharide pneumococcal vaccine (PPV) at 2 years and 5 yearly
thereafter.
Although all children are now offered the conjugate pneumococcal vaccine
Prevenar 13, there is evidence of a rise of infections causing invasive
pneumococcal disease that are not prevented by vaccination and emphasis must
remain on children continuing to take regular penicillin in addition to
immunisations1.
Furthermore, in order to ensure maximum coverage with PPV, there needs to be
a robust local system for policing the administration and recording of the PPV
vaccine; consideration should be given to administering this at the hospital
appointment, as is done in some large units, particularly in London, rather than in
primary care.

Travel requirements
Children with SCD should receive:
• meningitis ACWY if travelling to sub-Saharan Africa and Saudi Arabia if not
already received
• other recommended travel vaccinations for the country being visited
• malaria prophylaxis.

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 Ongoing issues

Recommendations
• Twice-daily penicillin prophylaxis or alternative should be prescribed by
90 days of age and continued throughout childhood. (A) See Standard 3.
• Local negotiation should be carried out between hospital, GPs and
pharmacies to ensure a reasonable length of prescription to encourage
compliance. (C)
• Reasons for parents not giving their children penicillin should be explored
and addressed as fully as possible. (C)
• Immunisation against pneumococcal infection should include Prevenar 13
and PPV according to national schedules. (C) See Standard 4.
• Two doses of MenACWY should be given in either the first or second year
of life. (C)
• A robust local policy should be in place to ensure that children receive
PPV (in hospital or primary care) and this information should be recorded
and shared between primary and secondary care. (C)
• Annual influenza immunisation should be offered. (C)
• When appropriate, malaria prophylaxis should be strongly recommended
and current guidance sought for the area of travel. (C)
• Parents should discuss with their medical team before their child travels by
plane. (C)

Management of pain at home

Most episodes of pain occur and are managed at home. Usually these are mild-
to-moderate painful episodes and it is not be necessary to bring the child to
hospital. Frequent pain may however lead to other problems, including negative
mood and considerable loss of schooling. Children should therefore be
encouraged to identify and avoid factors that regularly trigger acute pain (e.g.
exposure to cold or windy weather, excessive physical activity and dehydration).
This information should also be passed on to the school by a competent
healthcare professional.
It is important for older children, parents/carers and family members to know how
to manage pain at home with appropriate analgesia for the level of intensity. In
addition, other coping strategies should be considered, including distraction
techniques like games, computers and television, as these have been shown to
predict both pain experience and the utilisation of health services1.
It is usual to advise an increase in fluid intake if the child is unwell, as
dehydration will tend to prolong the painful episode. Paracetamol and ibuprofen
are the analgesics of choice in mild-to-moderate pain. Weak opiates can be
added at home for more severe pain: dihydrocodeine can be used in those under
13 years of age and codeine after this age, depending on local prescribing
practices; it should be recognised that at least 20% of children will not respond to
codeine because they lack the enzyme needed to convert it to morphine2.

51
 Ongoing issues

If there is no response to this regimen, the child should be assessed in hospital.

Children should not be treated with morphine at home, apart from in exceptional
circumstances and with individualised care plans.

If a child has more than two admissions in a year, an individual care plan should
be available in the A&E department (or children’s ward if there is a direct
admissions policy).
Hydroxycarbamide should be recommended if a child is getting significant
episodes of pain at home, even if these do not require medical attention.

Recommendations
• Parents/carers and older children should be given clear guidance on how
to assess and manage pain at home, including the type and dose of
analgesia to be used for different levels of pain intensity, and when to seek
medical advice. (C)
• Parents/carers should be informed about non-pharmacological therapies
for pain, such as massage. Children should be encouraged to use
psychological coping strategies, including distraction techniques such as
games, computers and television. (C)
• Children should be encouraged to identify and avoid factors that regularly
trigger acute pain, such as exposure to cold or windy weather, excessive
physical activity and dehydration. This information should also be passed
on to the school by a competent healthcare professional. (C)
• Hydroxycarbamide should be recommended to children getting significant
episodes of pain at home (C)

Nutrition and growth

The importance of nutrition in children with SCD is rarely discussed in the UK
and those with SCD are seldom referred to dieticians. This may be a missed
opportunity, as advice on healthy eating could enhance the general wellbeing of
children and young people with SCD1. Impaired growth, poor nutritional status
and delayed skeletal and sexual maturation are common in children with SCD. In
HbSS, growth retardation may become apparent after 6 months of age, possibly
due to decreased absorption of nutrients and/or an increase in metabolic rate. Poor
appetite is frequently reported, and anorexia associated with febrile or painful
episodes is common.

Pica – the eating of non-food stuffs – is frequently reported by parents and also by
adults with SCD. Although this can be associated with nutritional deficiencies (e.g.
iron), in most cases no nutritional deficiency is found. Psychological management
can help, particularly if the pica becomes a more generalised eating disorder2.
Studies of body composition in children with SCD show a significantly lower fat
mass in prepubertal children and lower fat-free mass in all children, with muscle

52
 Ongoing issues

wasting and low protein stores3. In extreme cases, growth can be accelerated by
providing extra calories via nasogastric feeding, although this is rarely
necessary4.

There is little evidence of specific nutrient deficits, although a randomised

controlled trial showed some improvement in height and weight after
supplementation with zinc sulphate5. Another controlled trial also showed a
reduction in infections and hospital admissions in those taking zinc
supplements6.

As a hypochromic microcytic blood picture may be caused by an associated

thalassaemia trait, iron supplementation should be given only if iron deficiency is
confirmed, typically by a low serum ferritin. There is no evidence that folic acid
supplementation is beneficial, although many parents choose that their children
should take it7,8.

Vitamin D deficiency is very prevalent in non-white children of all ages in the

UK9,10 and there has been a resurgence of rickets. Advice should be given
regarding vitamin supplementation, an adequate calcium intake and exposure to
sunlight. If children are found to have vitamin D deficiency, therapeutic vitamin D
supplementation should be prescribed, depending on local prescribing guidelines.
Some clinicians recommend the use of ethnically appropriate growth charts11, but not
specific sickle cell charts. Puberty may be delayed by about 6 months in HbSC
and by 2–3 years in HbSS12. However, delayed skeletal maturation during
adolescence allows for a longer growth period in the long bones, which results in
normal adult height, so children and their parents can usually be reassured.
Hormonal treatment may be indicated in children with physiological delay if they are
very concerned by their short stature.

An endocrinology opinion should be sought if there are no physical signs of

puberty in a girl at 14 years and a boy at 14.5 years13. It should also be
recognised that children on long-term transfusion programmes with significant
iron overload may develop pituitary +/- primary gonadal deficiencies.

Recommendations
• Height and weight should be measured at each visit and plotted on
appropriate growth centile charts. (C)
• Referral to a dietitian should be made to consider extra caloric input if the
child is hospitalised for frequent or long periods. (C)
• Zinc supplementation should be considered if growth is impaired. (B)
• Advice should be given on avoiding vitamin D deficiency, and Vitamin D
deficiency should be treated. (C)
• Children with delayed growth should be reassured if there is evidence of
delayed skeletal maturation; however, they should be referred to a

53
 Ongoing issues

paediatric endocrinologist if there are no physical signs of puberty at

14 years in a girl and 14.5 years in a boy. (C)
• Pica can usually be managed with explanation; a referral to a clinical
psychologist is recommended if the pica is part of a more generalised
eating disorder. (C)

Nocturnal enuresis
Nocturnal enuresis is common in all children – approximately 15% of children
aged 5 years and 3% of 15-year-old children still wet the bed more than once per
week.
There is an increased rate of nocturnal enuresis in children with SCD, particularly
in boys with HbSS; the reason for this is not entirely clear. Children with SCD
pass large quantities of dilute urine and have nocturia, but this should not
necessarily lead to incontinence. Overnight urinary volumes greater than
maximum functional bladder capacity have been posed as a possible cause1.
Parents often report that their children are heavy sleepers. It has been shown
that children with adenoidal hypertrophy and obstructive apnoea are more likely
to have nocturnal enuresis2 and it is possible that hypoxaemia plays a role in the
aetiology of nocturnal enuresis.
As in the normal population, most cases will resolve spontaneously. On the whole,
children with SCD do not respond to behavioural management techniques, such
as star charts or mattress alarms, but can be ‘trained’ by intermittent alarms and
parental waking to achieve continence. Despite nocturia, they learn to wake
themselves up and pass urine during the night without enuresis. Many children
respond to oral desmopressin and this is a useful adjunct, particularly for school
trips.

Recommendations
• If nocturnal enuresis is present over the age of 6 years, this should be
documented and parents should be given information and advice on
treatment, including avoidance of drinking at night time. (C)
• If the history is suggestive of sleep-disordered breathing, this should be
documented, overnight oxygen saturations should be measured and a
referral made for an ear, nose and throat (ENT) opinion. (C)
• Desmopressin therapy should be considered in those children who do not
respond to routine advice and management. (C)
• The child should be referred for specialist management (e.g. an enuresis
clinic) if there is no response to basic measures after the age of 7 years.
(C)

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 Ongoing issues

Dental health
Oral health and dental care are integral parts of general health and wellbeing
and may impact on the general wellbeing of those with SCD 1. SCD may be
associated with dental problems, which may influence the quality of life of
affected individuals. Dental infections, for example, can lead to an increased
likelihood of triggering a painful sickle cell episode2.
It is important to ensure there is good liaison between dentists treating children
with SCD and the paediatric/haematology team, especially if any child needs a
general anaesthetic.

Psychological issues
Psychological issues for people with SCD and their families result mainly from
the impact of pain and symptoms on their daily lives and society’s attitudes to the
condition and those affected.
There is considerable variability in how people with SCD cope with their
condition. People with SCD experience different levels of health and such
variations can lead to differences in psychosocial functioning. Some people cope
relatively well, attend school or work and are active physically and socially. Their
efforts should be recognised and encouraged where necessary. Others lead more
limited and secluded lives. Nonetheless, this may not necessarily be a
consequence of severe disease and the reasons should be sought and
addressed.
Quality of life in people with SCD may therefore be lower than that of the general
population and, for those with severe disease, may deteriorate as people grow
into adulthood. Children are also at greater risk of stroke with consequent
impairment of their psychosocial functioning and cognition.

Studies on providing psychological therapy as a standard adjunct to routine

medical management have shown encouraging results1. The overall goal is to
help patients cope better, fulfil roles and achieve a better quality of life. In addition,
there are specific indications for psychological intervention in the management of pain
and stroke. Reviews of psychosocial interventions for pain and other outcomes2–4
demonstrate that cognitive behavioural techniques are probably efficacious in treating
sickle cell pain.

Psycho-education
Psycho-educational interventions primarily focus on improving knowledge and
the understanding that patients have about their illness, while at the same time
providing psychological support. Group interventions have been shown to identify
issues and concerns in children and adolescents with SCD5 and family
interventions improve knowledge 6. The rationale behind this approach is that

55
 Ongoing issues

information can lead to improved knowledge and better coping with the
condition7 and children who feel isolated may benefit from the support and
motivation of others through shared experience.

Cognitive behavioural therapy

Cognitive behavioural therapies (CBT) are a range of talking therapies based on
the theory that thoughts, feelings, what we do and how our body feels are all
connected. If we change one of these, we can alter the others. When people feel
worried or distressed, we often fall into patterns of thinking and responding that can
worsen how we feel. CBT works to help us notice and change problematic thinking
styles or behaviour patterns so that we can feel better. CBT has been shown to
reduce pain, health service utilisation and coping in children and adolescents
with SCD4,8.

Recommendations
• All children and their families should have access to a clinical psychology
service. (C)
• CBT should be offered in addition to standard management in children
experiencing frequent pain episodes and emotional difficulties. (A)

References

Prevention of infection
1 Oligbu G, Collins S, Sheppard C, et al. Risk of invasive pneumococcal
disease in children with sickle cell disease in England: a national
observational cohort study, 2010–2015. Arch Dis Child 2018; 103: 643–7.
2 Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in
children with sickle cell anemia. N Engl J Med 1986; 314: 1593–9.
3 Falletta JM, Woods GM, Verter JI, et al. Discontinuing penicillin prophylaxis
in children with sickle cell anaemia. Prophylactic Penicillin Study II. J Pediatr
1995; 127: 685–90.

Management of pain at home

1 Anie KA, Steptoe A, Ball S, et al. Coping and health service utilisation in a
UK study of paediatric sickle cell pain. Arch Dis Child 2002; 86: 325–9.
2 Williams DG, Patel A, Howard RF. Pharmacogenetics of codeine metabolism
in an urban population of children and its implications for analgesic reliability.
Br J Anaesth 2002; 89: 839–45.

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 Ongoing issues

Nutrition and growth

1 NICE. Sickle cell disease: managing acute painful episodes in hospital.
CG143. Published: June 2012. https://www.nice.org.uk/guidance/cg143.
Accessed: 2 April 2019.
2 Aloni M, Lecerf P, Heijmans C, et al. Pica in children in sickle cell disease.
Blood 2010; 116: 4807.
3 Barden EM, Kawchak DA, Ohene-Frempong K, et al. Body composition in
children with sickle cell disease. Am J Clin Nutr 2002; 76: 218–25.
4 Heyman MB, Vichinsky E, Katz R, et al. Growth retardation in sickle-cell
disease treated by nutritional support. Lancet 1985; 1: 903–6.
5 Zemel BS, Kawchak DA, Fung EB, et al. Effect of zinc supplementation on
growth and body composition in children with sickle cell disease. Am J Clin
Nutr 2002; 75: 300–7.
6 Prasad AS, Beck WJ, Kaplan J, et al. Effect of zinc supplementation on
incidence of infections and hospital admissions in sickle cell disease (SCD).
Am J Hematol 1999; 61: 194–202.
7 Serjeant G. Treatment of sickle cell disease in early childhood in Jamaica.
Am J Pediatr Hematol Oncol 1985; 7: 235–9.
8 Rodriguez-Cortes HM, Griener JC, Hyland K, et al. Plasma homocysteine
levels in folate status in children with sickle cell anemia. J Pediatr Hematol
Oncol 1999; 21: 219–23.
9 Das G, Crocombe S, McGrath M, et al. Hypovitaminosis D among healthy
adolescent girls attending an inner city school. Arch Dis Child 2005; 91:
569–72.
10 Ashraf S, Mughal MZ. The prevalence of rickets among non-Caucasian
children. Arch Dis Child 2002; 87: 263–4.
11 Patey RA, Sylvester KP, Rafferty GF, et al. The importance of using ethnically
appropriate reference ranges for growth assessment in sickle cell disease.
Arch Dis Child 2002; 87: 352–3.
12 Serjeant GR, Singhal A, Hambleton IR, et al. Sickle cell disease and age at
menarche in Jamaican girls: observations from a cohort study. Arch Dis
Child 2001; 85: 375–8.
13 Constitutional delay of growth and puberty: A guide for parents and patients.
London: Child Growth Foundation, 2004. http://www.olchc.ie/Children-
Family/Parent-Patient-Information-leaflets/Endocrine-Constitutional-Delay-
Growth-and-Puberty-2017.pdf. Accessed: 25 August 2019.

Nocturnal enuresis
1 Readett DR, Morris J, Serjeant GR. Determinants of nocturnal enuresis in
homozygous sickle cell disease. Arch Dis Child 1990; 65: 615–8.
2 Brooks LJ, Topol HI. Enuresis in children with sleep apnoea. J Pediatr 2003;
142: 515–8.

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 Ongoing issues

Dental health
1 Fernandes ML, Kawachi I, Corrêa-Faria P, et al. Caries prevalence and
impact on oral health-related quality of life in children with sickle cell
disease: cross-sectional study. BMC Oral Health 2015; 15: 68.
2 Laurence B, Haywood C, Lanzkron S. Dental infections increase the
likelihood of hospital admissions among adult patients with sickle cell
disease. Community Dent Health 2013; 30: 168–72.

Psychological issues
1 Anie KA, Green J. Psychological therapies for sickle cell disease and pain.
Cochrane Database Syst Rev 2015; 5: CD001916.
2 Chen E, Cole SW, Kato PM. A review of empirically supported psychosocial
interventions for pain and adherence outcomes in sickle cell disease. J
Pediatr Psychol 2004; 29: 197–209.
3 Edwards LY, Edwards CL. Psychosocial treatments in pain management of
sickle cell disease. J Natl Med Assoc 2010; 102: 1084–94.
4 Williams H, Tanabe P. Sickle cell disease: a review of nonpharmacological
approaches for pain. J Pain Symptom Manage 2016; 51: 163–77.
5 Anie K, Smalling B, Fotopoulos C. Group work: children and adolescents
with sickle cell disease. Community Practitioner 2000; 73: 556–8.
6 Kaslow NJ, Collins MH, Rashid FL, et al. The efficacy of a pilot family
psycho-educational intervention for pediatric sickle cell disease. Family
Systems Health 2000; 18: 381–404.
7 Maxwell K, Streetly A, Bevan D. Experiences of hospital care and treatment-
seeking for pain from sickle cell disease: a qualitative study. BMJ 1993; 306:
1491–2.
8 Broome ME, Maikler V, Kelber S, et al. An intervention to increase coping
and reduce health care utilization for school-age children and adolescents
with sickle cell disease. J Natl Black Nurses Assoc 2001; 12: 6–14.

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 Chronic complications

Chronic complications

Cerebrovascular disease 60

Risk factors 60

Primary stroke prevention 60

The role of neuropsychology 61

Silent cerebral infarcts 61

Secondary stroke prevention 62

Priapism 63

Avascular necrosis of the femoral and humeral head 64

Liver disease 64

Kidney disease 65

Lung disease 65

Eye complications 67

Hearing impairment 67

Leg ulcers 68

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 Chronic complications

Cerebrovascular disease
In the multicentre Cooperative Study of Sickle Cell Disease in the USA, the
overall incidence of stroke in HbSS was 0.6/100 patient-years. The highest
incidence was in children aged 2–5 years (1.02/100 patient-years) and, by the
age of 20, about 11% of people with SCD had had a clinically evident stroke1. In
the absence of primary screening and prophylaxis, there is no reason to expect
rates to differ in the UK.
In children, the cerebral ischaemic damage is often in the supply territory of the
internal carotid/middle cerebral artery (ICA/MCA). However, damage in a
watershed distribution, between either the MCA and anterior cerebral artery
(ACA) or the MCA and posterior cerebral artery, is also commonly observed.
Stroke is associated with cerebrovascular stenotic lesions, commonly in the distal
ICA and proximal portions of the MCA and ACA. The high blood flow velocities
through these stenotic segments can be detected using TCD ultrasound
scanning.

Risk factors
A large prospective follow-up study showed that a high-risk group for stroke can
be identified by time-averaged mean velocities in the ICA/MCA/ACA segments
>200 cm/sec2. The risk is also increased, to a lesser extent, in those with
conditional velocities (170–200 cm/sec) and in those with absent or low signal.

Another important indicator of risk for stroke is a history of transient ischaemic

attacks. Other reported risk factors, such as low baseline Hb, high baseline white
cell count, low overnight oxygen saturation3, acute chest syndrome in the
previous 2 weeks, frequent episodes of acute chest syndrome and high systolic
blood pressure4, are too insensitive to be of any value in evaluating a child,
although high blood pressure obviously requires appropriate investigation and
management.

Stroke is more prevalent in HbSS and HbS/β0 thalassaemia compared to HbSC

and HbS/β+ thalassaemia, although there is limited information.
Haemorrhagic stroke is relatively rare in childhood, becoming more common in
the third decade. Identified risk factors include low Hb and high white cell count.
Intracerebral aneurysms are more common in those with SCD and can be
multiple. The pathogenesis is unclear. There are no established or proven ways
of screening for increased risk of haemorrhagic stroke.

Primary stroke prevention

A randomised controlled trial has shown that the risk of a first stroke can be
reduced by 90% by regular blood transfusions in children with SCD and
abnormal TCD scans (mean velocities >200 cm/sec)5.

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 Chronic complications

The TWiTCH study looked at the safety of switching children with abnormal
TCDs from regular transfusions to hydroxycarbamide and found that
hydroxycarbamide was equivalent to transfusion, with no increase in TCD
velocities or cerebrovascular events 6. Children entered into the study had been
transfused for at least a year and did not have severe vasculopathy (multiple
stenoses, moyamoya). Regular transfusions were continued until the maximum
tolerated dose of hydroxycarbamide was established.

The role of neuropsychology

Cerebrovascular disease in SCD can result in both obvious and subtle
neuropsychological deterioration. An overt stroke may cause intellectual
impairment with an increase in frontal lobe problems of attention and executive
functioning7. However, children who have silent infarcts also experience learning
and behavioural problems and are twice as likely to have school difficulties as
other children8,9.
The Intercollegiate Working Party for Paediatric Stroke10 and the British
Psychological Society Special Interest Group in Sickle Cell Disease and
Thalassaemia recommend a detailed assessment of the child’s cognitive and
social functioning following a stroke. There is evidence that neurocognitive
screening provides a useful means of identifying those who may have suffered
silent stroke8. MRI should be performed in any child with significant neurocognitive
problems, but is not currently routinely recommended for all children.

Silent cerebral infarcts

About 20% of children with sickle cell anaemia have silent cerebral infarcts on
MRI scan that are not associated with overt neurological episodes or symptoms.
These are relatively small white-matter lesions, often in the anterior watershed
distribution. They are associated with mild cognitive impairment and may be
suspected following neurocognitive testing11.
TCD screening in these patients shows normal results in 75% of cases. A
randomised trial in children with silent cerebral infarcts showed that regular
transfusions reduced the number of further neurological events compared with
monitoring alone12. There is no evidence on how best to screen children for
silent cerebral infarcts, although there should be a low threshold for performing
brain MRI when there are concerns about the cognitive performance of a child,
including poor school performance. When silent cerebral infarcts are found on
MRI, the option of starting regular blood transfusions should be discussed with
the parents and child.

The relative hazard for progression to overt stroke is approximately 14 times for a
patient with a silent infarct compared with those with a normal MRI. This
compares to 18 times normal in a patient with a high-risk TCD13.

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 Chronic complications

Secondary stroke prevention

Chronic transfusion has been established as effective secondary stroke
prevention, reducing the risk of recurrent stroke from 50–75% to about 13%14. The
aim of the transfusion regimen is to maintain the HbS level <30%. Some patients
may be able to reduce the intensity of transfusions after 3 years to maintain HbS at
50%.
The SWiTCH study showed that hydroxycarbamide was less effective at
secondary stroke prevention than continued transfusion15, and
hydroxycarbamide is only considered as an option when regular transfusions are
contraindicated (multiple alloantibodies, uncontrolled iron overload) or
unacceptable owing to sincere personal beliefs (most often Jehovah’s
Witnesses) 16. This trial in children with HbSS in the USA recommended that
transfusion therapy should be continued throughout childhood. This is because a
significant number of children reverted to the high-risk range of TCD velocities or
developed overt stroke after discontinuation16.

As iron overload is a serious consideration in long-term transfusion therapy, iron

chelation should be started when the patient has received approximately 1 year’s
worth of transfusions, has a serum ferritin >1000 ng/mL on two successive
readings 4 weeks apart, or has evidence of iron overloading in the liver on MRI.

Recommendations
• Annual TCD scans should be performed on all children with HbSS and
HbS0 thalassaemia from age 2. For children with abnormal TCD velocities,
the risks and benefits of starting regular blood transfusions and/or other
treatments should be fully discussed by an appropriate multidisciplinary team
with parents/carers. (A) See Standard 5.
• The option of switching from transfusions to hydroxycarbamide should be
discussed with eligible children and families. If it is agreed to switch to
hydroxycarbamide, transfusions should be continued until the child is
stabilised on the maximum tolerated dose of hydroxycarbamide. (A)
• The symptoms and signs of stroke should be discussed with parents/carers
in the first 2 years of life, with information given on what action to take
should the child develop neurological symptoms. (C)
• Appropriate imaging studies to assess the extent of cerebrovascular
disease should also be arranged if TCD scanning is abnormal, or there are
learning difficulties, atypical symptoms such as unusual behaviour during
acute pain, frequent headaches, fits or other unexplained neurological,
psychiatric or psychological symptoms. (C)
• The advantages and disadvantages of starting regular blood transfusions
should be discussed with all children and families if the child has one or
more silent cerebral infarcts on MRI. (A).
• Blood pressure should be measured and recorded annually. (C)

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 Chronic complications

• Overnight oxygen saturation monitoring should be performed if a child has

low steady-state oxygen saturations on air (<95%). (C)
• Children should have access to a clinical, educational or neuro-
psychologist to assess cognitive function, learning and behavioural
difficulties. (C)
• A comprehensive neuropsychological assessment should be carried out
and repeated annually in all children who have had a stroke. (C)
• Cognitive (or where available, neuropsychological) assessment should be
conducted in children with abnormal TCD or abnormal brain MRI. (C)
• Information about developmental progress and school performance should
be ascertained for all children annually; if there are significant concerns,
further assessments should be considered including cognitive or
neuropsychological assessment and brain MRI scan. (C)
• Transfusion therapy should be offered throughout childhood for the
secondary prevention of stroke. (B)

Priapism
(see also management of fulminant priapism)

Priapism, a sustained, painful and unwanted erection, mainly affects adolescents

and adults, and may go unreported.
Bicorporal priapism occurs in 3–5% of pre-pubertal boys and has a better
prognosis for normal erectile function than tricorporal priapism in post-pubertal
boys. Events may be classified as stuttering (occurring for <3 hours but several
times a week), minor (isolated or infrequent episodes of <3 hours) or fulminant
(events lasting >3 hours).
Fulminant episodes are often preceded by bouts of stuttering priapism. Bladder
emptying, exercise such as jogging, warm baths and analgesia may help abort an
attack. Oral etilefrine may reduce the frequency of stuttering priapism1 and, in a
prolonged episode, aspiration and irrigation of the corpora cavernosa with
epinephrine or etilefrine is now the treatment of choice2.
Children and their carers should be advised to seek treatment early and should
attend hospital as an emergency if priapism persists for >2 hours.

Recommendations
• All boys and their parents/carers should be warned early in childhood about
priapism being a complication of SCD. (C)
• Adolescent boys and their parents/carers should receive further information
about priapism and know to seek treatment early. (C)
• An enquiry about priapism should be included as part of the outpatient
consultation for pubertal boys. (C)

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 Chronic complications

• For minor events, complete bladder emptying before sleep, pain relief and
warm baths should be recommended. (C)
• Oral etilefrine should be considered in cases of stuttering priapism. (C)

Avascular necrosis of the femoral and humeral head

This may occur in all types of SCD and children with high HbF levels are not
protected. The shoulder joint is more likely to be affected in older age groups.
Although weight-bearing makes femoral head necrosis more likely to cause severe
joint destruction, healing with minimal destruction may be the outcome if it occurs
before closure of the femoral epiphysis.
X-ray changes will not be apparent until the repair process has changed the density
of the bone. Therefore, MRI scanning is the investigation of choice in a patient with
persistently painful hip or shoulder.
Typically, some form of radiological staging is used to evaluate the development
and progression of the disease1. Initial treatment should be conservative, with
analgesia, partial weight-bearing on crutches and physiotherapy support. There
is some evidence that decompression in the early stages may be beneficial, at
least in relieving pain.

Recommendations
• An MRI scan should be carried out where there is persistent pain in the hip
or shoulder. (C)
• The radiological stage of avascular necrosis should be documented. (C)
• Referral to an orthopaedic surgeon with an interest in SCD should be
made if pain persists or if avascular necrosis is at stage III or more. (C)

Liver disease
Gallstones occur in over 50% of children with SCD over the age of 10 years in the
UK1. They are usually asymptomatic and may not be the cause of intermittent
abdominal pain, which is relatively common. There is no evidence to recommend
cholecystectomy in asymptomatic cases, but it is advised for those with
symptomatic biliary disease.

Recommendations
• Annual steady-state liver function tests should be carried out; children with
evidence of progressive hepatopathy (increasing bilirubin, persistently high
ALT) should be referred to a paediatric hepatology service with experience
of SCD. (C)
• Recurrent episodes of abdominal pain should be investigated with an
ultrasound of the liver and biliary tree. (C)
• Elective cholecystectomy should be carried out in symptomatic biliary
disease. (C)

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 Chronic complications

Kidney disease
Renal complications are relatively common in SCD, particularly with increasing
age.
Renal failure primarily due to SCD is rare in childhood, but other paediatric
complications include the following (although there is little good information on the
frequency of these problems in childhood):
• nocturnal enuresis
• urinary tract infections – these should be investigated and treated
according to NICE guidance 1
• haematuria – hospital trusts will have their own guidelines for investigating
macroscopic haematuria and these should include renal ultrasound,
urinary bacterial cultures, electrolytes, and coagulation factors if the
bleeding is severe
• renal papillary necrosis, which is one possible cause of haematuria
• microscopic albuminuria – evidence is lacking as to whether screening for
this (and other signs of renal disease in childhood) leads to interventions
that can prevent problems in later life
• renal medullary carcinoma – this is rare but should be considered if
haematuria is persistent.
Hypertension can be a trigger to investigate further for renal disease, although it
is not known how blood pressure centiles apply to children with SCD. Because
these children normally have low blood pressures, it is thought that further
assessment should be carried out if the blood pressure is above the 70th centile.

Recommendations
• Any child with a urinary tract infection should be treated and then
investigated according to the NICE guidance. (C)
• Macroscopic haematuria should be fully investigated according to local
protocols. (C)
• Blood pressure, urea, creatinine, electrolytes and urine albumin:creatinine
ratio should be measured on a yearly basis and renal investigations
initiated if hypertension is present, if there are raised creatinine and urea
levels, or persistent significant albuminuria. (C)

Lung disease
Acute chest syndrome is a well-characterised complication of SCD in childhood1.
It is a potentially fatal complication and there is good evidence that recurrent
episodes can be prevented by hydroxycarbamide2. Asthma can cause very similar
signs and symptoms to acute chest syndrome and has been associated with
increased episodes of pain. It is not clear however whether asthma in SCD is a
distinct entity or whether they are part of the same condition3.

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 Chronic complications

Chronic lung complications are increasingly recognised, particularly in adults but

may occur in older children and adolescents. Three main problems are
recognised: chronic sickle lung disease, with a restrictive lung picture; a mixed
obstructive restrictive pattern; and pulmonary hypertension.

Anecdotal evidence suggests that, in chronic sickle lung disease, deterioration

can be prevented by hydroxycarbamide or regular blood transfusions. It is
therefore potentially important to detect the early development of these problems
in children.

Low blood-oxygen saturations, as assessed by overnight pulse oximetry, have

been linked to both cerebrovascular disease and frequent episodes of acute pain.
Referral to a specialist pulmonary hypertension centre with an interest in SCD
should be made if there is evidence of pulmonary hypertension4.

Recommendations
• Children with either two or more episodes of acute chest syndrome in the
last 2 years, or one episode requiring ventilatory support, should be offered
hydroxycarbamide. (A)
• A systematic and complete evaluation of asthma should be undertaken if
the diagnosis is suspected or if there are repeated episodes of acute chest
syndrome. (C)
• Oxygen saturations in air should be recorded on an annual basis using
pulse oximetry when the patient is well and seen in outpatients. If
saturations are <95%, overnight oxygen saturation monitoring should be
performed. (C)
• If the mean overnight oxygen saturation is <95%, the child should be
investigated for cerebrovascular disease and obstructive sleep apnoea;
formal pulmonary function tests and echocardiography should also be
arranged. (C)
• If pulmonary function tests suggest chronic sickle lung disease, the child
should be monitored with regular pulmonary function tests, plus overnight
pulse oximetry and a high-resolution computed tomography (CT) scan of
the lungs should be considered; treatment with home oxygen,
hydroxycarbamide or regular blood transfusions should be considered in
children who show signs of deterioration. (C)
• Echocardiography to assess for pulmonary hypertension should be
arranged if there is evidence of chronic sickle lung disease, chronic
unexplained hypoxia (oxygen saturations <95%) or other symptoms/signs
suggestive of pulmonary hypertension. (C)
• A child with significant pulmonary hypertension should be referred to a
specialist pulmonary hypertension centre with an interest in SCD. (C)

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 Chronic complications

Eye complications
Vaso-occlusive events can affect every vascular bed in the eye and may have
serious and permanent visual consequences. Detectable retinal disease is very
rare in early childhood, being found most commonly between the ages of 15 and
30 years. Patients with HbSC and HbS/β thalassaemia are more likely than those
with HbSS to have serious ocular problems1.
The clinical manifestations are grouped according to whether there is
neovascularisation or not. In non-neovascular or ‘non-proliferative’ cases, there
are rarely any visual consequences. In contrast, revascularisation and
proliferation may proceed to vitreous haemorrhage and retinal detachment.
However, there is a high rate of spontaneous regression or non-progression and
the indications for treatment are not clear2.
Given the uncertainty about the natural history of this complication, there is no
evidence to support routine ophthalmologic screening of children, although the
NHS recommends a routine eye test every 2 years (more frequently if
recommended by an ophthalmic practitioner).
Children and their carers should report any change in vision; if this occurs, they
should be referred for an ophthalmologic opinion as a matter of urgency.

Recommendations
• Children and their carers should be made aware of this potential
complication. (C)
• Any significant visual symptom should be reported immediately and the
child referred urgently for an ophthalmologic opinion. (C)

Hearing impairment
The cochlea is particularly vulnerable to vaso-occlusion because the labyrinthine
artery is its sole blood supply. If the labyrinthine artery becomes occluded,
ischaemia of the cochlear bed can result, which leads to sudden hearing loss.
However, despite this, hearing loss is infrequently reported clinically. It may
though be more prevalent than is recognised, possibly because it is often
unilateral. Hearing loss is more common in those who have had a prior cerebral
infarct or have abnormally high velocities on their TCD scan.
Recent studies have indicated about 10–20% of children with SCD may have
hearing impairment1–4; this includes children with middle ear disease but there is
also a higher incidence of sensorineural hearing loss. There is currently not
enough evidence to recommend routine screening for hearing loss in children
with SCD.
Regular blood transfusions for the management of cerebrovascular
complications, including abnormally high TCD velocities, lead to increased iron

67
 Chronic complications

load, which needs to be treated with a chelating agent. Desferrioxamine,

deferasirox and deferiprone can all cause sensorineural hearing loss and it is
recommended that children on any of these medications should have annual
hearing tests5.

Recommendations
• Parents and carers should be aware of the possibility of acquired hearing
problems which may be sudden. (C)
• All children with abnormal TCDs or following a cerebral infarct should have
a baseline hearing test. (C)
• All children receiving iron chelating agents should have hearing tests
annually. (C)

Leg ulcers
These are relatively uncommon in children in the UK. Nearly all ulcers develop in
the ankle region near the malleolus and they are often bilateral. They may be
painless or extremely painful. The pathogenesis of this condition is uncertain, but
is likely to result from poor microvascular blood flow of abnormal red cells
combined with reduced oxygen delivery. Low serum zinc levels have been
reported in non-sickle patients with venous leg ulcers; however, low serum zinc
levels are found in many patients with SCD and do not correlate specifically with
leg ulcers. A controlled study in a small number of patients did however show
accelerated healing of leg ulcers in those taking oral zinc sulphate1.
There has been a randomised double-blind controlled trial using granulocyte-
macrophage colony stimulating factor (GM-CSF) in non-sickle patients with chronic
venous leg ulcers, which showed acceleration of healing2. Another study showed
good response using topical GM-CSF in a small number of patients with SCD3.
Best practice is not clear in this group and neither regular transfusion therapy nor
hydroxycarbamide therapy seems to influence outcome.
In the first instance, ulcers should be treated with frequent dressing, support
bandages and antibiotics if infected. Physiotherapy to increase ankle mobility and
venous return is also likely to be helpful.

Recommendations
• Debridement of the ulcer and antibiotic therapy should be started if
infection is present. (C)
• Adequate pain relief should be prescribed. (C)
• Compression bandaging and physiotherapy should be arranged to
improve ankle mobility. (C)
• Oral zinc sulphate should be considered in children with persistent leg
ulcers. (B)

68
 Chronic complications

References

Cerebrovascular disease
1 Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular
accidents in sickle cell disease: rates and risk factors. Blood 1998; 91; 288–
94.
2 Adams RJ, McKie VC, Carl EM, et al. Long-term stroke risk in children with
sickle cell disease screened with transcranial Doppler. Ann Neurol 1997; 42:
699–704.
3 Kirkham FJ, Hewes DK, Pengler M, et al. Nocturnal hypoxaemia and central
nervous system events in sickle-cell disease. Lancet 2001; 357: 1656–9.
4 Miller ST, Sleeper LA, Pegelow CH, et al. Prediction of adverse outcomes in
children with sickle cell disease. N Engl J Med 2000; 342: 83–9.
5 Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by
transfusions in children with sickle cell anemia and abnormal results on
transcranial Doppler ultrasonography. N Engl J Med 1998; 339: 5–11.
6 Ware RE, Davis BR, Schultz WH, et al. Hydroxycarbamide versus chronic
transfusion for maintenance of transcranial doppler flow velocities in children
with sickle cell anaemia—TCD With Transfusions Changing to Hydroxyurea
(TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet
2016; 387: 661–70.
7 Kral MC, Brown RT, Hynd GW. Neuropsychological aspects of pediatric
sickle cell disease. Neuropsychol Rev 2001; 11: 179–96.
8 Daly B, Kral MC, Tarazi RA. The role of neuropsychological evaluation in
pediatric sickle cell disease. Clin Neuropsychol 2011; 25: 903–25.
9 Schatz J, Finke RL, Kellett JM, et al. Cognitive functioning in children with
sickle cell disease: a meta-analysis. J Pediatr Psychol 2002; 27: 739–48.
10 Intercollegiate Working Party for Paediatric Stroke. Clinical guidelines for the
diagnosis and management of acute stroke in childhood. London: The Royal
College of Physicians; 2004.
11 Pegelow CH, Macklin EA, Moser FG et al. Longitudinal changes in brain
magnetic resonance imaging findings in children with sickle cell disease.
Blood 2002; 90: 3014–8.
12 DeBaun MR, Gordon M, McKinstry RC, et al. Controlled trial of transfusions
for silent cerebral infarcts in sickle cell anemia. N Engl J Med 2014; 371:
669–710.
13 Miller ST, Macklin EA, Pegelow CH, et al. Silent infarction as a risk factor for
overt stroke in children with sickle cell anaemia: a report from the
Cooperative Study of Sickle Cell Disease. J Pediatr 2001; 138: 385–90.
14 Pegelow CH, Adams RJ, McKie V, et al. Risk of recurrent stroke in patients
with sickle cell disease treated with erythrocyte transfusions. J Pediatr 1995;
126: 896–9.

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 Chronic complications

15 Adams RJ, Brambilla D; STOP 2 Trial Investigators. Discontinuing

prophylactic transfusions used to prevent stroke in sickle cell disease. N
Engl J Med 2005; 353: 2769–78.
16 Ware RE, Helms RW. Stroke with transfusions changing to hydroxyurea
(SWiTCH). Blood 2012; 119: 3925–32.

Priapism
1 Gbadoe AD, Atakouma Y, Kusiaku K, et al. Management of sickle cell priapism
with etilefrine. Arch Dis Child 2001; 85: 52–3.
2 Mantadakis E, Ewalt DH, Cavender JD, et al. Outpatient penile aspiration
and epinephrine irrigation for young patients with sickle cell anaemia and
prolonged priapism. Blood 2000; 95: 78–82.

Avascular necrosis
1 Steinberg MF, Steinberg DR. Evaluation and staging of avascular necrosis.
Semin Arthroplasty 1991; 2: 175–81.

Liver disease
1 Bond LR, Hatty SR, Horn ME, et al. Gall stones in sickle cell disease in the
United Kingdom. Br Med J (Clin Res Ed) 1987; 295: 234–6.

Kidney disease
1 NICE. Urinary tract infection in under 16s: diagnosis and management.
CG54. Published: 2007. Available at:
https://www.nice.org.uk/Guidance/CG54. Accessed: 9 April 2019.

Lung disease
1 Vichinsky E, Neumayr LD, Earles AN, et al. Causes and outcomes of the
acute chest syndrome in sickle cell disease. National Acute Chest
Syndrome Study Group. N Engl J Med 2000; 342: 1855–65.
2 Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the
frequency of painful crises in sickle cell anemia. N Engl J Med 1995; 332:
1317–22.
3 Field JJ, DeBaun MR. Asthma and sickle cell disease: two distinct diseases
or part of the same process? Hematology Am Soc Hematol Educ Program
2009: 45–53.
4 Gladwin MT, Sachdev MD, Jison ML, et al. Pulmonary hypertension as a risk
factor for death in patients with sickle cell disease. N Engl J Med 2004; 350:
886–95.

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 Chronic complications

Eye complications
1 Condon PI, Serjeant GR. Ocular findings in homozygous sickle cell anemia
in Jamaica. Am J Ophthalmol 1972; 73: 533–43.
2 Condon PI, Serjeant GR. Behaviour of untreated proliferative sickle
retinopathy. Br J Ophthalmol 1980; 64: 404–11.

Hearing impairment
1 Farrell AN, Landy AM, Yee ME, et al. Sensorineural hearing loss in children
with sickle cell disease. Int J Pediatr Otolarygol 2019; 118: 110–4.
2 Towerman AS, Hayash SS, Hayashi RJ, et al. Prevalence and nature of
hearing loss in a cohort of children with sickle cell disease. Pediatr Blood
Cancer 2019; 66: e27457.
3 da Silva LPA, Nova CV, Lucena R. Sickle cell anemia and hearing loss
among children and youngsters: Literature review. Braz J Otorhinolaryngol
2012; 78; 126–31.
4 Bois E, Francois M, van den Abbeele T, et al. Hearing loss in children with
sickle cell disease: A prospective French cohort study. Pediatr Blood Cancer
2019; 66: e27468.
5 United Kingdom Thalassaemia Society. Standards for the Clinical Care of
Children and Adults with Thalassaemia in the UK. 3rd edn. 2016.
http://ukts.org/standards/Standards-2016final.pdf. Accessed: 1 July 2019.

Leg ulcers
1 Serjeant GR, Galloway RE, Gueri MC. Oral zinc sulphate in sickle-cell
ulcers. Lancet 1970; 2: 891–2.
2 Da Costa RM, Ribeiro Jesus FM, Aniceto C, et al. Randomized, double-
blind, placebo-controlled, dose ranging study of granulocyte-macrophage
colony stimulating factor in patients with chronic leg ulcers. Wound Repair
Regen 1999; 7: 17–25.
3 Méry L, Girot R, Aractingi S. Topical effectiveness of molgramostim (GM-
CSF) in sickle cell leg ulcers. Dermatology 2004; 208: 135–7.

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 Acute complications

Acute complications

Severe pain requiring management in hospital 73

Management of the febrile child 73

Acute anaemia 75

Acute chest syndrome 75

Acute neurological complications 76

Fulminant priapism 77

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 Acute complications

Severe pain requiring management in hospital

Pain is the most common cause of acute morbidity in SCD and frequent hospital
admission with acute pain has been associated with increased mortality1,2. There is
also some evidence in adults that painful episodes that are not treated promptly
may lead to a higher incidence of chronic pain owing to repeated inflammation3.
Recurrent painful episodes have a negative psychological impact and the
experience of poorly managed episodes in hospital, together with perceived
negative attitudes of some staff, are often reported. These attitudes make it more
difficult to develop effective long-term pain-coping strategies and may lead to
problematic behaviour on the ward4.
Guidance on pain management in SCD was recently published by NICE5. Validated
pain assessment tools should be used to measure the child’s self-report and
behaviour6. These should include parental and healthcare professional
assessment. Developmentally age-appropriate self-report tools should be used
whenever children are able to participate.

Recommendations
• Pain assessment should include the use of a validated pain assessment
tool that is developmentally age appropriate. (C)
• There should be a policy in the A&E department regarding triage, pain
assessment and length of acceptable time (not exceeding 30 minutes)
from arrival to administration of analgesia. (C)
• Children should be managed according to a standard local protocol. This
should be developed by collaboration between the LHT and SHT and
should include input from a pain control team, paediatric pharmacist and
paediatric anaesthetist. The protocol should provide clear guidance on
drugs, route of administration, dosage, and monitoring for analgesic effect
and side effects. (C)
• Medical and nursing staff involved in treating children for severe acute pain
should have regular training in pain management and in the application of
the local protocols. (C)
• Children should be monitored regularly for the effectiveness of their
analgesia and for signs of adverse effects (e.g. opiate-induced narcosis
and hypoventilation and acute sickle chest syndrome, among others). (C)
• The psychological needs of the child and family regarding coping with pain
and avoiding painful sickle cell episodes should be addressed during the
admission. (C)

Management of the febrile child

All children with SCD are at increased risk of infection, partly because of
hyposplenism. In addition, defects in opsonisation and in cell-mediated immunity
have been demonstrated. The risk is highest for the those with HbSS and in infants

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 Acute complications

up to the age of 5 years, a time of particularly high risk for infection with
encapsulated bacteria.

In the days before immunisation programmes and prophylactic antibiotics against

H. influenzae and pneumococcus, infections with these bacteria were common
and caused septicaemia, pneumonia and meningitis. Other infections that can
occur include:
• salmonella osteomyelitis, the reason for this increased susceptibility is not
known1,2
• pneumonia due to typical and atypical organisms
• malaria, particularly in children returning from holidays in Africa
• urinary tract infection
• acute cholecystitis
• parvovirus B19, which causes temporary red cell aplasia.
Diagnostic problems can occur. It is common for a child with a simple acute
painful episode to present with a fever and no obvious evidence of infection.
Some young children present with painful swollen joints or areas of swelling in a
long bone. In these cases, it may be difficult to differentiate between acute bone
infarction due to sickling and osteomyelitis or septic arthritis.
Blood cultures should always be taken and, if there is a high level of suspicion
(e.g. high swinging fever, septic child, localised very tender swelling), imaging
with ultrasound to look for a sub-periosteal fluid collection and surgical drainage
should be considered before starting antibiotics.
Prophylactic penicillin should always be continued in hospital if a different
antibiotic is not prescribed to treat an acute infection.

Empirical antibiotics appropriate for the range of likely infectious agents should
be given. An agent active against pneumococcus should always be included.
Cover for suspected chest infection should include agents against atypical
organisms.

Recommendations
• A protocol for antibiotic treatment of suspected or proven acute infection
should be prepared by the SHT in collaboration with the LHT and a
designated paediatric microbiologist. (C)
• Cultures of blood, urine and other possible sites of infection should be
routinely done on any child presenting with acute pain and fever. (C)
• Malaria films should be sent if there is any suspicion of malaria or if a
patient has returned from a malarial region in the previous year. (C)

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 Acute complications

Acute anaemia
The most common causes of an acute fall in Hb of >30 g/L below the steady-
state Hb level are acute splenic sequestration and transient red cell aplasia
(TRCA), which is usually due to parvovirus B19 infection1.
Acute splenic sequestration has been defined as an acute fall of Hb and
markedly elevated reticulocyte count, together with an acute increase in spleen
size. It is a serious complication of SCD and, if unrecognised, carries significant
mortality2. Mortality rates can be reduced substantially by parental education,
regular palpation of the abdomen at home to detect early signs of splenic
enlargement and prompt intervention with transfusion3,4. Recurrent splenic
sequestration is an indication for splenectomy.
TRCA is characterised by a drop in Hb over a period of about a week, often to
levels as low as 30 g/L, with a very low reticulocyte count. It may be associated
with fever, headache and abdominal pain. In a young child, it may be difficult to
differentiate between TRCA and acute splenic sequestration, as the spleen may
still be palpable. In contrast to acute splenic sequestration, the reticulocyte count
will be very low or absent and IgM for parvovirus B19 will be present. It usually
takes about 7 days for the reticulocyte to return to normal, and a top-up
transfusion is often needed until this happens.

Recommendations
• There should be a protocol for recognition and investigation of children
presenting with pallor with or without pain in hospital. (C)
• Parents should be taught how to palpate for splenic enlargement and
should be aware of the need to bring the child to hospital if they detect
pallor and/or an enlarging spleen; they should be aware of the local
procedure for emergency assessment. (C)
• Medical staff assessing children with acute sickle cell complications should
be made aware of these complications through regular training/education
sessions. (C)
• A local protocol for management, including indications for transfusion,
should be available. (C)
• Children with two or more episodes of acute splenic sequestration should
be considered for splenectomy. (C)

Acute chest syndrome

Acute chest syndrome is characterised by pleuritic chest pain, fever, abnormal chest
examination and new pulmonary infiltrates on the chest X-ray. It is an important
cause of morbidity and mortality in SCD1–3. It is particularly common in early
childhood4, at which age, the clinical features are generally more typical of
pneumonia. In later childhood and adulthood, the syndrome can develop during
acute pain or after anaesthesia5.

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 Acute complications

Early intervention with an effective treatment protocol including analgesia,

oxygen, physiotherapy, antibiotics and transfusion can significantly reduce morbidity
and mortality. A randomised controlled trial has shown that incentive spirometry
performed regularly every 2 hours reduces the risk of acute chest syndrome in
patients with chest and back pain6.

Recommendations
• Parents, patients and carers should be made aware of this complication;
they should know how to recognise the symptoms and should be familiar
with the local procedure for emergency assessment. (C)
• Children with chest pain, cough, respiratory distress, new chest signs or
worsening hypoxia, presenting either in A&E or during the course of a
hospital admission, should be carefully assessed and monitored and a
chest X-ray organised urgently. (C)
• Incentive spirometry should be used in children with acute chest and or
back pain admitted to hospital and requiring opiate analgesia. (A)
• Oxygen saturation monitoring should be used routinely, particularly in those
children with respiratory signs and symptoms, acute pain affecting the
trunk and girdle regions and those treated with opiates. (C)
• A local protocol should be available for the management of the acute chest
syndrome, which should include clear guidance on analgesia,
observations, oxygen delivery, antibiotics, intravenous fluids,
bronchodilators, physiotherapy, incentive spirometry and nursing
observations, as well as the indications for top-up transfusion, exchange
transfusion and ventilator support. There should also be a local protocol
covering the practical issues of carrying out an exchange transfusion. (C)
• Medical and nursing staff should be made aware of this complication;
regular training and education sessions should advise on how to recognise
it and provide updates on the local policy for management. (C)
• An agreement should be reached with the local PICU about the indications
for transfer, means of communication and the protocol for treatment in the
PICU. (C)

Acute neurological complications

(see also management of cerebrovascular disease)
Acute neurological complications are relatively common in children with SCD and
are potentially devastating. Cerebrovascular disease, particularly proximal vessel
stenosis, predisposes children to acute cerebral infarction. Occasionally older
children present with subarachnoid or intracerebral bleeds, which may be related
to single or multiple cerebral artery aneurysms. Acute neurological ischaemia is
more likely to occur in children with pre-existing cerebrovascular lesions, during
acute anaemic events, or with other acute complications.

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 Acute complications

Other acute neurological complications include behavioural changes, seizures

and loss of consciousness. The causes of these complications are not always
clear, even after extensive imaging1.

Symptoms suggestive of meningitis require urgent investigation, including

lumbar puncture, blood culture and prompt antibiotic treatment. Acute ischaemic
events require urgent investigation with a CT scan and/or MRI/magnetic
resonance angiography (MRA) scan to define the event and exclude a
haemorrhagic component. This should be followed as soon as possible by
exchange transfusion to reduce the risk of progression of the lesion.
Intracerebral or subarachnoid bleeds defined by such imaging need to be
assessed urgently by a paediatric neurosurgical team.
Although stroke in a child with SCD is likely to be secondary to cerebrovascular
pathology, it is important to remember that stroke in childhood can result from
alternative pathology, particularly a source of cardiovascular emboli; these should
be actively excluded. The RCPCH has published guidelines on the management
of all causes of acute stroke in childhood2.

Recommendations
• Each SHT should have access to a designated paediatric neurologist who
can assess and advise on acute neurological complications. (C)
• Each SHT should have a clear plan for access to a neurosurgical unit for
managing children and adolescents with cerebral haemorrhage and
subarachnoid bleeds. (C)
• RCPCH guidelines on the management of acute stroke should be followed
and specific guidelines for acute stroke in SCD should be prepared for the
LHT by the SHT. (C)
• Each SHT should have access to neuroimaging facilities including
paediatric CT, MRI/MRA and electroencephalogram (EEG). (C)

Fulminant priapism
(see also non-fulminant priapism)
Priapism is a sustained, painful and unwanted erection.

A prolonged attack, lasting >3 hours should be treated as a surgical emergency

as, if untreated, cavernosal fibrosis and impotence may ensue. The condition
becomes more common in adolescence and minor attacks may go unreported
because of a reluctance to tell parents or healthcare professionals1.
A prospective study of 15 young patients showed that aspiration and irrigation
with dilute epinephrine produced immediate detumescence on 37 out of 39
occasions2. Etilefrine may also be used3. In the event that this is not successful, a
glans-corporal shunt may need to be performed. If no relief occurs, the urologists

77
 Acute complications

may need to perform a bilateral non-parallel spongiosum corporal shunt or a

corporal-venous shunt 4. In addition, blood transfusion may be indicated as part of
the overall management plan if a shunt needs to be performed.

Recommendations
• A policy for the management of severe fulminant priapism should be
agreed with the appropriate paediatric urology team. (C)
• Priapism should be discussed with all boys and their carers at annual
review, and written information given, including the need to seek urgent
medical attention for prolonged (>2 hours) episodes of priapism. (C)
• Aspiration and irrigation with etilefrine or epinephrine should be the initial
treatment of choice. (C)

References

Severe pain managed in hospital

1 Gill FM, Sleeper LA, Weiner SJ, et al. Clinical events in the first decade in a
cohort of infants with sickle cell disease: the Cooperative Study of Sickle Cell
Disease. Blood 1995; 88: 776–83.
2 Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease.
Rates and risk factors. N Engl J Med 1991; 325: 11–16.
3 Ballas SK, Gupta K, Adams, Graves P. Sickle cell pain: a critical
reappraisal. Blood 2012; 120: 3647–56
4 Maxwell K, Streetly A, Bevan D. Experiences of hospital care and treatment
seeking for pain from sickle cell disease: a qualitative study. BMJ 1999; 318:
1585–90.
5 NICE. Sickle cell disease: managing acute painful episodes in hospital.
CG143. Published: June 2012. https://www.nice.org.uk/guidance/CG143.
Accessed: 2 April 2019.
6 Qureshi J, Buckingham S. A pain assessment tool for all children. Paediatr
Nurs 1994; 6: 11–13.

Febrile child
1 Gill FM, Sleeper LA, Weiner SJ, et al. Clinical events in the first decade in a
cohort of infants with sickle cell disease: the Cooperative Study of Sickle Cell
Disease. Blood. 1995; 88: 776–83.
2 Lee A, Thomas P, Cupidore L, et al. Improved survival in homozygous sickle
cell disease: lessons from a cohort study. BMJ 1995; 311: 1600–2.

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 Acute complications

Acute anaemia
1 Serjeant GR, Serjeant BF, Thomas PW, et al. Human parvovirus infection in
homozygous sickle cell disease. Lancet 1993; 341: 1237–40.
2 Emond AM, Collis R, Darvill D, et al. Acute splenic sequestration in
homozygous sickle cell disease: natural history and management. J Pediatr
1985; 107: 201–6.
3 Gill FM, Sleeper LA, Weiner SJ, et al. Clinical events in the first decade in a
cohort of infants with sickle cell disease: the Cooperative Study of Sickle Cell
Disease. Blood 1995; 88: 776–83.
4 Lee A, Thomas P, Cupidore L, et al. Improved survival in homozygous sickle
cell disease: lessons from a cohort study. BMJ 1995; 311: 1600–2.

Acute chest symptoms

1 Gill FM, Sleeper LA, Weiner SJ, et al. Clinical events in the first decade in a
cohort of infants with sickle cell disease: the Cooperative Study of Sickle Cell
Disease. Blood 1995; 88: 776–83.
2 Lee A, Thomas P, Cupidore L, et al. Improved survival in homozygous sickle
cell disease: lessons from a cohort study. BMJ 1995; 311: 1600–2.
3 Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease: life
expectancy and risk factors for early death. N Engl J Med 1994; 330: 1639–
44.
4 Castro O, Brambilla DJ, Thorington B, et al; Cooperative Study of Sickle Cell
Disease. The acute chest syndrome in sickle cell disease: incidence and risk
factors. Blood 1994; 84: 643–9.
5 Vichinsky EP, Styles LA, Colangelo LH, et al. Acute chest syndrome in sickle
cell disease: clinical presentation and course; Cooperative Study of Sickle
Cell Disease. Blood 1997; 89: 1787–92.
6 Bellett PS, Kalinyak KA, Shukla R, et al. Incentive spirometry to prevent
acute pulmonary complications in sickle cell disease. N Engl J Med 1995;
333: 699–703.

Acute neurological complications

1 Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular
accidents in sickle cell disease: rates and risk factors. Blood 1998; 91; 288–
94.
2 Stroke in Childhood: Clinical guideline for diagnosis, management and
rehabilitation. Published: May 2017.
https://www.rcpch.ac.uk/resources/stroke-childhood-clinical-guideline-
diagnosis-management-rehabilitation. Accessed: 2 April 2019.

79
 Acute complications

Fulminant priapism
1 Mantadakis E, Cavender JD, Rogers ZR, et al. Prevalence of priapism in
children and adolescents with sickle cell anemia. J Pediatr Hematol Oncol
1999; 21: 518–22.
2 Mantadakis E, Ewalt DH, Cavender JD, et al. Outpatient penile aspiration
and epinephrine irrigation for young patients with sickle cell anaemia and
prolonged priapism. Blood 2000; 95: 78–82.
3 Virag R, Bachir D, Lee K, et al. Preventive treatment of priapism in sickle cell
disease with oral and self administered intracavernous injection of etilefrine.
Urology 1986; 47: 777–81.
4 Winter CR. Priapism cured by creation of fistula between glans penis and
corpora cavernosa. J Urology 1978; 119: 227–8.

80
 Surgery and perioperative care

Elective surgery and perioperative care

Indications for surgery in children with sickle cell disease 82

Perioperative management plan 82

Preoperative transfusion 82

81
 Surgery and perioperative care

Indications for surgery in children with SCD

As well as needing operative procedures for complications of SCD, such as acute
splenic sequestration or gallstones, children may need routine operations for
adenoidal hypertrophy, serous otitis media, orchidopexy, dental extractions and
other complications that occur in childhood.

Perioperative management plan

All patients with SCD, even without previously severe complications, are at
increased risk of complications at the time of surgery. Certain patients are at greater
risk of perioperative complications including:
• those with a history of severe sickle-related problems, such as acute chest
syndrome, cerebrovascular disease and frequent painful episodes
• those with severe obstructive sleep apnoea.

The perioperative management of patients with SCD requires good

communication between surgeons, anaesthetists, haematologists, paediatricians
and nursing staff. A clear management plan should be written in the notes prior
to surgery.

Preoperative transfusion
The optimal preoperative transfusion policy in SCD is not clear. A randomised
controlled trial showed that, in patients with HbSS and HbS/β0 thalassaemia
undergoing low- and moderate-risk surgery, a preoperative top-up transfusion to
a target Hb of 100 g/L significantly reduced perioperative complications,
particularly acute chest syndrome1. An earlier randomised controlled trial showed
that a conservative transfusion regimen that raised Hb to 100 g/L was as effective
in preventing perioperative complications as an aggressive exchange regimen
that reduced HbS to <30%2.
Major surgery (including cardiovascular surgery and neurosurgery) typically
requires transfusion, usually with an exchange transfusion to reduce the HbS
level <30%.

The perioperative management of children with HbSC disease, or with a

baseline Hb >90 g/L, is less clear, particularly in low- or moderate-risk surgery,
and needs to be decided on an individual basis.

Recommendations
• A clear management plan, agreed by all healthcare professionals involved,
should be made and recorded before surgery. (C)
• SHTs should have guidelines on perioperative management in patients
with SCD to share with local hospitals. (C)

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 Surgery and perioperative care

• The transfusion laboratory should know the red cell phenotype/genotype and
a recent antibody screen should be available in case blood transfusion
becomes necessary before or after the operation. (C)
• Children with HbSS and HbS/β0 thalassaemia undergoing low- and
moderate-risk surgery should have a preoperative transfusion to increase
the Hb level to 100 g/L. (A)
• Children with SCD undergoing high-risk surgery, including neurosurgery
and cardiovascular operations, should have a preoperative transfusion to
reduce HbS to <30%, which will usually involve an exchange transfusion.
(C)

References
1 Howard J, Malfroy M, Llewelyn C, et al. The Transfusion Alternatives
Preoperatively in Sickle Cell Disease (TAPS) study: a randomised,
controlled, multicentre clinical trial. Lancet 2013; 381: 930–8.
2 Vichinsky EP, Haberken CM, Neumayr L, et al. A comparison of
conservative and aggressive transfusion regimens in the perioperative
management of sickle cell disease. N Engl J Med 1995; 333: 206–13.

83
 Specific treatments

Specific treatments

Hydroxycarbamide 85

Use of transfusion therapy 86

Indications for acute transfusion 87

Indications for regular, long-term transfusion 88

Haemopoietic stem cell transplantation 89

84
 Specific treatments

Hydroxycarbamide
Hydroxycarbamide (previously known as hydroxyurea) promotes HbF synthesis,
improves red cell hydration, decreases the neutrophil count and modifies red
cell–endothelial cell interactions.
The Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) showed a
reduction in the frequency of painful episodes, incidence of chest syndrome and
transfusion requirement without serious short-term side effects1. A paediatric
study in Belgium showed similar beneficial results2. Long-term data from the
MSH study has shown a reduction in mortality in the hydroxycarbamide group.
More recently, the BABY HUG trial also showed that hydroxycarbamide
significantly reduced the frequency of acute pain and other vaso-occlusive
complications in very young children, from the age of 9 months3. However, the
same trial also failed to show that early use of hydroxycarbamide reduced early
splenic and renal damage. Hydroxycarbamide has also been shown to be
effective in primary stroke prevention in children with abnormal TCD velocities4.

Hydroxycarbamide has a number of side effects, of which myelosuppression is

the most common in the short term. In conditions already predisposed to
leukaemia (e.g. polycythaemia rubra vera), there is an increase in the incidence
of leukaemia in patients who received hydroxycarbamide treatment. There is no
evidence to date from its use in SCD to suggest that children on hydroxy-
carbamide are more at risk.

The long-term teratogenic risk is also not known, but sexually active individuals
taking hydroxycarbamide should be advised to use contraception. There are
concerns about possible effects on fertility, particularly in boys, although there is
no good evidence in this area.

Guidelines from the USA suggest that all children with HbSS or HbSβ0
thalassaemia should be offered hydroxycarbamide at the age of 9 months5, and
recent UK guidelines similarly recommend that children aged 9–42 months
should be offered hydroxycarbamide regardless of the clinical severity of their
illness6. However, it should be noted that hydroxycarbamide is not licensed for
children in the UK until the age of 2 years and any offer should only ever follow
an in-depth discussion.

There are still some areas which need clarification including: the optimal dose,
impact on long-term organ function and effects on fertility.

Recommendations
• Hydroxycarbamide, including its potential benefits and side-effects, should
be discussed with all children and parents in the first year of life, and at
subsequent annual reviews. (C)

85
 Specific treatments

• Hydroxycarbamide should be offered to all children with HbSS/Sβ0

thalassaemia aged 9–42 months regardless of the clinical severity of their
illness. (A) See Standard 6.
• Hydroxycarbamide should be offered to all children older than 42 months
who have recurrent episodes of acute pain or who have had two or more
episodes of acute sickle chest syndrome. (A)
• Hydroxycarbamide should be offered to all children older than 42 months
whose lives are significantly affected by symptoms of SCD, including
those with frequent episodes of pain that disrupt normal activities. (A)
• Hydroxycarbamide should be offered to all children older than 42 months
who are at high risk of progressive organ damage caused by SCD,
including those with hypoxemia, significant albuminuria, conditional TCD
velocities, or significant anaemia (steady state Hb<70 g/L). (B)
• The decision to start hydroxycarbamide should be made in conjunction with
the SHT, and agreement should be reached as to which centre will monitor
blood counts and maintain the optimal dose, and how these will be
communicated between centres. (C)
• The protocol should include information about dose regimen, frequency of
blood test monitoring, management of myelosuppression and
contraindications for the use of hydroxycarbamide. (C)
• The patient and/or their parents/carer should be given a patient information
sheet. Current knowledge about side effects, including subfertility,
cytopenias and the possible risk of leukaemia or other malignancies,
should be discussed; this discussion should be documented in the patient’s
notes. (C)
• Boys of the appropriate age should be offered semen storage before
starting hydroxycarbamide. (C)

Use of transfusion therapy

(see also sections on lung disease, cerebrovascular disease and perioperative
management)
Transfusion is an essential and life-saving therapy for some acute complications
of SCD and has been shown to reduce the risk of chronic progressive organ
damage in the case of ischaemic stroke 1. There may be a beneficial effect in
preventing other forms of organ damage, but studies are currently lacking.

Transfusion should not be undertaken without careful consideration of the

benefits and risks. Informed consent from the parents, or child where appropriate,
should always be obtained prior to transfusion.

There is an incidence of about 18% of alloimmunisation following blood

transfusion in the sickle population, and two-thirds of antibodies described are in
the rhesus (Rh) or Kell systems2. However, the risk may be less in those on

86
 Specific treatments

chronic exchange transfusion programmes3,4. This is in part because the blood

donor population and sickle patient population are from different ethnic origins5.
The risk of alloimmunisation can be reduced by transfusing only if absolutely
necessary and using blood that is compatible for Rh and Kell antigens.

There is an incidence of delayed haemolytic transfusion reactions in SCD of

between 4% and 22%, which is significantly higher than in other patients6. These
can mimic episodes of acute sickle pain and clinicians should have a high index
of suspicion for investigating for the development of antibodies when painful
episodes develop in the post-transfusion period. Once an alloantibody has been
identified, antigen-negative blood should be given, other than in the case of anti-
M and anti-Kpa, when crossmatch-compatible blood may suffice. More detailed
guidance is given in the recent BSH guideline on principles and laboratory
aspects of transfusion for SCD7.
Hyperhaemolysis has also been described post-transfusion without the
development of antibodies. This may be due to bystander haemolysis and one
study has shown a possible benefit for high-dose steroids and intravenous
immunoglobulin8, with further case reports describing the use of other forms of
immunosuppression e.g. rituximab9.
The viscosity of blood increases with increasing Hb and HbS-containing cells
add to that viscosity, so it is important to balance target Hb levels with HbS
concentrations. With this in mind, the target of a top-up transfusion for the
treatment of acute anaemia is usually no higher than the steady-state Hb level.
In monthly top-up transfusions (e.g. for the management of stroke where the HbS
is being maintained <30%), the target Hb is usually 120–130 g/L.
Urgent blood transfusion may be beneficial in some acute complications. The aim
is usually to correct the anaemia and sometimes to reduce the HbS level to
<30% or <50%. Reducing the HbS level to <30% will often require an exchange
transfusion, although a top-up transfusion may be adequate if the child is initially
very anaemic.

Indications for acute transfusion 10

Acute transfusion may be indicated in:
• acute anaemia due to
− parvovirus B19 infection
− acute splenic or hepatic sequestration
• acute chest syndrome – early top-up transfusion may avoid the need for
exchange transfusion
• stroke or acute neurological deficit – exchange transfusion is usually
necessary to reduce the HbS to <30%, with a target Hb of 100–110 g/L
• multiorgan failure
• preparation for surgery.

87
 Specific treatments

Indications for regular, long-term transfusion10

Regular transfusions may be indicated for:
• primary and secondary stroke prevention
• recurrent acute chest syndrome or painful episodes not prevented by
hydroxycarbamide
• progressive organ failure.
Iron chelation therapy should be considered in children on regular transfusions
according to standard protocols11. They should also be offered vaccination
against hepatitis A and B, and reviewed regularly with respect to iron and HbS
levels.

Recommendations
• At diagnosis or first clinic attendance, all patients should have an extended
red cell phenotype performed. As an alternative, a red cell genotype with
variant antigen analysis may be obtained. (C)
• All blood transfused should be matched for Rhesus and Kell blood groups.
If alloantibodies are identified, further transfusions should be negative for
the corresponding antigen. (C)
• Blood group genotyping should be considered in children with SCD who
develop alloantibodies or who start a long-term transfusion programme.
(C).
• Red cells for transfusion to patients with SCD should be sickle test negative
and if possible <7 days old for exchange or <10 days for top-up transfusion.
(C)
• Urgent red cell transfusion should be used in children with rapidly
progressive acute chest syndrome or acute neurological symptoms or in
those who are severely unwell, aiming to achieve an HbS level <30% and
an Hb of 100–110 g/L. This will often require an exchange transfusion. (C).
• Long-term transfusion regimens should be used after a cerebrovascular
event to prevent recurrence and should be considered if cerebral artery
velocities are abnormal on TCD scans. (A)
• Iron chelation should be considered in all children on regular blood
transfusions. (C)
• Immunisation against hepatitis A and B should be offered to all those on
long-term transfusion programmes. (C)
• Children starting regular blood transfusions should be reviewed initially by
a multidisciplinary team (including checks of HbS levels, iron stores and
neurological status, as appropriate) and regularly thereafter. (C)

88
 Specific treatments

Haemopoietic stem cell transplantation

Hemopoietic stem cell transplantation, which includes bone marrow
transplantation (BMT), along with transplantation of stem cells collected from the
peripheral blood or umbilical cord blood, is currently the only treatment for SCD
that is potentially curative.
Published experience describes a 92–94% survival rate and a 75–84% disease-
free survival rate1–3. There is no recurrence of clinical vaso-occlusive events in
patients with stable engraftment, but 10% of patients experience rejection or
recurrent SCD. The majority of patients have an excellent quality of life after stem
cell/bone marrow transplantation.
There are however significant risks associated with stem cell transplantation. The
most common early complications are acute graft-versus-host disease (GVHD)
and neurological events, including intracerebral haemorrhage and seizures.
Chronic GVHD is the most common cause of late mortality and morbidity, with an
incidence of 5% in the UK. Other late complications include gonadal dysfunction
and an increased risk of malignancy.
Unlike thalassaemia major, where the clinical course is fairly predictable, there is
a large variation of severity in SCD. In view of this and the high risk of mortality
and morbidity from the procedure, stem cell transplantation is not appropriate in
every patient.
Since the publication of trials using hydroxycarbamide, some of the
recommendations have been modified, as recurrent pain and chest disease are
probably now best treated initially with hydroxycarbamide, with stem cell
transplantation reserved for those patients who do not respond to
hydroxycarbamide.

Recommendations
• All patients or families with a child with SCD should be offered the
opportunity to discuss stem cell transplantation as a treatment option; this
should not depend on the family having an available donor at the time. (C)
• Haemopoietic stem cell transplantation should be performed in centres
experienced in transplants for haemoglobinopathies. Transplants from any
donor other than an HLA-identical family member should be undertaken
only in exceptional circumstances and as part of a clinical trial. Each SHT
should have clear referral links to a suitable transplant centre. (C)

89
 Specific treatments

References

Hydroxycarbamide
1 Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young
children with sickle-cell anaemia: a multicentre, randomised, controlled trial
(BABY HUG). Lancet 2011; 377: 1663–72.
2 Charache S, Terrin ML, Moore RD, et al. Effect of Hydroxyurea on the
frequency of painful crises in sickle cell Anemia. N Engl J Med 1995; 332:
1317–22.
3 Ferster A, Vermylen C, Cornu G, et al. Hydroxyurea for treatment of severe
sickle cell anemia: a pediatric clinical trial. Blood 1996; 88: 1960–4.
4 Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by
transfusions in children with sickle cell anemia and abnormal results on
transcranial Doppler ultrasonography. N Engl J Med 1998; 339: 5–11.
5 Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell
disease: summary of the 2014 evidence-based report by expert panel
members. JAMA 2014; 312: 1033–4.
6 Qureshi A, Kaya B, Pancham S, et al. Guidelines for the use of
hydroxycarbamide in children and adults with sickle cell disease: A British
Society for Haematology Guideline. Br J Haematol 2018; 181: 460–75.

Transfusion therapy
1 Pegelow CH, Adams RJ, McKie V, et al. Risk of recurrent stroke in patients
with sickle cell disease treated with erythrocyte transfusions. J Pediatr 1995;
126: 869–99.
2 Yazdanbakhsh K, Ware RE, Noizat-Pirenne F. Red blood cell
alloimmunization in sickle cell disease: pathophysiology, risk factors, and
transfusion management. Blood 2012; 120: 528–37.
3 Murao M, Viana MB. Risk factors for alloimmunization by patients with sickle
cell disease. Braz J Med Biol Res 2005; 38: 675–82.
4 Gill FM, Sleeper LA, Weiner SJ, et al. Clinical events in the first decade in a
cohort of infants with sickle cell disease: Cooperative Study of Sickle Cell
Disease. Blood 1995; 86: 776–83.
5 Vichinsky EP, Earles A, Johnson RA, et al. Alloimmunization in sickle cell
anemia and transfusion of racially unmatched blood. N Engl J Med 1990;
322; 1617–21.
6 Garratty G. Severe reactions associated with transfusion of patients with
sickle cell disease. Transfusion 1997; 37: 357–61.
7 Davis BA, Allard S, Qureshi A, et al. Guidelines on red cell transfusion in
sickle cell disease. Part I: principles and laboratory aspects. B J Haem
2017; 176: 179–91.

90
 Specific treatments

8 Cullis JO, Win N, Dudley JM, et al. Post-transfusion hyperhaemolysis in a

patient with sickle cell disease: use of steroids and intravenous
immunoglobulin to prevent further red cell destruction. Vox Sang 1995; 69:
355–7.
9 Bachmeyer C, Maury J, Parrot A, et al. Rituximab as an effective treatment
of hyperhemolysis syndrome in sickle cell anemia. Am J Hematol 2010; 85:
91–2.
10 Davis BA, Allard S, Qureshi A, et al. Guidelines on red cell transfusion in
sickle cell disease. Part II: indications for transfusion. B J Haem 2017; 176:
192–209.
11 Ballas SK, Zeidan AM, Duong VH, et al. The effect of iron chelation therapy
on overall survival in sickle cell disease and β‐thalassemia: A systematic
review. Am J Hematol 2018; 93: 943–52.

Haemopoietic stem cell transplantation

1 Bernaudin F, Souillet G, Vannie JP, et al. Report of the French experience
concerning 26 children transplanted for severe sickle cell disease. Bone
Marrow Transplant 1997; 19 (Suppl 2): 112.
2 Vermylen C, Cornu G, Ferster A, et al. Haematopoietic stem cell transplantation
for sickle cell anaemia: the first 50 patients transplanted in Belgium. Bone
Marrow Transplant 1998; 22: 1–6.
3 Walters MC, Storb R, Patience M, et al. Impact of bone marrow
transplantation for symptomatic sickle cell disease: an interim report.
Multicenter investigation of bone marrow transplantation for sickle cell
disease. Blood 2000; 95: 1918–24.

91
 Standards

Standards

Standard 1: Sickle cell and thalassaemia screening – reporting

newborn screen-positive results to parents 93

Standard 2: Sickle cell and thalassaemia screening – timely

follow-up, diagnosis and treatment of newborn infants

with a positive screening result 94

Standard 3: Timeliness of penicillin prophylaxis 95

Standard 4: Coverage of pneumococcal immunisation at 2 years 96

Standard 5 Coverage of transcranial Doppler (TCD) scanning 96

Standard 6: Coverage of hydroxycarbamide (hydroxyurea) therapy 97

Standard 7: Coverage of children identified through the screening

programmed subsequently registered on the national

haemoglobinopathy registry (NHR) 98

Standard 8: Coverage of children who have had an annual review 99

92
 Standards

Standard 1 (SCT-S08): Sickle cell and thalassaemia screening – reporting

newborn screen-positive results to parents

Description Proportion of parents receiving newborn screen-positive results

≤28 days of age
Rationale To provide timely results to parents of screen-positive infants in
order to give support to parents and carers, emphasise the
importance of early penicillin prophylaxis and to ensure prompt
referral into treatment (see Informing parents)
Definition
Number of newborn infants with screen-
positive results for whom parents receive
Expressed as
results ≤28 days of age
a percentage
Number of newborn infants born within the
reporting period with screen-positive results

Specified conditions to be detected in newborn screening are:

HbSS, HbSC, HbS/β thalassaemia (S/β+, S/β0, HbS/δβ, HbS/γδβ,
S/Lepore), HbS/DPunjab, HbS/E, HbS/OArab, HbS/HPFH, HbS with
any other variant and no HbA, and other clinically significant
haemoglobinopathies likely to be detected as by-products of
newborn screening, including β thalassaemia major,
HbE/β thalassaemia and β thalassaemia intermedia
Carrier results need to be followed up but are excluded from this
standard
Performance Acceptable: ≥90%
thresholds Achievable: ≥95%
Caveats Detection of thalassaemia is not part of the programme but we
expect β thalassaemia major to be detected as a by-product and
the same standards for communicating results to parents and
enrolment into care apply
Data Reporting focus: haemoglobinopathy centre
collection and Publishing focus: haemoglobinopathy centre
reporting Data source: haemoglobinopathy centre
Responsible for submission: newborn screening outcomes system
Responsible for data quality and completeness:
haemoglobinopathy centre
Reporting Annually 1 April–31 March
period Deadline: 30 June

93
 Standards

Standard 2 (SCT-09): Sickle cell and thalassaemia screening – timely follow-

up, diagnosis and treatment of newborn infants with a positive screening
result

Description Proportion of newborn infants with a positive screening result who

are (a) seen at a paediatric clinic or (b) discharged for insignificant
results ≤90 days of age
Rationale To optimise individual health outcomes, penicillin prophylaxis
should start by 90 days of age in children with SCD. Parents of
infants with insignificant results must be informed and reassured
as early as possible (see Confirmation of diagnosis)
Definition
Number of newborn infants:
a) with clinically significant results who are
seen by a paediatrician by ≤90 days of age;
and Expressed as
b) with insignificant results who are discharged a percentage
by ≤90 days of age
Number of newborn infants with a screen-
positive result born within the reporting period

Specified conditions to be detected in newborn screening are:

HbSS, HbSC, HbS/β thalassaemia (S/β+, S/β0, HbS/δβ, HbS/γδβ,
S/Lepore), HbS/DPunjab, HbS/E, HbS/OArab, HbS/HPFH, HbS with
any other variant and no HbA, and other clinically significant
haemoglobinopathies likely to be detected as by-products of
newborn screening, including β thalassaemia major,
HbE/β thalassaemia and β thalassaemia intermedia
Exclusions include:
– infants born outside of England
– infants who die or move abroad before 90 days of age
Performance Acceptable: ≥90%
thresholds Achievable: ≥95%
Caveats None

94
 Standards

Reporting Reporting focus: haemoglobinopathy centre

Publishing focus: haemoglobinopathy centre
Data source: haemoglobinopathy centre
Responsible for submission: newborn screening outcomes system
Responsible for data quality and completeness:
haemoglobinopathy centre
See dashboard HAEM04A Screening to access to specialist care
Reporting Annually 1 April–31March
period Deadline: 31 July

Standard 3: Timeliness of penicillin prophylaxis

Description The proportion of infants with HbSS and HbS/β0 thalassaemia who
are offered penicillin (or alternative) prophylaxis by ≤90 days of
age
Rationale To ensure optimum protection against invasive pneumococcal
infection before the onset of hyposplenism (see Prevention of
infection)
Definition
Number of infants with SCD offered penicillin
(or equivalent) prophylaxis ≤90 days Expressed as
Number of infants born with SCD and eligible* a percentage
for antibiotic prophylaxis

* Infants with HbSC disease are excluded because the evidence is

only available for giving penicillin prophylaxis to children with
HbSS and HbS/β0 thalassaemia. However, most centres will offer
penicillin prophylaxis to children with HbSC disease as
hyposplenism can develop but at a later age
Performance Acceptable: ≥95%
thresholds Achievable: ≥99%
Caveats Record parental refusal and reason
Reporting Reporting focus: paediatric service
arrangements Data source: paediatric service responsible for submission to
newborn outcomes system
Reporting Annually: 1 April–31 March
period Deadline: 30 September
See dashboard HAEM04B Screening to access to specialist care

95
 Standards

Standard 4: Coverage of pneumococcal immunisation at 2 years

Description The proportion of infants with SCD who have been given PPV
between 24 and 27 months of age
Rationale To ensure optimum protection against invasive pneumococcal
infection as PPV contains more serotypes than Prevenar 13. PPV
is less effective before 2 years of age (see Immunisations)
Definition
Number of children with SCD given PPV at 24–
27 months Expressed as
Number of children born with SCD aged 24– a percentage
27 months

Performance Acceptable: ≥95%

thresholds Achievable: ≥99%
Caveats Record parental decline. The paediatric service is responsible for
monitoring coverage wherever the vaccine is given
Reporting Reporting focus: paediatric service
arrangements Data source: to be determined

Reporting Annually: 1 April–31 March

period Deadline: 30 September

Standard 5 Coverage of transcranial Doppler (TCD) scanning

Description (1) The proportion of children with HbSS and HbS/β0 thalassaemia
who have their first TCD at 24–36 months
(2) The proportion of children with HbSS and HbS/β0 thalassaemia
aged 3–16 years who have annual TCD
Rationale To ensure timely screening of cerebral blood vessels to determine
a child’s potential risk of stroke and to continue to monitor
throughout childhood. The incidence of stroke is highest in
younger children (see Provision of TCD)
Definition (1)
Number of children with HbSS and
HbS/β0 thalassaemia who have their first TCD
aged ≥24 and ≤36 months Expressed as
Number of children with HbSS and a percentage
HbS/β0 thalassaemia aged ≥24 and
≤36 months

96
 Standards

Definition (2)
Number of children with HbSS and
HbS/β0 thalassaemia aged ≥3 to ≤16 years
Expressed as
tested by TCD in the last 12 months
a percentage
Number of children with HbSS and
HbS/β0 thalassaemia aged ≥3 and ≤16 years

Performance Acceptable: 99%

thresholds
Caveats Record parental decline
Record other means of surveillance e.g. if technically difficult and
child having regular MRI scan
Reporting Reporting focus: paediatric service
arrangements Data source: paediatric service

Reporting Annually 1 April–31 March

period Deadline: 30 September
See dashboard HAEM02 Transcranial Doppler (TCD) monitoring

Standard 6: Coverage of hydroxycarbamide (hydroxyurea) therapy

Description Documented evidence that a discussion has been held with a

child’s parents regarding the beneficial effects of
hydroxycarbamide
The proportion of children with HbSS and HbS/β0 thalassaemia
who are offered hydroxycarbamide
Rationale To optimise long-term clinical outcome in children with HbSS and
HbS/β0 thalassaemia (see Hydroxycarbamide)
Definition
Number of children with HbSS and
HbSβ0 thalassaemia aged ≥9 to ≤42 months
where there is documented evidence of a Expressed as
discussion about hydroxycarbamide a percentage
Number of children with HbSS and
HbSβ0 thalassaemia aged ≥9 to ≤42 months
Number of children with HbSS and
HbSβ0 thalassaemia aged ≥2 to ≤16 years
Expressed as
prescribed hydroxycarbamide
a percentage
Number of children with HbSS and
HbSβ0 thalassaemia aged ≥2 to ≤16 years

97
 Standards

Performance Acceptable (for children aged ≥9 to ≤42 months): ≥99% (see also
thresholds BSH guideline)
Acceptable (aged ≥2 to ≤16 years): To be determined
Caveats Hydroxycarbamide is only licensed for use in children over the age
of 2 years
Reporting Reporting focus: paediatric service
arrangements Data source: to be determined

Reporting Annually: 1 April–31 March

period Deadline: 30 September

Standard 7: Coverage of children identified through the screening

programmed subsequently registered on the national haemoglobinopathy
registry (NHR)

Description Proportion of children with SCD identified by the newborn

screening programme registered on the NHR
Rationale Completeness of coverage on the NHR is important to fulfil its
central aim of improving patient care. The newborn outcomes
system when fully implemented will hold denominator data and
record data transfer to the NHR. This will identify variance across
networks which can be further explored (see Organisation of
follow-up)
Definition
Number of infants with SCD registered on the
newborn outcomes system where data has
Expressed as
been pulled through to the NHR
a percentage
Number of infants with SCD registered on the
newborn outcomes system

Performance Acceptable: to be determined

thresholds Achievable: to be determined
Caveats From 2019, all infants identified as having SCD will be referred
from the newborn screening laboratory to paediatric care using the
newborn outcomes system. Data can be pulled through to the
NHR when key data and parental consent are recorded on the
newborn outcomes system

98
 Standards

Reporting Reporting focus: paediatric service

arrangements Data source: paediatric service responsible for submission to
newborn outcomes service
Reporting Annually: 1 April–31 March
period Deadline: 30 September

Standard 8: Coverage of children who have had an annual review

Description Proportion of children with SCD that have an annual review

Rationale To ensure all children with SCD have the benefit of annual
assessment and do not miss out on screening tests and treatment
interventions (see Annual review)
Definition
Number of children with SCD aged ≥1 to
≤16 years who have started annual review Expressed as
Number of children with SCD aged ≥1 to a percentage
≤16 years

Performance Acceptable: ≥85%

thresholds
Caveats None
Reporting Reporting focus: paediatric service
arrangements Data source: paediatric service
Reporting Annually: 1 April–31 March
period Deadline: 30 September
See dashboard HAEM05 Annual review via NHR

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