Overview of the management and prognosis of sickle cell

disease
Authors: Joshua J Field, MD, Elliott P Vichinsky, MD
Section Editor: Michael R DeBaun, MD, MPH
Deputy Editor: Jennifer S Tirnauer, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2024. | This topic last updated: Jul 18, 2024.

INTRODUCTION

Vaso-occlusive phenomena and hemolysis are the clinical hallmarks of sickle cell disease (SCD).
Vaso-occlusion results in recurrent painful episodes (previously called sickle cell crisis) and a
variety of serious organ system complications that can lead to life-long disabilities and even
death. Hemolysis of red blood cells (RBC) causes chronic anemia and pigment gallstones and
releases free hemoglobin which generates harmful metabolites like heme. (See "Overview of
the clinical manifestations of sickle cell disease".)

There are multiple components to the management of SCD, including the prevention and
treatment of the complications as well as consideration of potentially curative therapies.

This topic review discusses general principles of SCD management (infection prevention,
nutrition, travel advice, general principles of in-hospital care) and on prognosis.

Separate topics discuss:

● Prevention of complications – Primary prevention of the acute complications of SCD
includes routine health management with a hematologist or a health care provider with
expertise in SCD. Initial prevention of complications includes the use of penicillin
prophylaxis started in the newborn period, appropriate immunizations, and blood
transfusions for those at risk for stroke. (See 'Infection prevention' below.)

Therapies to prevent pain episodes in SCD including hydroxyurea, L-glutamine, and others
are discussed separately. (See "Hydroxyurea use in sickle cell disease" and "Disease-
modifying therapies to prevent pain and other complications of sickle cell disease".)

Other approaches under investigation are discussed in detail separately. (See

"Investigational pharmacologic therapies for sickle cell disease".)
 ● Curative therapies – A life-long cure for SCD is available only through hematopoietic stem
cell transplantation. Gene therapy and gene editing products were approved in 2023 This
subject is discussed in detail separately. (See "Curative therapies in sickle cell disease
including hematopoietic stem cell transplantation and gene therapy".)
● Treatment of complications – These important management issues are presented
separately, as follows:

• Acute chest syndrome – (See "Acute chest syndrome (ACS) in sickle cell disease (adults
and children)".)
• Bone and joint complications – (See "Acute and chronic bone complications of sickle cell
disease".)
• Cerebrovascular disease – (See "Acute stroke (ischemic and hemorrhagic) in children and
adults with sickle cell disease".)
• Children – (See "Sickle cell disease in infancy and childhood: Routine health care
maintenance and anticipatory guidance".)
• Fever – (See "Evaluation and management of fever in children and adults with sickle cell
disease".)
• Hepatic disease – (See "Hepatic manifestations of sickle cell disease".)
• Pain management – (See "Acute vaso-occlusive pain management in sickle cell disease".)
• Pregnancy – (See "Sickle cell disease: Obstetric considerations".)
• Prenatal testing – (See "Hemoglobinopathy: Screening and counseling in the
reproductive setting and fetal diagnosis".)
• Priapism – (See "Priapism and erectile dysfunction in sickle cell disease".)
• Pulmonary complications – (See "Overview of the pulmonary complications of sickle cell
disease".)
• Pulmonary hypertension – (See "Pulmonary hypertension associated with sickle cell
disease".)
• Kidney manifestations – (See "Sickle cell disease effects on the kidney".)
• Transfusion – (See "Red blood cell transfusion in sickle cell disease: Indications, RBC
matching, and modifications".)
• Transition from pediatric to adult care – (See "Sickle cell disease (SCD) in adolescents and
young adults (AYA): Transition from pediatric to adult care".)

GENERAL PRINCIPLES AND GUIDELINES

Modifications to care during COVID-19 pandemic — Clinicians can consult the American
Society of Hematology resource page on management of SCD during the coronavirus disease
2019 (COVID-19) pandemic [1].

Individuals with SCD are immunosuppressed, and avoiding exposure to individuals who may
transmit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is critical. (See
"COVID-19: Epidemiology, virology, and prevention", section on 'Prevention'.)

Individuals with SCD are immunocompromised and at high risk for severe COVID-19; COVID-19
vaccination (including booster doses) is especially important. (See 'Immunizations' below.)

Individuals with SCD who require medical attention should be encouraged to seek it when
needed, and individuals who are receiving chronic transfusions for the prevention of serious or
life-threatening events, such as those with a recent stroke or transient ischemic attack, should
continue to receive transfusions. (See "Red blood cell transfusion in sickle cell disease:
Indications, RBC matching, and modifications", section on 'Indications for transfusion'.)

Additional considerations related to acute chest syndrome and early institution of exchange
transfusion are discussed separately. (See "Acute chest syndrome (ACS) in sickle cell disease
(adults and children)", section on 'COVID-19'.)

Comprehensive health care maintenance — Individuals with SCD should be seen regularly by
the clinician and treatment team ideally as part of a comprehensive health care maintenance
program, recognizing that most adults in the US are not cared for in a specialized center [2].
Routine office visits are used to educate the affected individual and family/caregivers about
SCD, infection prevention, pain management strategies, and anticipatory guidance for possible
complications (eg, splenic sequestration, avascular necrosis of the femoral head, stroke, leg
ulcers). Education regarding the nature of the disease, genetic counseling, and psychosocial
assessments of individuals and their families/caregivers are also best accomplished during
these visits, reinforced, when possible, with telephone-based outreach programs [3,4].

In addition, obtaining steady state laboratory values (eg, hemoglobin, reticulocyte count, white
blood cell count, pulse oximetry readings) during routine visits will provide standards for
comparison during clinical exacerbations, because these values are often abnormal at baseline.

A comprehensive health care maintenance program for SCD individuals should include the
components discussed below [5,6]. (See 'Routine evaluations and treatments' below and
'Nutrition' below and 'Infection prevention' below.)

Evidence base and guidelines — Evidence-based recommendations for the management of

SCD were published in 2014 by the National Heart, Lung, and Blood Institute (NHLBI) of the
National Institutes of Health (NIH) and endorsed by a number of societies including the
American Academy of Pediatrics and the American Society of Hematology; these are available
on the NHLBI website and in summary form [7,8]. The American Society of Hematology
published additional guidelines in 2019 to 2020. Recommendations are largely consistent with
those presented here.

A Centers for Disease Control and Prevention website

( www.cdc.gov/ncbddd/sicklecell/index.html) also provides information on SCD [9].

Links to various society guidelines are listed in a separate topic review. (See 'Society guideline
links' below.)

PREVENTION AND TREATMENT OF VASO-OCCLUSIVE EVENTS AND THEIR

COMPLICATIONS

Hydroxyurea and other disease-modifying agents — The use of hydroxyurea is a mainstay

in the overall management of individuals with SCD, since it reduces the incidence of acute vaso-
occlusive pain episodes and other vaso-occlusive events including acute chest syndrome and in
some cases stroke; decreases hospitalization rates; and prolongs survival. The table
summarizes these benefits ( table 1). (See "Hydroxyurea use in sickle cell disease".)

Other medications to reduce vaso-occlusive complications are available (and more are under
investigation) if hydroxyurea is ineffective, if it cannot be tolerated, and can be used in
combination with hydroxyurea, provided hydroxyurea is providing benefit but vaso-occlusive
episodes continue.

Blood transfusion — Blood transfusions are used to treat and prevent complications of SCD,
including preparation for surgery; treatment of symptomatic anemia, acute stroke, multiorgan
failure, and acute chest syndrome; and prevention of stroke, acute chest syndrome/critical
illness. These indications, along with practical aspects of central venous access, crossmatching,
leukoreduction, simple versus exchange transfusion, and management of excess iron stores,
are discussed in detail separately. (See "Red blood cell transfusion in sickle cell disease:
Indications, RBC matching, and modifications".)

Curative treatments — A life-long cure for SCD is available only through hematopoietic stem
cell transplantation (allogeneic, or autologous with gene therapy or gene editing). (See
"Curative therapies in sickle cell disease including hematopoietic stem cell transplantation and
gene therapy".)

INFECTION PREVENTION
Overview — Individuals with SCD are highly susceptible to bacterial and viral infections, largely
due to functional asplenia that develops early in childhood. Their clinical course from these
infections is often more severe than individuals without SCD. (See "Overview of the clinical
manifestations of sickle cell disease", section on 'Infection'.)

The two major measures for preventing infection in individuals with SCD are immunization for
all patients, and prophylactic penicillin for all young children (eg, <5 years of age) [7]. A review
of the patient's immunizations should be performed at every medical contact to ensure that
they are up to date, and parents/caregivers of young children should confirm that prophylactic
penicillin is being used appropriately. Infection prevention in those with certain compound
heterozygous SCD syndromes (eg, hemoglobin SC, sickle cell-beta thalassemia) depends on the
degree of functional asplenia. (See 'Immunizations' below and 'Prophylactic penicillin' below
and 'Hb SC disease and sickle cell-beta thalassemia' below.)

Parents and caregivers of infants and children with SCD should also be instructed regarding
early recognition of infection, which may present with isolated fever. A formal plan should be
created for seeking medical attention for a predetermined elevated temperature (>38.5°C or
>101.5°F), and a strategy discussed regarding plans in case a fever develops during travel or
when visiting with family members or caregivers who may not be familiar with the routine.
Adults should also have a clear plan for seeking medical attention for signs of infection. Fever
should be considered a medical emergency requiring prompt medical attention, blood culture,
and treatment with antibiotics. This important issue is discussed separately. (See "Evaluation
and management of fever in children and adults with sickle cell disease".)

Immunizations — Immunizations are a cornerstone of infection prevention in SCD.

● Children with SCD should receive all routinely recommended childhood vaccines, including
those against Streptococcus pneumoniae, seasonal influenza, Neisseria meningitidis,
Haemophilus influenzae type B, and hepatitis B virus [10-15].
● People with SCD have increased morbidity and mortality from COVID-19, and COVID-19
vaccination (including booster doses) is recommended.
● Annual seasonal influenza vaccination should also be provided.
● When feasible, antibiotic prophylaxis may be indicated for individuals with SCD who are
household contacts of persons with these infections.
● Data from a large randomized trial of hydroxyurea use (the BABY HUG trial) are reassuring
that the use of hydroxyurea does not interfere with the response to immunizations [16].
 COVID-19 — People with SCD are immunosuppressed due to functional asplenia and have
increased morbidity and mortality from COVID-19.

Vaccination (including booster doses) is recommended; significant antibody responses have

been reported [17,18]. (See "Prevention of infection in patients with impaired splenic function",
section on 'COVID-19 vaccination'.)

Pneumococcal disease — Vaccination has led to a decrease in the incidence of invasive

pneumococcal disease in children with SCD [15,19,20]. In the United States, a 13-valent, 15-
valent, and 20-valent pneumococcal conjugate vaccine (PCV) and a 23-valent pneumococcal
polysaccharide vaccine (PPSV23) are available.

The PCV can be administered as early as six weeks of age and elicits an effective immunologic
response during the first two years of life. The pneumococcal polysaccharide vaccine (PPSV23)
includes a greater number of serotypes but is not immunogenic in children <2 years of age.
Penicillin prophylaxis does not appear to interfere with an IgG response to immunization [13].

Vaccination recommendations have changed with the introduction of the PCV20 vaccine, since
individuals who have received PCV20 do not require PPSV23 (previously, those who received
PCV13 or PCV15 did require PPSV23). Details are discussed separately, including:

Decision tool – A decision tool from the Centers for Disease Control and Prevention
( PneumoRecs VaxAdvisor) provides updated advice based on the individual's age (all age
groups are included) and previous pneumococcal vaccinations [21].

Additional details regarding pneumococcal vaccination and catch-up vaccination are presented
separately.
● Children – (See "Pneumococcal vaccination in children".)
● Adults – (See "Pneumococcal vaccination in adults".)
● Other relevant information – (See "Prevention of infection in patients with impaired
splenic function".)

Influenza — Annual seasonal influenza vaccination is recommended for all individuals with
SCD. Vaccination should be administered annually at the start of the flu season, beginning at
six months of age. Individuals with SCD should receive that inactivated vaccine rather than the
live-attenuated vaccine because of the increased risk of severe or complicated infection
( table 2). (See "Seasonal influenza in children: Prevention with vaccines" and "Seasonal
influenza vaccination in adults".)

Analysis of Healthcare Cost and Utilization Project (HCUP) 2003 to 2005 state inpatient data
indicated that although children with SCD were hospitalized for influenza 56 times more often
than those without SCD, neither the length nor cost of hospitalization differed [22]. Therefore,
effective influenza vaccination may decrease the hospitalization rate by decreasing the number
of febrile episodes that require evaluation and treatment. (See "Prevention of infection in
patients with impaired splenic function", section on 'Vaccinations'.)

Meningococcus — In the United States, early meningococcal vaccination is recommended for

all asplenic children, including those with SCD. Details are included in the summary table for
ages 2 months through 23 months ( table 3) and age 2 years ( table 4) and in a separate
topic review. (See "Meningococcal vaccination in children and adults", section on 'Immunization
of persons at increased risk'.)

Other standard vaccinations — Children with SCD should receive all standard childhood
vaccinations, including those against hepatitis A and B; measles, mumps, and rubella; varicella;
rotavirus; Haemophilus influenzae; tetanus, diphtheria, and pertussis; and poliovirus in
countries where it is still endemic. (See "Hepatitis B virus immunization in adults" and "Standard
immunizations for children and adolescents: Overview", section on 'Routine schedule' and
"Rotavirus vaccines for infants" and "Prevention of Haemophilus influenzae type b infection"
and "Poliovirus vaccination".)

Most of these vaccinations should be updated periodically during adulthood, according to the
recommendations of the Centers for Disease Control or other national regulatory agency.
Inactivated virus vaccines are preferred. (See "Standard immunizations for nonpregnant
adults".)

Prophylactic penicillin — Prophylactic penicillin should be given to all individuals with SCD at
least until age five [7,23]. The dose from age three months to three years is 125 mg penicillin V
orally twice daily, and at age three years this should be increased to 250 mg twice daily until the
age of five [24,25]. (See "Prevention of infection in patients with impaired splenic function",
section on 'Antibiotic prophylaxis'.)

After the age of five years, some parents/caregivers, with consultation of their clinicians, elect
to stop penicillin prophylaxis, while others will continue [26]. This is an important issue given
the lifelong persistence of splenic dysfunction starting in late childhood and continuing
through adulthood. Patients and families should be reminded that fever is a medical
emergency for a patient with SCD, regardless of whether they are taking penicillin.

Patients with penicillin allergies should receive prophylactic erythromycin BID. Other alternative
antibiotic choices for penicillin-allergic individuals are discussed separately. (See "Prevention of
infection in patients with impaired splenic function", section on 'Antibiotic prophylaxis'.)
The benefit of prophylactic penicillin has been demonstrated in two large randomized trials
[27,28]. A 2012 Cochrane review of these trials included data from 457 patients with SCD [29].
As compared with no treatment or placebo, penicillin prophylaxis was associated with a
decreased risk of pneumococcal infection (odds ratio 0.37, 95% CI 0.16-0.86) and a decreased
risk of death (odds ratio 0.11, 95% CI 0.01-2.11). Adverse effects were minimal. Further
discussion of these trials and related issues, such as penicillin resistance and country-specific
guidelines, is presented elsewhere. (See "Prevention of infection in patients with impaired
splenic function", section on 'Antibiotic prophylaxis'.)

A randomized trial directly evaluated the safety of stopping penicillin prophylaxis in 400
children with SCD who had received penicillin prophylaxis for at least two years immediately
before their fifth birthdays and had received the 23-valent pneumococcal vaccine between two
and three years of age, and again at the time of randomization (ie, had received optimal
prophylaxis) [25]. The incidence of systemic pneumococcal infection during 3.2 years of follow-
up was very low and not significantly different in those receiving placebo or continued penicillin
prophylaxis (2 versus 1 percent).

The decision of whether to continue antibiotic prophylaxis after age five must be made on a
case-by-case basis. Based upon the above data, many pediatric clinicians elect to stop
prophylaxis if the child has not had a prior severe pneumococcal infection or splenectomy and
is receiving comprehensive care, including administration of the pneumococcal polysaccharide
vaccine (PPSV23) [7,26]. However, others will continue penicillin prophylaxis through adulthood
because of the lifelong risk of pneumococcal infection, including infection with pneumococcal
disease with serotypes not included in the vaccines [30]. (See 'Pneumococcal disease' above.)

Regardless of the decision, careful monitoring should be continued because fever is a life-
threatening condition among individuals with SCD. Pneumococcal sepsis does occur in children
taking penicillin who have received the pneumococcal vaccine, and factors affecting adequacy
of pneumococcal prophylaxis should be explored [31,32]. As an example, publicly insured
children with SCD often receive inadequate antibiotic prophylaxis. In a review of Washington
State and Tennessee Medicaid programs, the average SCD patient was dispensed only 148 days
of prophylactic medication per year [33]. Efforts to improve penicillin access should therefore
be investigated. (See "Evaluation and management of fever in children and adults with sickle
cell disease".)

Hb SC disease and sickle cell-beta thalassemia — Compared to patients with hemoglobin SS

(Hb SS), those with certain compound heterozygous SCD syndromes (hemoglobin SC disease,
sickle cell-beta thalassemia) may have reduced susceptibility to serious infections, depending
on the disease severity. The risk of infection is proportional to disease severity due to the
resulting effect on splenic function. (See "Overview of compound sickle cell syndromes".)
● Hb SC – Those with Hb SC disease are less likely to develop invasive bacterial infection than
those with Hb SS [34-36], because they maintain some splenic function during early
childhood [37]. In addition, patients with Hb SC who develop bacteremia are less likely to
develop sepsis and septic shock [34,36]. Although there are case reports of fatal bacterial
infection in children with Hb SC disease [38], the risk of death due to overwhelming sepsis
is significantly lower than that of patients with Hb SS. While routine childhood
immunizations and a clear plan for seeking medical therapy for any febrile episode are
important, individuals with Hb SC are not routinely prescribed prophylactic penicillin [36].
● Sickle cell-beta thalassemia – Among patients with sickle cell-beta thalassemia, severity
of the disease varies with the production of hemoglobin A (Hb A), and management varies
accordingly:

• Patients with sickle cell-beta0 thalassemia (Hb S-beta0 thalassemia) have a clinical course
similar to patients with Hb SS disease, with development of functional asplenia early in
childhood and a similar risk of invasive bacterial infection. As a result, their infection
prevention strategy should be the same as those with Hb SS, including immunizations,
prophylactic penicillin, and empiric antibiotic therapy when they are febrile.

• Patients with sickle cell-beta+ thalassemia (Hb S-beta+ thalassemia) produce variable
amounts of Hb A and in general have less severe SCD complications, although limited
data are available regarding their risk of infection [36]. In general, they are treated in a
manner similar to those with Hb SC.

INFECTION MANAGEMENT

Infection is a frequent complication of SCD, and historically it has been the major cause of
death in children. Fever may be the first indication of a serious bacterial infection, and as such
should be considered a medical emergency. Patients should seek prompt medical attention
and be rapidly evaluated for a temperature >38.5°C (101.5°F). The important issue of infection
management in individuals with SCD is discussed in detail separately. (See "Evaluation and
management of fever in children and adults with sickle cell disease".)
● The evaluation should include a brief history for localizing symptoms and an abbreviated
physical examination focused on hemodynamic stability, signs of localized or generalized
 infection, splenic size, and evidence of stroke. (See "Evaluation and management of fever in
children and adults with sickle cell disease", section on 'Initial evaluation'.)

During the COVID-19 pandemic, testing for SARS-CoV-2 infection is appropriate for any
individual with SCD who presents with fever. (See "Clinical features, evaluation, and
management of fever in patients with impaired splenic function", section on 'COVID-19
considerations'.)
● Blood cultures and complete blood count with differential and reticulocyte count should be
obtained. Empiric parenteral antibiotics should be started as soon as possible, ideally
within 60 minutes of triage. Evaluation for pneumonia is important [39]; however,
antibiotics should not be delayed while awaiting chest radiography. (See "Evaluation and
management of fever in children and adults with sickle cell disease", section on 'Empiric
antibiotic therapy'.)

LEG ULCERS

The clinical characteristics and natural history of skin ulcers in individuals with SCD differ from
those seen in individuals with other hemolytic anemias. Severe pain at the wound site is
disproportionately greater in SCD than in other populations. Animal models support this
observation.

The best approach to leg ulcers is prevention, which includes attention to properly fitting shoes
and immediate treatment for early signs of skin injury. (See "Basic principles of wound
management".)

If a patient develops a leg ulcer, we routinely use lower extremity Doppler to evaluate for deep
vein thrombosis (DVT). Forty-four percent of leg ulcers in patients with SCD are associated with
a DVT, likely due to lower extremity edema [40]. In addition, since pulmonary hypertension is
associated with the development of lower extremity ulcers, we evaluate for pulmonary
hypertension with a transthoracic Doppler echocardiography and obtain a complete blood
count (CBC), lactate dehydrogenase (LDH) level, and serum chemistries. We do not routinely
evaluate for peripheral vascular disease with ankle brachial pressure index or for osteomyelitis,
unless there is clinical suspicion.

Management of large skin ulcers requires a multidisciplinary team. Although many systemic
and local therapies have been examined, the mainstays of therapy are wound care,
compression, and SCD-based therapy with hydroxyurea or chronic transfusion. Components of
management may include the following [41-45]:
 ● Immediate attention to the pain. Many providers use systemic opioids. Topical opioids also
have been examined and found to relieve pain and facilitate healing [46,47]. Topical opioids
also decrease local fluid extravasation.
● Local edema must be minimized with rest, lower extremity elevation, and compression
bandages. In some cases, diuresis is also appropriate. Coban compression may be more
beneficial than Unna boots.
● We have found bedrest, though difficult to comply with, is essential for healing of large
and/or recalcitrant ulcers [48,49].
● Therapeutic debridement is important to remove fibrotic tissue and stimulate healing. In
general, we initially refer the patient to a wound care specialist for debridement, dressing
changes and, if necessary, topical antibiotics [50]. Wet to dry dressings and Duoderm
hydrocolloid dressings may also facilitate healing.
● Infections require treatment, but antibiotics are often not helpful and should be used
appropriately.
● In our experience, repeated transfusion therapy accelerates wound healing and is often a
core therapy [51]. Alternatively, hydroxyurea may be beneficial, even though hydroxyurea-
related skin ulcers have been reported. Patients can be managed initially with hydroxyurea
and transitioned to chronic transfusion, or treated with chronic transfusion initially,
depending on other comorbidities and patient factors.
● Grafts may be necessary, but they have a very high failure rate and should be used
conservatively [52].

These therapies are discussed in more detail separately. (See "Overview of treatment of chronic
wounds".)

In addition to the specific therapies listed above, many patients with SCD and skin ulcers have
multiple other problems that impair wound healing, including malnutrition, vitamin D and
nutritional deficiencies, pulmonary hypertension, and depression. These confounding factors
also need to be addressed.

There are multiple therapies that may be beneficial but remain unproven, including Apligraf (a
skin equivalent), topical sodium nitrite 2% cream, RGD peptide dressings, and topical Timolol
[53-56]. We do not routinely use these therapies, but rely on pain relief, bedrest, transfusion
therapy, local wound care, and when necessary, consultation with chronic ulcer programs.

NUTRITION
There are few prospective data regarding clinical benefit of nutritional interventions that can be
used to guide nutritional management in patients with SCD. However, growing evidence
suggests that these individuals have vitamin and micronutrient deficiencies that may influence
the course of their disease [57-61]. We therefore use the following in our patients:
● Folic acid is given to all individuals in an oral dose of 1 mg daily. However, some clinicians
may reasonably omit folic acid supplementation for patients who have sufficient dietary
intake, especially in settings where grains and cereals are routinely supplemented. Folate
deficiency has been found in several observational studies of patients with SCD [60,62-65].
Increased folate consumption from ongoing hemolytic anemia is often proposed as a
rationale for the use of folic acid in these patients. However, there are no data that folic
acid supplementation increases the hematocrit in individuals with SCD; a randomized trial
of folic acid supplementation in 117 children with SCD showed that compared with
controls, those receiving folic acid did not show an improvement in hemoglobin levels or
growth characteristics but did have a decrease in mean cell volume and less dactylitis [63].
Despite this, we believe that the potential yet unknown benefit from folic acid
supplementation outweighs the potential harms.
● We use a daily multivitamin without iron for all of our patients. This replaces some of the
vitamins and micronutrients commonly reported to be deficient in these individuals,
including zinc, vitamin D, vitamin E, vitamin C, vitamin A, magnesium, selenium,
carotenoids, and flavonoids [57-60]. Excessive iron stores and oxidative injury may
contribute to the depletion of antioxidant vitamins.
● We screen all infants with SCD for risk factors for iron deficiency, including those not
receiving transfusions, during the first two years of life. We also use laboratory screening at
one year of age, as advised by the American Academy of Pediatrics (AAP). All children with
SCD who have evidence of iron deficiency anemia should be treated because iron
deficiency has a negative effect on neurodevelopment. (See "Iron deficiency in infants and
children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section
on 'Screening recommendations'.)
● Non-transfused young women with risk factors for iron deficiency or those who practice
breast feeding also should undergo screening and treatment. In patients with iron
deficiency, it is important to establish the cause. However, in contrast with children, in
adults with SCD there is a controversy surrounding management of iron deficiency since
preliminary data suggest iron deficiency may decrease polymerization of sickle hemoglobin
[66,67]. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults"
and "Pathophysiology of sickle cell disease".)
 ● For individuals found to be vitamin D deficient, additional supplementation with oral
vitamin D and calcium is appropriate. Vitamin D deficiency is under-recognized and
undertreated in the SCD population; observational studies have demonstrated that a
majority of children with SCD are vitamin D deficient and have inadequate calcium intake
[68,69]. These deficiencies may contribute to osteopenia and osteoporosis, which affect up
to 80 percent of patients with SCD. There is also an incompletely understood relationship
between vitamin D deficiency and chronic pain in children with SCD [69,70].

TRAVEL ADVICE

There are no travel restrictions for individuals with SCD. However, we generally advise
individuals with SCD to postpone elective travel if they are ill. For those who are well or at their
baseline, we provide advice regarding the following:

Planning for care away from home — It is important to have a plan should disease
complications occur, such as infection (or fever) or vaso-occlusive events (pain, acute chest
syndrome). This plan should be discussed with family members and caregivers who may not be
familiar with SCD.

Planning can be divided into preparation, during travel, and at the destination:
● Pre-travel

• Pack appropriately for the destination, including proper clothing for the destination and
during travel (eg, loose fitting clothes and something to keep warm on a cold airplane),
medications with labels (keep on the airplane, not in checked baggage), personalized
health plan and pain management plan, and letter for clinicians at the destination.
Identify health care resources at the destination should they be needed.

• For international travel, obtain recommended immunizations and possible prophylaxis if

traveling to risk areas [71].
● During travel

• Ensure adequate hydration.

• Move frequently to reduce venous thromboembolism risk.
• Have supplementary oxygen available if there is a history of chronic pulmonary
complications.
• Additional advice specific to air travel is listed below. (See 'Advice specific to air travel'
below.)
● Destination
 • Avoid situations that could lead to dehydration or could exacerbate pain (eg, avoid long
lines and temperature extremes).

• Fever should be considered a medical emergency requiring prompt medical attention,

blood culture, and treatment with antibiotics. (See "Evaluation and management of fever
in children and adults with sickle cell disease".)

• Pain episodes should be treated promptly, and caregivers and local clinicians should
follow an individualized care plan that has been established for that individual. (See
"Disease-modifying therapies to prevent pain and other complications of sickle cell
disease", section on 'Individualized care plan' and "Acute vaso-occlusive pain
management in sickle cell disease".)

We often provide a letter for the individual or parents/caregivers to share with local medical
services that includes the individual's diagnosis, contact information for the primary
hematologist or on-call coverage, and a list of concerning symptoms with our preferred
evaluation and treatment. This includes:
● Fever >101.4 °F – Aggressive evaluation for the source of fever, including complete blood
count (CBC), reticulocyte count, blood culture, urine culture, and chest radiograph, with
antibiotics given pending the results (intravenous if toxic-appearing; oral if not toxic-
appearing).
● Acute chest pain or dyspnea – CBC, reticulocyte count, chest radiograph, and possibly
arterial blood gas, with antibiotics for fever and hospitalization for severe pain.
● Neurologic symptoms (seizures, focal findings, severe headache) – Extensive neurologic
evaluation including evaluation for ischemic or hemorrhagic stroke; exchange transfusion
may be indicated.
● Acute pain not relieved by usual outpatient measures – Aggressive evaluation for the
source, including CBC, reticulocyte count, and other testing, with opioid analgesia given
rapidly.
● Marked lethargy or dehydration – Examination, documentation of spleen size, CBC,
reticulocyte count, and electrolytes, with hydration with saline solution.

Advice specific to air travel — Individuals with SCD can use standard commercial airline travel
and should not be discouraged from doing so. Avoid travel in unpressurized aircraft above 5000
feet (increased risk for vaso-occlusive events). The risk for in-flight vaso-occlusive complications
on commercial airlines are considered to be low, although evidence is limited.
 ● As noted above, hydration is important; individuals with SCD should have adequate intake
of liquids. It may be necessary to obtain drinking water or other beverages after passing
through airport security.
● Air travel (or other prolonged travel) increases the risk of deep vein thrombosis, and
individuals with SCD should be encouraged to walk around when possible and move their
legs, similar to individuals without SCD. (See "Pathogenesis, risk factors, and prevention of
venous thromboembolism in adult travelers".)
● Several large case series and our own experience have shown that hypoxic events related
to airlines are uncommon [72,73]. We do not advise individuals with SCD to use
supplemental oxygen on commercial airline flights, although individuals with SCD can and
should request oxygen if they become short of breath during air travel, similar to those
without SCD, and those with known hypoxic lung disease or using home oxygen should
have oxygen while traveling.
● Individuals with SCD should be aware of the possible risk of splenic infarction, a risk that is
very small but may be increased in those with splenomegaly. The risk is also increased in
those with certain compound heterozygous SCD syndromes, as some of these individuals
can have some preservation of splenic function. (See "Splenomegaly and other splenic
disorders in adults", section on 'Focal splenic lesions' and "Overview of compound sickle
cell syndromes".)

ROUTINE EVALUATIONS AND TREATMENTS

Routine evaluations and associated treatments of individuals with SCD are extensive [2]. While
the following list serves as a guideline for screening, it is important to adopt a comprehensive
approach that can be followed by the patient. The transition from pediatric to adult providers
can be associated with lapses in care, and this is an important time to ensure that routine
evaluations have been performed.

We screen for the following:

● Hypertension – Blood pressure screening should be done at every visit. Early treatment of
systemic hypertension is critical because mild elevations in blood pressure are associated
with an increased risk of overt stroke and silent cerebral infarct in individuals with SCD
[74,75]. (See "Overview of hypertension in adults" and "Choice of drug therapy in primary
(essential) hypertension".)
● Cerebral complications
• TCD screening for stroke risk – In children ≤16 years of age with hemoglobin SS or
hemoglobin S-beta thalassemia that produces no hemoglobin A, (Hb S-beta0
thalassemia), cerebral blood flow should be evaluated by transcranial Doppler (TCD)
annually, because children at risk for strokes can be identified with this technique and
the incidence of stroke can be reduced by the use of regular blood transfusion therapy
aimed at maintaining the maximum hemoglobin S level at less than 30 percent [76]. In
contrast, children with hemoglobin S beta+ thalassemia and hemoglobin SC disease do
not require TCD screening [23]. In the United States, appropriate TCD screening appears
to be decreasing, and obstacles must be overcome to improve screening rates [77]. (See
"Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Risk
assessment for first stroke'.)

Optimal intervals for TCD measurements have not been formally evaluated, but TCD
measurements should be started at two years of age and performed annually [7]. Serial
TCD screening is recommended because normal flow velocity on a single screening does
not assure a continued low-risk status. Individuals with abnormal velocity on TCD should
be seen by a specialist with expertise in chronic transfusion therapy and stroke
prevention. These issues are discussed in detail separately. (See "Red blood cell
transfusion in sickle cell disease: Indications, RBC matching, and modifications", section
on 'Primary and secondary stroke prevention' and "Prevention of stroke (initial or
recurrent) in sickle cell disease", section on 'Prevention of a first ischemic stroke (primary
stroke prophylaxis)'.)

TCD measurements are lower in adults with SCD compared with children, and there is no
evidence to suggest that TCD velocities are predictive of stroke risk in adults. We do not
recommend TCD screening in individuals >16 years of age [78,79]. (See "Prevention of
stroke (initial or recurrent) in sickle cell disease", section on 'Risk assessment for first
stroke'.)

• Screening for neurocognitive dysfunction – We also screen individuals with any sign
of cognitive/neurologic dysfunction (eg, poor school performance, headaches, concerns
expressed by family members, caregivers, or teachers) for silent infarcts using magnetic
resonance imaging (MRI), based on observations that silent infarcts correlate with
cognitive deficits and these findings may identify individuals who would benefit from
early interventions. (See "Prevention of stroke (initial or recurrent) in sickle cell disease",
section on 'Management of cognitive and behavioral dysfunction'.)

Adults may have progressive neurocognitive injury that may not be detected without a
formal protocol. In addition, screening for health literacy and activities of daily living are
 recommended [80]. If deficits in health literacy and activities of daily living are impaired,
neuropsychological testing is appropriate, and neurocognitive remediation programs
may be indicated. As patients age, preliminary data suggest they are at risk for
premature dementia. The Rowland Universal Dementia Assessment Scale (RUDAS) was
specifically designed for cognitive screening [81]. The RUDAS evaluates executive
function, memory, language, and perceptual-motor function. It was designed to
minimize educational bias and can be administered in six minutes. Use of the RUDAS in
adults with SCD documented scores consistent with dementia in 29 of 252 participants
(12 percent); the proportion increased with age, up to 15 percent in the 40 to 59 years
age group and 36 percent in the ≥60 years age group [81].
● Retinopathy – Retinal evaluation is begun at 10 years of age and continued routinely to
detect early proliferative sickle retinopathy [7,23]. (See "Overview of the clinical
manifestations of sickle cell disease", section on 'Retinopathy'.)
● Pulmonary hypertension (PH) – We take a thorough history of respiratory symptoms in all
patients. For symptomatic patients, we have a low threshold for evaluation of PH risk. It is
important to note that symptoms of PH are variable; patients may report chronic dyspnea,
chest pain, presyncope, or exercise intolerance; or they may gradually limit activities
without recognizing specific symptoms. Details of the evaluation of symptomatic patients
are presented separately. (See "Pulmonary hypertension associated with sickle cell
disease", section on 'Evaluation for PH'.)

It is also important to note that children presenting with acute or chronic respiratory
symptoms should be evaluated for more common conditions, such as asthma and acute
chest syndrome, in addition to evaluation for PH. (See "Overview of the pulmonary
complications of sickle cell disease" and "Acute chest syndrome (ACS) in sickle cell disease
(adults and children)".)

For patients who are truly asymptomatic, we do not screen for PH.

An elevated tricuspid regurgitant jet velocity on echocardiographic screening may be a

marker of risk for conditions other than PH, including venous thromboembolic disease and
disordered sleep breathing [82]. Details of the management of patients with abnormal
findings from non-invasive screening, which may include additional screening,
supplemental oxygen, diuretics, escalation of hydroxyurea therapy, anticoagulation, and/or
pulmonary vasodilator therapy, are presented separately. (See "Pulmonary hypertension
associated with sickle cell disease" and "Overview of the pulmonary complications of sickle
cell disease".)
● Priapism – Males with SCD should be educated about priapism and asked questions about
the presence of priapism; this is usually not volunteered because of the sensitivity of the
issue. Implementation of a short annual priapism profile questionnaire is helpful. This
short 12-question questionnaire will determine activity, severity, and quality-of-life issues
that may guide therapy [83]. (See "Priapism and erectile dysfunction in sickle cell disease".)
● Kidney disease – Identifying kidney disease is important because individuals with SCD
hyper-excrete creatinine, which may mask impaired kidney function; however, high quality
evidence for the optimal screening is lacking. Kidney function can be assessed with a
chemistry panel including creatinine and a urine for proteinuria and/or albuminuria.
Evaluation is initiated often by age three to five or no later than the age of 10 years; adults
are monitored at regular visits, typically four to six times per year [7,23]. Individuals
receiving an iron chelator may require more frequent monitoring. Abnormal findings are
evaluated further, as discussed separately. (See "Sickle cell disease effects on the kidney"
and "Evaluation of proteinuria in children" and "Assessment of urinary protein excretion
and evaluation of isolated non-nephrotic proteinuria in adults".)
● Hepatitis C virus – We screen for hepatitis C virus, as discussed in detail separately. (See
"Screening and diagnosis of chronic hepatitis C virus infection".)
● Birth control and family planning – We assess family planning and birth control needs in
all adults and in adolescents in an age-appropriate manner, with ongoing discussion of
options. (See "Hemoglobinopathy: Screening and counseling in the reproductive setting
and fetal diagnosis" and "Sickle cell disease: Obstetric considerations".)

Preconception counseling and screening for red blood cell alloantibodies is provided to
individuals of childbearing age who are planning a pregnancy [7,23]. Referral of a partner
of unknown SCD status for hemoglobinopathy screening is appropriate prior to
conception. (See "Sickle cell disease: Obstetric considerations".)
● Stress and depression – Individuals with SCD should have ongoing assessment of
psychological well-being; depression is a serious component of chronic disease.

Depression is underdiagnosed in adolescents and adults with SCD. In adults with SCD,
depression (defined as a PHQ-9 score of ≥10 on two separate occasions at least four weeks
apart) occurred in 16 percent, and depression was an independent risk factor for earlier
mortality after adjustment for heart, lung, and kidney disease [84].

At least annual screening for depression and annual screening for neurocognitive deficits
that may impair decision making and complex problem solving should be considered. In
high-risk individuals, such as those with major school difficulties or signs of neurocognitive
 dysfunction, detailed neurocognitive testing is advised. (See "Screening for depression in
adults".)

Therapy for depression should be addressed when appropriate. (See "Overview of

prevention and treatment for pediatric depression" and "Major depressive disorder in
adults: Approach to initial management".)
● Bone health – We assess contributors to bone health including calcium intake, vitamin D
status, and bone density at 12 years of age, and perform a screening physical exam for
avascular necrosis [68,85]. We repeat vitamin D screening annually and bone density
testing every one to three years. (See "Acute and chronic bone complications of sickle cell
disease".)
● Growth – We measure height and weight in children and adolescents, and weight in adults,
because children with SCD may show delayed growth trajectories [86]. If children have
decreased growth trajectories, we evaluate nutritional and environmental factors as
potential contributors. Growth disturbances are common in sickle cell disease and have
multiple etiologies that can be corrected. Correction of nutritional deficiencies may be
beneficial, particularly zinc, which is associated with improved linear growth and weight
gain [87]. An increased metabolic rate resulting in elevated resting energy expenditure and
increased caloric requirements is common and may be improved by caloric intake or
decreasing energy expenditures [88-90]. Transfusion therapy or hydroxyurea decreases
metabolic rate and improves growth. Finally, monitoring growth and weight velocity may
uncover growth hormone disturbances, which are responsive to growth hormone
replacement [91]. In general, we watch closely before we initiate a more extensive
evaluation because of the known rate delayed maturation.

These routine evaluations and treatments should be tailored for individual patients when co-
morbidities are present (eg, chronic renal insufficiency, interstitial lung disease). This is
especially true for adults with SCD, as end-organ dysfunction is prevalent.

PAIN MANAGEMENT

Acute vaso-occlusive pain episodes are one of the most frequent reasons for individuals with
SCD to seek medical attention, and chronic pain affects a large number of these individuals.
Chronic pain is a significant problem; by adulthood, one-half of individuals with SCD have
chronic pain [92]. Management of acute pain episodes, chronic pain, preventive strategies, and
opioid side effects are discussed in detail separately. (See "Acute vaso-occlusive pain
management in sickle cell disease".)
MANAGEMENT DURING HOSPITALIZATION

Individuals with SCD who are hospitalized require vigilance for many of the same conditions as
those without SCD, as well as some that are specific to their disease. Management of individual
complications of SCD is discussed separately. (See 'Introduction' above and "Acute vaso-
occlusive pain management in sickle cell disease".)

Inpatient management issues that should be considered regardless of the admission diagnosis
include consideration of hydration status, incentive spirometry, and venous thromboembolism
prophylaxis, and reinstitution of prophylactic penicillin upon discharge. Hydroxyurea should be
continued during hospitalization as long as there is no excess hematologic toxicity. Children
and adults with SCD with mental health disease have an independent increased rate of
hospitalization [93] and early mortality [84], respectively. (See "Hydroxyurea use in sickle cell
disease", section on 'Hospitalization'.)

Hydration — Adequate hydration is important to reduce complications of SCD during

hospitalization. The choice of replacement fluid depends on the patient's volume status and
whether transfusion is required.
● For those who require transfusion (eg, acute splenic sequestration crisis, transient aplasia
from infection), transfusion should not be delayed while giving other fluids. (See "Red
blood cell transfusion in sickle cell disease: Indications, RBC matching, and modifications",
section on 'Symptomatic or severe anemia'.)
● If the patient is hypovolemic, lactated ringers solution should be used rather than normal
saline (0.9 percent saline). This is due to emerging preclinical and clinical evidence
indicating the benefit of lactated ringers solution over normal saline [94,95]. (See
"Treatment of severe hypovolemia or hypovolemic shock in adults" and "Treatment of
hypovolemia (dehydration) in children in resource-abundant settings".)
● If the patient is euvolemic (or has become euvolemic after fluid replacement), careful
consideration should be made for maintaining euvolemia and avoiding hypervolemia with
oral fluids, intravenous fluids one-quarter to one-half normal saline, or a combination of
oral and intravenous fluids. For those receiving maintenance intravenous fluids, we use
one-quarter or one-half normal saline with or without glucose. This approach differs from
maintenance fluid replacement in patients without SCD, who often receive normal saline.
Patients with SCD may have a decreased ability to excrete sodium and may become
hypernatremic from receiving normal saline. Hypernatremia in turn may lead to red blood
 cell dehydration, which increases sickling. (See "Maintenance intravenous fluid therapy in
children" and "Maintenance and replacement fluid therapy in adults".)
● If the patient is euvolemic and able to take oral fluids adequately, this should be
encouraged.

Incentive spirometry — Incentive spirometry is used to reduce the risk of acute chest
syndrome. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section
on 'Respiratory support' and "Acute chest syndrome (ACS) in sickle cell disease (adults and
children)", section on 'Incentive spirometry during hospitalization'.)

Thromboembolism prophylaxis — Patients with SCD appear to have a hypercoagulable state

at baseline, and they often have other factors that further increase the risk of venous
thromboembolism (VTE) (eg, indwelling catheter, immobility, infection) [96]. For all adults (ie,
those >18 years) with SCD who are admitted to the hospital for an acute medical condition, we
recommend thromboprophylaxis. (See "Prevention of venous thromboembolic disease in
acutely ill hospitalized medical adults" and "Prevention of venous thromboembolic disease in
adult nonorthopedic surgical patients".)

In contrast, we do not use routine thromboprophylaxis for VTE in hospitalized children and
adolescents under 18 years of age. General recommendations regarding thromboprophylaxis
in children are discussed separately. (See "Venous thrombosis and thromboembolism (VTE) in
children: Treatment, prevention, and outcome", section on 'Approach to VTE prophylaxis'.)

Splenic and hepatic sequestration

Overview — Splenic sequestration is a potentially life-threatening complication of SCD that

requires admission to the hospital for maintenance of hemodynamic stability [97,98]. Splenic
sequestration in SCD is characterized by the following four features:
● Splenic enlargement, often tender
● A drop in hemoglobin concentration of at least 2 g/dL
● Thrombocytopenia
● Reticulocytosis

Splenic sequestration is commonly observed in infants and children, including those as young
as two months of age [99]. Less commonly, acute splenic sequestration episodes may occur in
adolescents and adults, particularly those with SCD-SC [100,101]. (See "Overview of the clinical
manifestations of sickle cell disease", section on 'Splenic sequestration crisis'.)

The primary concern in the event of a splenic sequestration episode is hypovolemic shock
resulting from a disproportionate amount of the intravascular blood volume being sequestered
in the spleen because of ensnared red and white blood cells. Hence, management should be
directed at maintaining the individual in a euvolemic state.

Hepatic sequestration can also occur; this complication and its management are discussed
separately. (See "Hepatic manifestations of sickle cell disease", section on 'Acute hepatic
sequestration'.)

Initial management — The optimal management of an acute splenic sequestration episode is

based on the following principles:
● A high index of suspicion when an individual presents with a sudden drop in hemoglobin,
thrombocytopenia, reticulocytosis, and an enlarged spleen.
● Assessment of volume status and immediate intravenous fluid resuscitation if needed, with
the goal of maintaining the individual in a euvolemic state [7,23]. This may require
administration of isotonic solution. (See 'Hydration' above.)

When the individual is hypovolemic and is symptomatic from anemia, a simple blood
transfusion therapy should be considered. However, caution should be used when transfusing
the individual, as the blood trapped in the spleen is still available to re-enter the circulation.
Accordingly, following such transfusion the individual's hemoglobin may rise acutely to levels
that result in hyperviscosity syndrome. (See "Red blood cell transfusion in sickle cell disease:
Indications, RBC matching, and modifications", section on 'Symptomatic or severe anemia'.)

To decrease the likelihood of hyperviscosity syndrome occurring after a simple blood

transfusion, we typically transfuse the individual with approximately 50 percent of what we
would commonly transfuse. Thus, instead of transfusing the adult individual with two units of
blood, we transfuse a single unit of blood or calculate (and deliver) the amount of blood
needed to get the individual back to their baseline level and re-evaluate the clinical status after
transfusion. (See "Red blood cell transfusion in sickle cell disease: Indications, RBC matching,
and modifications", section on 'Risk of hyperviscosity syndrome from simple transfusion'.)

Follow-up care — The natural history of splenic sequestration in infants and toddlers with SCD
is well documented, with a reasonable proportion having a second event within 12 months of
the first event. In adults with SCD there are limited data to describe the risk of subsequent
splenic sequestration episodes, but in general we would manage them in similar way [102].
● Future management should include education about self-palpation of the spleen and
instructions on what to do in the event of an enlarging spleen.
● After consideration of risks and benefits, there should be a discussion of the potential
removal of the spleen in a non-acute setting.
 ● Institution of regular blood transfusion therapy to prevent subsequent episodes of acute
splenic episodes is not indicated and has not proven to be of benefit.

Surgical considerations — (See "Perioperative management of adults with sickle cell disease
or thalassemia", section on 'Sickle cell disease'.)

AVOIDANCE OF G-CSF

Case reports have indicated that the use of granulocyte colony-stimulating factor (G-CSF) in
individuals with SCD, including some compound heterozygous SCD syndromes (Hb SC disease
and Hb S-beta+ thalassemia), has been associated with sickle cell vaso-occlusion and
multiorgan failure; at least one individual (a hematopoietic stem cell donor for a sibling) died as
a result of this complication [103-105]. G-CSF may also play a role in the acute chest syndrome
and the complications associated with it [106].

We and others therefore do not use G-CSF administration in individuals with Hb SS or

compound heterozygous SCD syndromes [107,108]. However, there may be a rare case in which
the potential benefits of G-CSF therapy outweigh the risks (eg, treatment of chemotherapy-
induced fever with sepsis), and the judicious use of G-CSF may be justified [107,109]. Instead of
G-CSF, the ongoing gene therapy trials in SCD are using the CXCR4 antagonist plerixafor for
stem cell mobilization.

In contrast to those with sickle cell syndromes, individuals with sickle cell trait may receive G-
CSF [107,110]. (See "Sickle cell trait", section on 'Blood and stem cell donation'.)

SURVIVAL AND PROGNOSIS

The survival for individuals with SCD who have access to comprehensive care has improved
dramatically, with the major causes of death shifting from infections to progressive end-organ
damage.

Overall survival — Survival of individuals with SCD is reduced compared with those without
SCD, but the prognosis for SCD has been steadily improving following the institution of
comprehensive care that includes newborn screening, immunizations, antibiotics, hydroxyurea,
and more rapid prevention and treatment of disease complications (eg, stroke). In regions
where comprehensive care is available, the disease has shifted from a fatal pediatric illness to a
chronic disease often associated with progressive deterioration in quality-of-life and organ
function [111-115].
Adults — Survival well into adulthood for those with access to comprehensive care was
illustrated in 2014 study involving a cohort of adult patients followed at a tertiary care medical
center in the United States, in which median survival for Hb SS and Hb S-beta0 was 58 years,
and median survival for Hb SC and Hb S-beta+ was 66 years [116]. In a 2016 study involving 712
patients followed at a tertiary center in the United Kingdom, the median survival for Hb SS and
Hb S-beta0 was 67 years [117]. This improved survival was attributed to care at a specialist
hematology clinic, inpatient management by a dedicated team, involvement of specialists in
other organ systems, availability of on-site red blood cell (RBC) exchange, and a focused
"transition program" to facilitate safe transition from pediatric to adult care. A study of the
general United States population showed a younger median age of death (43 years) but a
similar overall trend towards improved survival [115].

Data regarding the impact of hydroxyurea on survival include the following:

● In an adult cohort study that evaluated risk factors for death in 383 adults with Hb SS,
hydroxyurea use was associated with improved survival (hazard ratio [HR] 0.58, 95% CI
0.34-0.97) [118]. The greatest benefit of hydroxyurea therapy was seen in the subgroup
taking the recommended dose of 15 to 35 mg/kg/day (HR 0.36, 95% CI 0.17-0.73).
Participants with higher fetal hemoglobin (an indication of better response to therapy or
greater medication adherence) had the greatest benefit.
● In a cohort study that compared outcomes in 131 patients with SCD of various genotypes
who were treated with hydroxyurea versus 199 patients who did not receive hydroxyurea,
10-year survival was 86 versus 65 percent [119].
● In the Belgian cohort discussed above, the use of hydroxyurea therapy was not associated
with prolonged survival; however, the analysis only included hydroxyurea prescription, and
did not take into account the hydroxyurea dose.

These data are especially impressive because in many cases the individuals treated with
hydroxyurea are likely to have had more severe disease and thus would have been expected to
have a higher overall mortality rate than those with less severe disease. Collectively, these data
support the premise that at a minimum all adults with SCD who have genotypes of Hb SS and
Hb S-beta0 thalassemia should be treated with hydroxyurea. (See "Hydroxyurea use in sickle cell
disease".)

Individuals who survive into later adulthood may have long-term disease complications not
seen in younger patients. This was illustrated in a cohort of individuals who survived beyond
age 60 with SCD [120]. Renal insufficiency was seen in 34 of 40 (85 percent).
Children — The mortality rate of infants and young children with SCD who have access to
comprehensive care has decreased more dramatically than that of adults, in large part because
of the decrease in sepsis from early use of prophylactic antibiotics and immunizations. Less
dramatic decreases in the mortality rate of older children may reflect increased survival beyond
infancy, lapses in care during the transition from pediatric to adult care providers, and lack of
adequate preventive measures for non-infectious complications of SCD (eg, acute chest
syndrome, organ failure). (See "Sickle cell disease (SCD) in adolescents and young adults (AYA):
Transition from pediatric to adult care", section on 'Health care transition as a vulnerable time'.)

The improvements in survival for infants and young children are illustrated by the following
studies:
● The Center for Disease Control and Prevention's National Center for Health Statistics
analyzed trends in pediatric SCD-related mortality from 1983 through 2002 [121]. Mortality
declined over the course of the study in all age cohorts, with decreases of 68, 39, and 24
percent for children aged zero to three years, four to nine years, and 10 to 14 years,
respectively. By 1999 to 2002, all-cause death rates per 100,000 were as follows:

• Zero to three years – 0.78

• Four to nine years – 0.43
• Ten to 14 years – 0.44
These declines were temporally correlated with the introduction of the 7-valent
pneumococcal conjugate vaccine.
● The Dallas (Texas, United States) Newborn Cohort began prospectively accruing newborns
diagnosed with SCD in 1983. A 2010 report on 940 individuals with a median follow-up of
9.2 years found the following [122]:

• The incidence of death has been decreasing steadily, with death rates (deaths per 100
patient-years) of 0.67, 0.37, and 0.15 for the periods 1983 to 1990, 1991 to 1999, and
2000 to 2007, respectively.

• The estimated overall survival at 18 years was 94 percent for those with Hb SS and 98
percent for those with Hb SC or Hb S-beta thalassemia.

• The median age of death gradually increased, from three years of age during the period
1983 to 1990, to 17 years of age during the period 2001 to 2007. All of the seven deaths
since 2002 were in individuals ≥18 years of age.

Data on survival benefits related to hydroxyurea use in children include:

 ● In a cohort of children in Belgium with SCD who were treated with either hydroxyurea,
hematopoietic stem cell transplantation, or observation, the estimated 15-year survival
rates were 99, 94, and 95 percent, respectively [123].
● In a cohort of 1760 children in the Paediatric Hydroxycarbamide Program, survival was
greater in the 267 who received hydroxyurea even after a median of only two years of
treatment (99.5 versus 94.5 percent) [124]. The survival benefit was primarily due to fewer
deaths from acute chest syndrome and infection.

Details of the use of hydroxyurea in children are discussed separately. (See "Hydroxyurea use in
sickle cell disease".)

Causes of death — In regions where comprehensive care is available, the causes of death in
patients with SCD have shifted following the introduction of infection prevention measures. As
examples:
● In the Dallas Newborn cohort of 940 patients, acute chest syndrome and multi-organ
failure have replaced bacterial sepsis as the leading causes of death [122].
● In a study that analyzed clinical and/or autopsy findings among 141 adults with SCD from
1976 to 2001, leading causes of death included pulmonary hypertension (26 percent),
sudden death (23 percent), renal failure (23 percent) and infection (18 percent) [125].
● Another study that analyzed the cause of death in 209 adults with SCD found that 18
percent of deaths occurred in individuals with overt organ failure, predominantly renal
[111].

In contrast, in regions of Africa where newborn screening for SCD and prophylactic
antibacterials are not routinely used, infections are a leading cause of death, including bacterial
sepsis and malaria [126]. Despite the protective effect of the sickle mutation against malaria, a
study of 1393 children in Kenya with severe malaria reported higher mortality in children with
SCD than those without SCD (death rate 80 versus 10 percent, respectively) [126].

Predictors of morbidity and mortality — Overall, markers of more severe disease tend to
predict greater morbidity and mortality in individuals with SCD, although some modifiable risk
factors (eg, stroke) may be declining in importance [127-129]. As examples:
● Two large comprehensive studies have demonstrated the high survival rate of children with
SCD in resource-rich countries in the modern era. In a 2015 study from Belgium, 469
children with SCD were prospectively followed, many since diagnosis, for a total of over
5110 patient-years [123]. Children with more severe SCD treated with hydroxyurea had a
Kaplan Meir survival estimate of 99 percent at 15 years. Similar results were seen in a 2016
 study from France, in which 1033 children with SCD born between 1995 and 2009 were
followed for 6776 patient-years [130]. The five-year survival was over 98 percent for the
entire cohort, and over 99 percent for those born after 2006. These studies illustrate that
SCD is no longer a life-threatening disease of childhood, but rather is a chronic childhood
disease with life-threatening episodes.
● An attempt to identify risk factors for mortality in adults was made using computer
modeling in cohort of 964 individuals with SCD, 209 of whom died [111]. Predictors of an
increased risk of early death in this model included acute chest syndrome, renal failure, a
baseline white blood count >15,000/microL, and a fetal hemoglobin (Hb F) ≤8.6 percent.
Other studies have corroborated an increased mortality rate in individuals with SCD who
develop renal failure, even if they are treated with dialysis [131].
● A more sophisticated statistical model for estimating risk of death within five years was
developed using clinical and laboratory data from 2280 patients with SCD [132]. The major
risk factors for mortality included renal insufficiency, leukocytosis, and the severity of
hemolytic anemia. The model was validated using two other data sets; however, it has not
been validated by other groups.
● Risk factors for death in two cohorts of adults from tertiary medical centers included
greater frequency of hospitalization, iron overload, elevated tricuspid regurgitant jet
velocity (TRJV) on Doppler echocardiography (>2.5 m/sec), a history of any cerebrovascular
event, a lower estimated GFR, at least one pain episode in the last year [116,117].
Laboratory findings associated with increased risk of death in these cohorts included low
hemoglobin, high WBC count, low baseline Hb F, high lactate dehydrogenase (LDH), and
high C-reactive protein, and elevated NT-proBNP.
● Analysis of data from children enrolled in the Silent Cerebral Infarct Multi-Center Clinical
(SIT) trial suggest that higher baseline hemoglobin levels and higher education level of the
head of the household correlated with improved growth, whereas household income did
not [86].
● An older prospective cohort study (1978 to 1988) in 392 infants with homozygous Hb SS
looked for predictors of severe SCD before age two years and severe outcomes after 10
years [127]. Adverse outcomes occurred in 70 individuals (18 percent), including stroke,
frequent pain episodes, recurrent acute chest syndrome, and death. Significant predictors
of an adverse outcome included dactylitis before age one year (relative risk [RR] 2.6, 95% CI
1.39-4.67), hemoglobin concentration <7 g/dL (RR 2.5, 95% CI 1.14-5.33), and leukocytosis
without infection (RR 1.8, 95% CI 1.05-3.09). However, these data have become outdated as
events in early infancy do not predict adverse events in childhood in the modern era of
 comprehensive care. The cohort was assembled before the routine use of prophylactic
penicillin, conjugate pneumococcal and influenza vaccination, hydroxyurea, and
transcranial Doppler screening for stroke risk, coupled with regular blood transfusion
therapy for stroke prevention.

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Sickle cell disease and
thalassemias" and "Society guideline links: COVID-19 – Index of guideline topics".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Sickle cell disease (The Basics)" and "Patient
education: When your child has sickle cell disease (The Basics)")

PATIENT PERSPECTIVE TOPIC

Patient perspectives are provided for selected disorders to help clinicians better understand the
patient experience and patient concerns. These narratives may offer insights into patient
values and preferences not included in other UpToDate topics. (See "Patient perspective: Sickle
cell disease".)
SUMMARY AND RECOMMENDATIONS
● Comprehensive care – Individuals with sickle cell disease (SCD) should be seen regularly
by the treatment team for comprehensive health care. (See 'General principles and
guidelines' above.)
● Hydroxyurea – Hydroxyurea is the mainstay of treatment. It reduces pain and other vaso-
occlusive complications ( table 1), decreases hospitalization, and improves survival.
Options for individuals who cannot tolerate hydroxyurea or who have continued pain
despite hydroxyurea include L-glutamine and crizanlizumab. (See "Hydroxyurea use in
sickle cell disease" and "Disease-modifying therapies to prevent pain and other
complications of sickle cell disease".)
● Transfusions – Blood transfusion is indicated in preparation for surgery; treatment of
symptomatic anemia, acute stroke, multiorgan failure, and acute chest syndrome; and
prevention of stroke, acute chest syndrome/critical illness. Supporting evidence and details
of administration are discussed separately. (See "Red blood cell transfusion in sickle cell
disease: Indications, RBC matching, and modifications" and "Transfusion in sickle cell
disease: Management of complications including iron overload".)
● Infection prevention – Individuals with SCD become functionally asplenic within the first
year of life. All should receive age-appropriate vaccinations, including COVID-19,
Streptococcus pneumoniae, seasonal influenza, Neisseria meningitidis, Haemophilus
influenzae type B, and hepatitis B. Routine antibiotic prophylaxis with penicillin (or
erythromycin if penicillin-allergic) is started within the first three months of life. We suggest
continuing antibiotics until age five rather than a shorter duration (Grade 2C). Antibiotic
prophylaxis after age five is decided on a case-by-case basis. (See 'Infection prevention'
above.)
● Nutrition – SCD is a chronic hemolytic anemia. We suggest all individuals with SCD receive
folic acid (Grade 2C). We use a multivitamin without iron in all patients, and we replace
vitamin D and calcium (which are often deficient) as needed. (See 'Nutrition' above.)
● Travel – Individuals with SCD who travel should discuss plans for management of infection
and be provided with advice to reduce the risk of complications. (See 'Travel advice' above.)
● Routine evaluations

• TCD – Individuals with SCD are at risk for stroke. For children with Hb SS or Hb S-beta0
thalassemia or other SCD syndromes with low baseline hemoglobin, we recommend
transcranial Doppler (TCD) ultrasound evaluation of cerebral blood flow be initiated at
 age two years and performed annually until age 16. We also screen children with any
cognitive dysfunction for silent infarcts using magnetic resonance imaging (MRI). (See
"Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Risk
assessment for first stroke'.)

• Ophthalmology – Individuals with SCD are at risk for proliferative retinopathy. Retinal
evaluation is begun at 10 years of age and continued routinely to detect early
proliferative sickle retinopathy. (See "Overview of the clinical manifestations of sickle cell
disease", section on 'Retinopathy'.)

• Laboratory – Additional routine evaluations are directed towards detecting and

preventing end-organ damage. (See 'Routine evaluations and treatments' above.)
● Pain management – All individuals with SCD who present with acute pain should receive
adequate analgesia and hydration (oral or intravenous hydration). We suggest a fast-acting
oral or intravenous opiate as initial therapy, rather than a non-opiate analgesic (Grade 2C).
(See "Acute vaso-occlusive pain management in sickle cell disease".)
● Hospitalization – Adults with SCD admitted with an acute medical illness should receive
thromboprophylaxis unless contraindicated. For hypovolemia, we use lactated ringers
solution; for euvolemic individuals who require intravenous hydration, we use one-quarter
or one-half normal saline, with or without glucose. (See 'Management during
hospitalization' above.)
● Prognosis – Survival is reduced compared with the general population, but prognosis has
been steadily improving. Comprehensive care has shifted the disease from a fatal pediatric
illness to a chronic disease often with progressive deterioration in quality-of-life and organ
function. (See 'Survival and prognosis' above.)

ACKNOWLEDGMENT

UpToDate gratefully acknowledges Stanley L Schrier, MD, who contributed as Section Editor on
earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.

The UpToDate editorial staff also acknowledges extensive contributions of Donald H Mahoney,
Jr, MD, to earlier versions of this topic review.

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