Recent treatment guidelines for managing adult patients with sickle cell disease: challenges in access to care, social issues, and adherence

ABSTRACT

Introduction: Advances in research, medical care, and public health practice have led to individuals with sickle cell disease (SCD) living into adulthood. However, premature mortality persists in youth and young adults with SCD, and adults with SCD are subjected to increased disease burden, organ damage, pain, and disruptions in family and work life.

Areas covered: These issues have led to inappropriate utilization of hospital resources, significantly increasing costs related to prolonged inpatient stays, high readmission rates, and increased emergency room visits.

Expert commentary: Steps are being taken to address these challenges to improve care, including development of evidence-based guidelines targeted to primary care providers, innovative care models, and programs to prepare adolescents for transition to adult care. Previous and current guidelines, as well as health-care policies and practices, for treatment of adults with SCD are reviewed.

KEYWORDS:

• Adult
• guidelines
• hospitalization
• sickle cell complications
• sickle cell disease
• transition

1. Introduction

Sickle cell disease (SCD), a genetic condition characterized by painful episodes due to the blockage of blood vessels, affects an increasing number of American adults [1]. It is estimated that there are 90,000–100,000 individuals with SCD in the United States, of which ~60% are adults [2,3]. Advances in treatment have led to individuals with SCD living longer and, as a result, SCD is no longer considered a childhood disease. The life expectancy of an individual with SCD in the United States was <20 years in the 1970s [4,5], but rose to a median of 42 years for men and 48 years for women by the early 1990s according to data from the Cooperative Study of Sickle Cell Disease (CSSCD) [4]. Patients with the hemoglobin SC (HbSC) genotype may survive into their sixties (median survival of 60 years for men; 68 years for women) [4]. Another source (National Center for Health Statistics) indicated that median SCD survival in 2005 was 38 years for men and 42 years for women [5], while another study using population-based surveillance data from 2004 to 2008 found slightly higher median SCD survival (41.9 years for men; 43.5 years for women) [6]. Although these data were derived from different data sets encompassing different patient populations and cannot be directly compared, their survival analyses may be an indication of unexpected trends.

While the mortality rate for children showed an annual decrease of 3% over the time period from 1979 to 2005, there was an annual increase of 1% in the mortality rate for adults over the same time period [5]. Increased mortality for adults is a source of concern, as it may reflect a lack of access to quality, comprehensive care for adults with SCD [5]. The objective of this review is to increase awareness of challenges affecting the care of adult patients with SCD, with a focus on access to care, social considerations, and adherence to treatment, as well as implementation of SCD guidelines in clinical practice.

2. Treatment guidelines

There is a need for evidence-based treatment guidelines in order to provide quality care for adult patients with SCD. However, guidance for the treatment of adults with SCD is often based on clinical experience and/or extrapolated from pediatric populations due to the lack of gold-standard, research-driven data specific to adult populations. Until the publication of ‘Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014’ [7,8], there were no evidence-based guidelines for SCD (Table 1). The recommendations are identified as strong, weak, or low. For SCD, there are fewer strong recommendations due to research gaps compared with other well-reported guidelines.

Table 1. Guidelines for the management of sickle cell disease in adults.

Source	Year of publication	Title/Description	Evidence-based
WHO [9]	2011	Pharmacotherapy of Sickle Cell Disease	No
Sickle Cell Society (UK) [10]	2008	Standards for the Clinical Care of Adults with Sickle Cell Disease in the UK	No
NIH/NHLBI [11]	2002	The Management of Sickle Cell Disease	No
NIH/NHLBI [7,8]	2014	Evidence-Based Management of Sickle Cell Disease	Yes

NIH/NHLBI: National Institutes of Health/National Heart, Lung, and Blood Institute; WHO: World Health Organization.

The Management of Sickle Cell Disease from the National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI) includes a chapter on ‘Adult Health Care Maintenance’ that addresses initial and ongoing health-care visits, patient education about complications, and psychosocial services [11]; the book lists only six evidence-based recommendations, three of which refer solely to children [11]. One of these evidence-based recommendations – treatment with hydroxyurea – is based on a randomized clinical trial (Multicenter Study of Hydroxyurea in Sickle Cell Anemia), and the recommendation is strong for adults with hemoglobin SS (HbSS) [11–13]. The World Health Organization guidelines on ‘Pharmacotherapy of Sickle Cell Disease’ address the needs of both adults and children and focus on treatment with hydroxyurea and supportive care measures [9]. The UK Sickle Cell Society published a book, Standards for the Clinical Care of Adults with Sickle Cell Disease in the UK, specifically directed at adults; topics include coordination of care, acute and chronic complications, pregnancy/fertility issues, blood transfusion, iron overload/iron chelation, surgery, and hydroxyurea [10]. ‘Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014’ offers practical guidance for busy primary-care providers who care for adults with SCD [7,8]. In addition, there are evidence-based guidelines from the American Thoracic Society for the diagnosis, risk stratification, and management of patients with SCD with pulmonary hypertension [14]. Increasing involvement of primary-care physicians in the care of adults with SCD will improve the health outcomes and well-being of adults with SCD.

3. Disease management within the context of basic needs

3.1. Health maintenance strategies for adults with SCD

It is important to treat SCD as a chronic debilitating disease that has physical, emotional, and social well-being challenges, and which begins at birth and extends across the lifespan of individuals and families. Therefore, management of SCD requires coordinated, multispecialty, social, and community services that address a holistic approach. Care and services need to be comprehensive. Recommendations for preventive care for SCD patients in the realms of pain management, blood transfusions with chelation, and regular assessments to maximize therapeutic options such as hydroxyurea therapy must be addressed. Additionally, alternative and complementary therapies such as meditation and patient self-management training could be considered.

According to the 2014 NIH/NHLBI recommendations on the management of SCD, care should be coordinated between community health-care settings, primary-care providers, specialists, emergency departments, laboratories, and hospitals [7]. The ‘medical home’ model is one strategy that may be implemented to coordinate care and social services [7]. Due to the risk of acute and chronic multisystem conditions in individuals with SCD, screening and appropriate preventive measures are recommended [7].

Adults do not usually need the antibiotic prophylaxis prescribed to children with SCD for the prevention of sepsis; however, adults may have penicillin to use as needed in case of fever [11]. As virtually all adults with SCD are functionally asplenic [11], they should receive the following vaccinations per the Advisory Committee on Immunization Practices (ACIP) guidelines from the Centers for Disease Control and Prevention (CDC): a single dose of Haemophilus influenzae type b vaccine, two doses of the meningococcal ACWY vaccine 8–12 weeks apart, the 13-valent pneumococcal conjugate vaccine, and the 23-valent pneumococcal polysaccharide vaccine (PPSV23), with PPSV23 revaccination 5 years after the initial dose [15–17]. Because the recommended vaccination schedule can change as frequently as four times per year, it is important to use the current ACIP vaccination recommendations found at the following website: http://www.cdc.gov/vaccines/schedules [7].

Other health-maintenance recommendations for adults with SCD include screening for renal disease, pulmonary hypertension, retinopathy, and hepatitis C virus [7,8]. Electrocardiogram screening, neuroimaging screening for stroke, and pulmonary function tests are not recommended for asymptomatic individuals [7,8]. Adults should also be counseled during primary-care visits on contraception, reproductive plans, and opioid use during pregnancy [7,8].

The day-to-day lives of patients and their families who care for them can be stressful. As high as 40% of children and adults meet the Social Security Administration medical condition criteria for disability [18]. Health and social accommodations for those with special needs must be addressed, enabling them to receive community-based services and supported educational and job training so that they may live independently [19].

3.2. SCD-related pain in adults

Despite the substantial burden of pain experienced by adult patients with SCD, health-care providers may have misconceptions that lead to SCD pain being undertreated. In a survey of physicians at seven NIH-funded, university-based SCD centers from 1998 to 2003, three of the top five barriers to optimal management of SCD pain were ‘Fear that the patient is a drug abuser,’ ‘reluctance to prescribe opioids,’ and ‘disbelief in patient’s report of pain severity’ [20]. The 2014 Expert Panel Report provides a treatment algorithm for addressing acute pain episodes in patients with SCD, and recommendations include the rapid initiation of analgesics (within 30 min of triage or 60 min of registration) [7]. While nonsteroidal anti-inflammatory drugs are recommended for mild-to-moderate pain (Moderate Recommendation, Low-Quality Evidence), parenteral opioids are indicated in patients with severe pain (Strong Recommendation, High-Quality Evidence) [7,8]. Pain should be reassessed and opioids administered every 15–30 min until the pain is controlled according to patient report; the dose may be escalated by 25% [7]. Around-the-clock dosing is preferable to intermittent or ‘as requested’ dosing [7,8]. Other considerations related to the treatment of SCD-related pain include hydration, use of nonpharmacologic approaches such as heat, and use of oral antihistamines if needed for itching secondary to opioid administration [7]. It is recommended that clinicians use either an individualized or SCD-specific protocol to guide the use of analgesics to manage SCD-related pain [7,8].

4. Impact of SCD in adult patients

4.1. Clinical presentation and manifestations

The hallmark of SCD is the acute painful crisis. It is the greatest cause of hospitalization for this disease, and its precipitating triggers are both known and unknown [21,22]. This recurrent acute painful crisis is responsible for the most damage to patients with SCD [23]. Pain episodes and utilization of the health-care system become more frequent as patients with SCD transition into adulthood [24,25]. Pain is a major day-to-day symptom for adults with SCD and was reported on more than half of the patient-days analyzed (54.5%) in a prospective cohort study of patients with SCD ≥16 years of age [24]. In the CSSCD, which included patients with SCD from 23 centers in the United States, 22% of deaths in adult patients were preceded by pain episodes [4]. Other clinical manifestations of adult SCD include acute and chronic organ failure, chronic leg ulcers, priapism, vision changes indicative of retinopathy, thromboembolism, and neurocognitive impairment [11,26].

It is important to be aware that some individuals may be misdiagnosed or incorrectly self-report that they have SCD [27]. Thus, it is imperative to document the hemoglobin genotype. SCD is a recessive disorder in which individuals have at least one sickle hemoglobin (HbS) allele, which is an abnormal allele for the β-globin gene [27]. While homozygous HbSS is the most common SCD genotype, individuals with SCD may also have HbSC (HbS plus the hemoglobin C [HbC] allele) or HbS/β-thalassemia (HbS plus the β-thalassemia allele) [27]. HbC allele is not detected by sickledex screening, as such fractionated Hb is required to confirm hemoglobin status. Individuals with only one abnormal allele are carriers for sickle cell trait [27]. In a study of older African-American adults with self-reported SCD (n = 51; median age 53 years, range 40–69), only 5.9% were confirmed to have SCD through genetic testing, 68.6% were carriers for either sickle HbS or HbC, and 25.5% had no abnormal alleles [27]. It should be noted that the median age for this population was higher than the current median survival for adults with SCD [5], and the majority of younger individuals would have been screened for SCD as newborns [11]. Individuals who are proven to not have SCD should have a comprehensive medical and psychological evaluation to rule out other diagnoses that may cause SCD-like symptoms such as rheumatologic disorders, other types of anemia, or a factitious disorder.

4.2. Comorbidities and complications

The risk of comorbidities and SCD complications, such as stroke, renal disease, acute chest syndrome (ACS), pulmonary hypertension, leg ulcers, and liver pathology, increases with age. Here, we highlight some of the data demonstrating the increased burden of these comorbidities and complications in adults with SCD; a more comprehensive review of the acute and chronic complications of SCD and recommendations for management can be found in ‘Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014’ [7,8].

4.2.1. Stroke

According to 1998–2007 data from the California Patient Discharge Databases, the incidence of stroke was increased for middle-aged and elderly adults with SCD compared with those of younger ages (rate per 100,000 person-years: 310 for age <18 years; 360 for age 18–34 years; 1160 for age 35–64 years; 4700 for age ≥65 years) [28]. In addition, greater percentage of strokes in adults with SCD were hemorrhagic strokes (34% vs. 13% in children with SCD), which were associated with greater mortality than ischemic strokes (30% vs. 7%) [28]. A retrospective study analyzing 1970–2008 data from the French Adult Sickle-Cell Referral Center found hemorrhagic strokes occurred primarily in adult patients with SCD (age range 14.9–46.2 years) [29]. In both studies, stroke in adults with SCD was associated with hypertension [28,29].

4.2.2. Renal disease

In a 5-year cohort study of 98 adult patients with SCD at the Diggs–Kraus Comprehensive Sickle Cell Center in Memphis, Tennessee, older age was significantly associated with development and progression of chronic kidney disease in patients with SCD; prevalence of chronic kidney disease increased from 28.6% to 41.8% over the course of the study [30]. A study using data from the Centers for Medicare and Medicaid Services found that patients with end-stage renal disease (ESRD) with SCD had a greater risk of mortality compared with patients with ESRD without SCD (hazard ratio [HR] = 2.95, 95% confidence interval [CI], 2.55–3.41 at 4.25 years of follow-up; HR = 2.80, 95% CI, 2.31–3.38 during the first year of dialysis) [31]. In addition to SCD, older age and presence of other comorbidities were among patient factors associated with an increased risk of mortality [31].

4.2.3. ACS

In the CSSCD, over 10% of deaths in adult patients were preceded by ACS [4], an SCD complication characterized by symptoms such as fever, cough, and chest pain [32]. Moreover, ACS was associated with higher mortality in adult patients with SCD than in pediatric patients with SCD (4.3% vs. 1.1%) [32].

4.2.4. Pulmonary hypertension

The prevalence of pulmonary hypertension in adult patients with SCD is in the range of 10–30% [33,34]. Patients with SCD with pulmonary hypertension have an increased risk of mortality compared with patients with SCD without pulmonary hypertension [33,34]. In a study of 195 adults with SCD, pulmonary hypertension was independently associated with self-reported cardiovascular or renal disease, and univariate analysis showed an association between pulmonary hypertension and increased age [33,34].

4.2.5. Leg ulcers

Among patients with SCD, leg ulcers occur mainly in adults [35,36]. In a recent survey of US health-care providers, most of whom were in the Sickle Cell Adult Provider Network, nearly all respondents (96%) had patients with active leg ulcers [36].

4.2.6. Liver pathology

Liver pathologies found in adults with SCD are heterogeneous and include acute hepatocellular necrosis, acute sequestration and cholestasis, cirrhosis, chronic sickle hepatopathy, mechanical biliary obstruction, siderosis (with extrahepatic iron overload predominating), cholangiopathy, and venous outflow obstruction [37].

4.2.7. Pregnancy

A study of births to women with SCD in the United States in the Healthcare Cost and Utilization Project Nationwide Inpatient Sample from 1999 to 2008 found a significantly increased risk of maternal mortality compared with women without SCD (0.16% vs. 0.01%, P < 0.001) as well as an increased risk of pregnancy-related maternal complications, including preeclampsia, eclampsia, venous thromboembolism, cardiomyopathy, Cesarean section, and preterm premature rupture of membranes (P < 0.001 for each) compared with women without SCD [38]. There was also an increase in fetal complications, including intrauterine growth restriction (P < 0.001) and intrauterine fetal demise (P = 0.023) compared with women without SCD [38]. The study included 4262 births to women with SCD diagnoses from a cohort of over 8 million delivery-related discharges [38].

4.2.8. Fertility

Both SCD and hydroxyurea have been shown to have a detrimental effect on sperm parameters [39]; the effects of hydroxyurea on sperm may last as long as 5 years following cessation of hydroxyurea treatment according to results from a retrospective study conducted at two centers from 1994 to 2004 (n = 44) [39].

4.2.9. Priapism

By age 20, the majority of men with SCD will have experienced an episode of priapism [40,41]. In a patient survey conducted at a single center in the United States (n = 98), the median age of onset for priapism was 12 years and there was an 89% probability of having an episode by age 20 [40]. In a patient survey conducted at five centers in the United Kingdom and Nigeria (n = 130), the mean age of onset was 15 years, and 75% of patients had an episode by age 20 [41]. Priapism can result in impotence and was associated with a significant increase in the likelihood of serious SCD complications such as stroke and renal failure (P < 0.05) compared with men with SCD without priapism in a 27-year longitudinal cohort study (n = 461) [42].

4.2.10. Osteonecrosis

In the CSSCD (n = 2590), osteonecrosis of the femoral head was more common in older age groups (1.3% for age 5–9 years, 4.6% for age 10–14 years, 8.2% for age 15–24 years, 18.8% for age 25–34 years, 21.9% for age 35–44 years, and 32.5% for age ≥45 years) [43]. In that study, 17.4% of patients with osteonecrosis of the femoral head required arthroplasty, and nearly one-third of those requiring arthroplasty had both hips replaced; the majority of patients undergoing arthroplasty were <35 years of age [43].

4.3. Predictors of mortality

Despite survival gains in recent decades, patients with SCD are at an increased risk of early death. Predictors of mortality for adults with SCD identified in the CSSCD and other studies include some of the conditions mentioned above, such as renal failure, ACS (especially when mechanical ventilation is required), pulmonary hypertension, vaso-occlusive episodes, and stroke, as well as laboratory findings such as low percentage of fetal hemoglobin, low-hemoglobin levels, and an elevated white blood cell count [4,31,33,34,44,45]. Data from the National Center for Health Statistics indicated that stroke, pulmonary hypertension, and renal disease are more commonly listed as a cause of death in older patients with SCD than in younger patients [5]. In a recent cohort of over 500 adult patients with SCD at three US university hospitals, there was significantly greater survival in patients with fewer organ damage comorbidities (organ severity score of 0 or 1) compared with patients with a greater number of organ damage comorbidities (organ severity score >1) (HR = 1.502, P = 0.0263) [45]. Predictors of increased mortality in that cohort included pulmonary hypertension, the N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels, cerebrovascular events, low estimated glomerular filtration rate, leg ulcers, pain crises, and soluble vascular cell adhesion molecule-1 (sVCAM-1) levels [45]. In a cohort of over 600 patients from the United States and United Kingdom with SCD, there was a significantly increased risk of mortality with increased tricuspid regurgitation velocity (TRV) and NT-proBNP, both of which are biomarkers associated with pulmonary hypertension [46]. Another cohort of over 200 adult patients with sickle cell anemia at a single US referral institution also found an increased risk of mortality with higher TRV; other independent risk factors for mortality in that cohort were severe vaso-occlusive crisis in the past year, elevated ferritin, and low estimated glomerular filtration rate [47]. While hydroxyurea use has been associated with decreased mortality in SCD [48], it was not found to be a significant predictor of survival when evaluated in these cohorts [45,46].

4.4. Effect of iron overload

Iron overload resulting from the use of transfusions for SCD may be the underlying cause of organ failure, a major cause of death for patients with SCD [4,49,50]. A study conducted from 1987 to 1998 found that iron overload was associated with increases in painful episodes, organ failure, and mortality (64%, 71%, and 64%, respectively, for patients with serum ferritin >1500 ng/mL and >50% transferrin saturation vs. 38%, 19%, and 5%, respectively, for patients with serum ferritin <100 ng/mL and <50% transferrin saturation) [51]. Iron overload in patients with SCD may lead to iron deposition in organs (liver, heart, pituitary, and pancreas), with end-organ damage potentially occurring before the onset of symptoms [49,50,52–54]. It has also been associated with liver fibrosis and cardiac dysfunction, although these pathologies do not appear to show a clear correlation with hepatic or cardiac iron concentrations, respectively [49,50]. While liver iron overload and liver damage may be detected as early as 1 year after patients with SCD start transfusions, it may take more than a decade for cardiac iron overload to be detected [49,50]. In an analysis of 141 adult patients with SCD who died at a US university hospital from 1976 to 2001, iron overload was found at the time of death in 7% of patients and was significantly more frequent in patients with cirrhosis than in those without cirrhosis (43.8% vs. 2.4%, P < 0.001) [55]. In that study, iron overload was also associated with myocardial iron deposition (P = 0.028) and myocardial fibrosis (P = 0.043) [55]. Cardiac iron overload is not the typical finding in SCD. In contrast to thalassemia [56,57], there is a paucity of data on outcomes in patients with SCD with cardiac iron deposition.

5. Social and economic issues

5.1. Health disparities

It is recognized that African-Americans and other ethnic minorities in the United States experience disparities in the health care they receive. The 2013 National Healthcare Disparities Report issued by the Agency for Healthcare Research and Quality noted that ~40% of health-care quality measures analyzed were worse for African-Americans and Hispanics compared with white Americans [58]. SCD has been studied in the United States for more than 100 years; much is known about its disparate treatment, stigma, and lack of national disease awareness. However, SCD was not included as a health disparity topic in the CDC Health Disparities and Inequalities Report from 2011 or 2013 [59,60]. Compared with other genetic disorders diagnosed in US newborns such as hemophilia and cystic fibrosis, there have been striking disparities in access to comprehensive treatment centers, federal funding, and medication assistance such as the 403(b) program.

5.2. Access to care

In a study using 2007 data from California, adult age, distance from a comprehensive SCD center, and insurance status were associated with increased rates of emergency department utilization; adults and the uninsured were more likely to make multiple visits to multiple facilities, indicating a lack of a ‘medical home’ [61]. Lower socioeconomic status, particularly for rural patients, may further limit access to care [62]. Moreover, as patients transition from pediatric to adult SCD care, they are less likely to receive appropriate care [63]. The Affordable Care Act (ACA) may provide improved access to health insurance for some adult patients with SCD by eliminating denial of insurance based on preexisting conditions and allowing young adults to remain on their parents’ insurance until age 26, and has the potential to reduce some barriers related to access to care [64]. However, the revised federal poverty level will cause some patients with SCD who reside in states that do not participate in Medicaid expansion to lose their insurance. To date, southern states have not participated in the ACA Medicaid expansion; these states are home to more than 50,000 individuals in the United States with SCD, which is more than half of the nation’s population of individuals with SCD. For individuals with SCD, race, politics, and stigma play a role in their disparate care.

SCD programs across the United States have reported that race and disease-related factors appear to play a role in the perceived or unintentional discrimination, poor provider communication, and long emergency department wait times faced by adult patients with SCD in their interactions with the health-care system [65–67]. In a study conducted in patients with SCD aged ≥15 years in the Baltimore/Washington, DC, area (n = 291; mean age 34.5 years; 97% African-American), patients perceived greater disease-based discrimination than race-based discrimination [66]. Overall, 39% of patients reported difficulty convincing health-care providers about their pain, and more than half (54%) reported having daily chronic pain [66]. Both race-based and disease-based discrimination were associated with patient age and with patients having difficulty convincing health-care providers about their pain [66]. Disease-based discrimination was also associated with greater emergency room use and more daily chronic pain [66]. Poor provider communication with regard to listening, demonstrating respect, and spending sufficient time with patients was more commonly reported by adult patients with SCD than by a comparator sample of African-American patients, indicating that race alone does not account for the communication problems experienced by patients with SCD [67]. While emergency department wait times tend to be longer for African-Americans in general (13% longer than whites, P < 0.001) [68], a study using national data from the CDC National Hospital Ambulatory Medical Care Survey indicated that mean wait times were ~50% higher for patients with SCD compared with African-American patients presenting with a different painful condition (long bone fracture), even when adjusting for patient and hospital factors [69].

5.3. Public health response to SCD

In 2011, the US Department of Health and Human Services (HHS) announced the start of the Sickle Cell Disease Initiative, an initiative that aims to improve the care of patients with SCD [70]. Goals included the creation of a comprehensive database of patients with SCD, furthering the development of evidence-based guidelines for the treatment of SCD, and supporting the development of novel treatments and facilitating their approval [70]. The initiative also intended to expand ‘medical homes’ where patients with SCD can receive high-quality specialty care [70]. The CDC has started a multidisciplinary working group to increase awareness of SCD, communicate and collaborate with other key players such as the NIH and the Health Resources and Services Administration, and improve surveillance, SCD-management guidelines, and monitoring for SCD complications [71]. The NHLBI and CDC collaborated on the Registry and Surveillance System for Hemoglobinopathies (RuSH), a pilot program to collect data from seven states with the goal of determining the number of people living with SCD in the United States [70,72]. A report from RuSH conducted after 2 years revealed limitations related to data collection (e.g. issues with the use of ICD codes or Medicaid data, and incomplete or duplicated data) and the need for adequate time, funding, and staff [73]. In July 2014, the Think Tank for Implementation Programs in Adults with Sickle Cell Disease was convened to address the challenges of SCD adult care from the perspective of a patient, physician, health system, government, and community. One goal of this meeting was to incorporate implementation science into the equation of care equals improved health outcomes and well-being.

5.4. Pharmacoeconomic considerations

There is a high economic burden associated with the treatment of SCD. In a 2009 study, annual costs for the treatment of the ~70,000 patients with SCD in the United States were calculated to be greater than $1.1 billion [74]. The cost of treating SCD in the United States may be higher today, as the number of patients with SCD in the United States may be higher (90,000–100,000) based on estimates from Brousseau et al. (~89,000) and Hassell (72,000–98,000, corrected for early mortality) [2,3,72], and more recent estimates of the mean yearly cost of treating SCD are higher (~$30,000 vs. ~$16,000 in the 2009 study) [74,75].

Much of the economic burden of treating SCD is related to the care of adults, for whom there are increased health-care costs and utilization that begin during the transition from pediatric to adult care. In a study using Medicaid data from five US states (Florida, Iowa, Kansas, Missouri, and New Jersey), patients with SCD in the transition (age 16–20 years) or post-transition period (age >20 years) were significantly more likely to have high-cost events than patients younger than age 16 years [75]. Health-care costs were also found to increase in the post-transition period compared with the pre-transition period for patients with SCD receiving chronic transfusions, but the increase was statistically significant only for patients not receiving iron chelation therapy [63]. Costs related to hospitalization and emergency room visits increased significantly post-transition compared with pre-transition whether or not patients were receiving iron chelation therapies [63]. Adults aged 18–44 years account for the majority (approximately two-thirds) of all SCD hospitalizations [76]; rehospitalizations are also a concern. In a retrospective cohort study using data from the Healthcare Cost and Utilization Project State Inpatient Databases and State Emergency Department Databases from eight states (Arizona, California, Florida, Massachusetts, Missouri, New York, South Carolina, and Tennessee) with approximately one-third of US patients with SCD, young adults (age 18–30 years) had the highest rate of 30-day rehospitalizations (41.1%) [77]. As was discussed in a previous section, taking an innovative approach to the care of adults with SCD can improve the cost-effectiveness of SCD care by reducing emergency department usage and hospital admissions.

5.5. Treatment adherence: focus on hydroxyurea and iron chelation

It has been shown that the economic burden of SCD, particularly the costs and resource utilization related to hospitalizations and emergency department visits, can be reduced through improved adherence to hydroxyurea and iron chelation [78,79]. Evidence-based techniques for improving adherence in chronic disease, such as the use of text messaging, should be implemented with SCD patients where possible [80].

5.5.1. Hydroxyurea

Hydroxyurea is the only disease-modifying agent for SCD approved by the US FDA [13]. In the multicenter study of hydroxyurea in sickle cell anemia, which enrolled patients with SCD ≥18 years of age, hydroxyurea was associated with a 44% reduction in the median number of pain episodes per year compared with placebo (4.5 vs. 2.5, P < 0.001) as well as a reduction in the median number of pain episodes requiring hospitalization (2.4 vs. 1.0 per year, P < 0.001) [12]. Although hydroxyurea has shown efficacy for the treatment of both children and adults with SCD, it is currently underutilized [13]. The effectiveness of hydroxyurea largely depends on patient adherence, and the lag of 3–6 months between hydroxyurea initiation and the patient experiencing a clinical response tends to reduce adherence [13]. Other reasons for nonadherence to hydroxyurea are not known but they may include issues related to its effects on fertility, including the potential for reduced sperm counts and pregnancy concerns [13].

5.5.2. Iron chelation

Patients with SCD who receive transfusions should be screened by serial serum ferritins at their baseline for iron overload (ferritin > 1000) and managed appropriately with iron chelation therapy in order to avoid serious complications [7]. A study by Ballas showed in a small subset of individuals with SCD that elevated ferritin compared to those with normal ferritins was associated with increased pain crisis, morbidity, and mortality [51]. Deferasirox, an oral iron chelator administered once daily, has shown comparable efficacy with deferoxamine, an iron chelator administered subcutaneously or intravenously [7,81]. Moreover, a new tablet formulation is available that may improve compliance (Jadenu^®). Patients receiving deferasirox should be monitored for serum ferritin (every month) and liver iron concentration (every 6 months) in order to guide dose adjustments [82]. Patients should also undergo regular laboratory monitoring for renal and hepatic function and blood counts due to the potential for toxicities [82]. Another oral iron chelator, deferiprone, is administered three times daily and is associated with an increased risk of agranulocytosis, which necessitates monitoring [7]. The strength of the recommendation for use of iron chelation therapy is considered moderate and is supported by moderate-quality evidence [7].

A retrospective study comparing deferoxamine versus deferasirox usage in both pediatric and adult Medicaid recipients from 2006 to 2010 in 10 US states (n = 404; 44.8% ≥ 18 years of age) found that 84.3% and 62.6%, respectively, had discontinued treatment by 12 months after initiating iron chelation therapy; 95.2% and 80.3%, respectively, had discontinued treatment by 18 months [83]. The measurement of persistence/discontinuation was based on medication possession ratio (MPR) and a refill gap of ≥6 weeks [83]. There was significantly increased risk of discontinuation in patients aged ≥18 years (HR = 1.304; 95% CI: 1.059–1.605; P = 0.013) and with deferoxamine compared with deferasirox (HR = 1.305; 95% CI: 1.059–1.607; P = 0.012) [83]. Another study of Medicaid claims in three states found similar results, with significantly lower persistence at 6 and 12 months (with discontinuation defined as ≥1 refill gap: log-rank P = 0.0002) and compliance (based on MPR ≥0.80: 41.8% compliant vs. 54.9% compliant, P < 0.0001) with deferoxamine (n = 217) versus any deferasirox use (n = 275) [84].

5.6. Issues surrounding transition from young adult to adult care

For young adults with SCD, the transition to adult care is a challenging time, and effective education about preparing for the transition is essential. Health-care transition from pediatric to adult care is among the federal Maternal and Child Health Bureau’s new national performance objectives. These objectives call for the percentage of adolescents with and without special health-care needs who receive services that are necessary to make transitions to adult health care to be increased. Nationally, most adolescent and young adults and their families do not receive health-care transition support even in the face of professional recommendations (American Academy of Pediatrics, the American Academy of Family Physicians, the American College of Physicians) calling for such preparation for all youth, particularly those with special needs, to begin early in adolescence and continue into young adulthood [85].

In fact, many adolescents with SCD may have little recognition of receiving transition education and little understanding of SCD. In a survey of adolescent patients (n = 37; mean age 14.9 years), only 43% reported having been told that they will transition to an adult provider, and only 22% reported that they had been previously taught about transitioning [86]; 38% did not know their sickle cell genotype [86]. However, over 90% indicated that they were interested in learning more about the transition and meeting the adult provider prior to transition [86]. They also wanted more information about the effect of SCD on organs as well as other topics such as health insurance and health-care providers [86]. Another study of transitioning adolescents (n = 33; average age 20 years) found a high level of knowledge (97%) about SCD, how to take their medications, and how they acquired SCD; the majority did not report feeling very worried or anxious about the transition [87]. Due to the wide variation in transition readiness of young adults with SCD, it is important to assess the level of knowledge and preparation for each individual patient.

As young adults with SCD transition into adult care, their disease burden increases but this burden is inversely related to health services. According to a retrospective study of claims data for over 3000 patients with SCD in five US states (Florida, Iowa, Kansas, Missouri, and New Jersey), patients who are transitioning receive fewer transfusions (~1.38 per patient per quarter for age 9–16 years, then decreasing to 0.74 by age 22 years) and less iron chelation (~47% for age 10–14 years, then decreasing to 10% by age 25 years) [63]. In this study, health-care costs in patients receiving transfusions were largely due to SCD complications and transfusions; costs associated with iron chelation and hydroxyurea treatment were offset by lower inpatient and outpatient costs, respectively [63].

5.7. Possible indicators for successful transition to adult care

Youth on a chronic transfusion program experienced more success with transition as reported by one study (n = 47), which found that being on a chronic transfusion program was associated with a successful transition from pediatric to adult SCD care [88]. Older age (≥21 years) at the time of transition and living more than 20 miles from the adult SCD center were factors associated with an unsuccessful transition [88]. A ‘Transition Pilot Program’ for adolescent patients with SCD (age 17–19 years), which included a tour of adult SCD programs, lunch discussion with pediatric staff, and scheduling the first visit to an adult SCD program, was associated with increased completion of a first visit to an adult SCD provider within 3 months of leaving a pediatric SCD program (74% vs. 33%, P = 0.0002) [89]. All patients, parents, and pediatric and adult providers who participated in the program rated it as helpful or very helpful [89]. Improving communication skills in transitioning patients with SCD may be useful in reducing stigma, as lack of preparation for the transition to adult care may contribute to the health-related stigma experienced by young adults with SCD, particularly in their interactions with health-care providers for the treatment of pain [90].

Both day hospital and chronic-care models are multidisciplinary approaches that may be especially effective in the transition process of young adults with SCD. In the day hospital model, patients with SCD with painful but otherwise uncomplicated vaso-occlusive episodes can be treated in an outpatient infusion center or an SCD-specific day hospital setting in which there are knowledgeable and skilled staff [91]. The chronic care model, also known as a ‘medical home,’ is a family-centered practice delivering a full spectrum of care from preventive, to acute illness and chronic condition management for pediatric patients. It could also coordinate patient support and transition services [92,93]. A similar, system of coordinated care for treatment of patient and family is needed for adolescent patients with SCD [94].

5.8. Innovative care models

Innovative care models, such as SCD day centers or day hospitals, comprehensive SCD centers, and SCD inpatient units, have shown value in reducing emergency department usage and hospital admissions. A day hospital at the Bronx Comprehensive Sickle Cell Center at Montefiore Medical Center in Bronx, New York, was established in an attempt to shift the burden of care from the emergency department [95]. The day hospital, with a staff trained in the care of patients with SCD along with a triage room, three beds, a clinical laboratory, and an outpatient facility, was open 9 am–5 pm Monday through Friday and was open to walk-in patients as well as referrals from the emergency department [95]. The staff used a standard assessment and treatment protocol to assess pain and manage medication [95]. The average length of stay in the day hospital compared with the emergency department was shorter (4.5 vs. 13 h in the emergency department) and the hospitalization rate was reduced (8% vs. 51% in the emergency department); over the course of 5 years, the average length of stay for admitted patients followed by day hospital physicians was reduced from 9.3 days in the first year to 7.3 days in the fifth year [95]. Reductions in hospital admission rate and length of stay for inpatients resulted in savings of ~$1.7 million [95].

The Memorial Sickle Cell Day Hospital at Memorial Regional Hospital in Hollywood, Florida, is the only SCD program with ‘Disease-Specific Certification’ from the Joint Commission [96]. The day hospital provides an alternative to inpatient care and includes space for infusions (nine infusion chairs in a single room; two infusion chairs each in two semiprivate rooms), a room containing a bed, and two exam rooms [96]. Although patients may be referred to the program by the emergency department, physicians, or managed-care companies, most patients come to the program through self-referral [96]. The staff consists of a director, a patient-care assistant who greets all new patients, an internal medicine physician, a primary-care nurse practitioner, two registered nurses, a hematologist, a palliative care physician, a social worker, a clinical research associate, an epidemiologist, and an outreach educator [96]. Patients receive acute pain management through an internally developed protocol [96]. The day hospital also provides customized, comprehensive care, including primary care, twice yearly psychosocial assessments, a weekly palliative care clinic on symptom management, and complementary/alternative therapies such as nutritional supplements [96]. Patient monitoring is facilitated by an SCD registry at the health system, which interfaces with the health system’s electronic clinical and administrative databases [96]. Patients treated at the day hospital have a 2-day shorter length of stay and 33% fewer emergency department visits compared with similar patients treated at Memorial Regional Hospital but not at the day hospital [96].

The Georgia Comprehensive Sickle Cell Center, a 24-h care facility, was established in 1984 at Grady Health System in Atlanta, Georgia [97,98]. It provides comprehensive primary care for adult patients with SCD, including acute care, chronic transfusions, management of pain and leg ulcers, and services to facilitate transition from pediatric to adult care; it has a pharmacy, laboratory, and infusion center on site [98]. In 2010, the hospital admission rate for this center was reported to be 20% [97].

In 2004, the Diggs–Kraus Sickle Cell Center at Regional Medical Center (renamed Regional One Health) in Memphis, Tennessee, started a dedicated inpatient unit for patients with SCD with 10 rooms [1]. Nurses for the inpatient unit are required to take a computer-based education program on SCD developed by the medical director and a multidisciplinary team; educational materials are also available for patients and visitors [1]. The SCD inpatient unit led to reductions in emergency department utilization and average length of stay (from 5.8 to 4.6 days) and improved patient satisfaction [1]. One of the main benefits is the decreased waiting time for patients – 95% received their first shot for pain within 1 h [1].

The adult SCD clinic at Froedtert Hospital and Medical College of Wisconsin (FH/MCW) was established in 2011 with an intensive management strategy for patients with high rates of acute care utilization (12 or more emergency department or hospital admissions per year) [99]. A physician and nurse practitioner had visits every 1–4 weeks with patients in this subgroup; at each visit, the patient was assessed and changes could be made to the patient’s management [99]. This strategy resulted in a significant reduction in emergency department and hospital admissions (from 27.9 to 13.5 per patient-year, P < 0.001) and in 30-day readmissions (from 13.5 to 1.8 per patient-year, P < 0.001) for this subgroup of patients [99].

The Johns Hopkins Sickle Cell Infusion Center for adult patients was established in 2008 for adults with vaso-occlusive crisis [100,101]. It is open 7 days a week and has five acute care treatment slots (four infusion beds and one examination room) [100,101]. Staff includes 1–2 registered nurses, a medical office coordinator, a clinical technician, a social worker, and a physician extender [100,101]. The clinic resulted in a significant decrease in hospital admissions from the emergency department as well as a decrease in SCD hospital admissions and readmissions at other hospitals in the community [100]. A quality improvement analysis found that an increased nurse-to-patient ratio (from 1:4 to 1:2) decreased the time to first pain medication dose for SCD patients at the clinic [101].

The Foundation for Sickle Cell Disease Research (FSCDR) was established in 2014 and serves as a stand-alone nonprofit clinical center in the community that uses a holistic approach by providing specialty and primary-care services, care coordination, case management, and social services for individuals with SCD [102,103]. The FSCDR has an SCD electronic health record and registry for SCD population health management and recruitment and retention of subjects for clinical research. The FSCDR uses patient self-management skills to help an individual to problem solve and respond as their disease gets better or worse; to maintain a healthy lifestyle with regular exercise, healthy eating, sound sleeping habits, and stress management; to manage common symptoms; to make decisions about when to seek medical help and what treatments to try; to work effectively with their health-care team; and to use medications safely and effectively.

Despite these innovative strategies that improve health outcomes and reduce acute care services, few dedicated programs to address the complexity of SCD from a holistic perspective exist [104].

6. Conclusions

Although SCD was once considered a childhood disease, individuals with SCD are now living well into adulthood as the result of advances in care. Lack of adult providers, particularly adult providers knowledgeable about how to care for adults with SCD, contributes to poorly managed disease, comorbidities, and complications in SCD. There is a paucity of medical homes for adults living with SCD; nationally, the system of care is currently fragmented and does not address the health care, psychological, or social needs of individuals with SCD across their lifespan. Treatment of adults with SCD is challenging due to increased disease burden, health-care and social disparities, and lack of preparation for the transition from pediatric to adult care (Figure 1). In addition, adherence to medications such as hydroxyurea and iron chelation therapy is often suboptimal (Figure 1). New evidence-based treatment guidelines and other efforts from the NHLBI, HHS, and CDC, along with the development of specialized SCD centers using alternative models of care (e.g. day hospitals), have the potential to improve the well-being of adults with SCD.

Figure 1. Overview of the challenges faced by adults with sickle cell disease (SCD) in the United States.

7. Expert commentary

Management of SCD requires multidisciplinary comprehensive care that addresses recommendations for preventive care, pain management, utilization of blood transfusions coupled with iron chelation, and hydroxyurea to palliate SCD-associated complications. Screening techniques and early intervention therapies have sharply lowered mortality in children with SCD as the vast majority now lives to adulthood, but these efforts have not gone far enough. A vital challenge is access to quality care, especially among adults, which is lacking among different SCD populations across the United States and across the world. Although underutilized, hydroxyurea and blood transfusion coupled with chelation have decreased pain and other complications in adults and children alike. Nevertheless, we need to expand treatment options by discovery research and drug development. Hematopoietic transplantation procedures offer a cure for some individuals with SCD; however, they are complex, costly, and therefore not widely available for patients with SCD. Improvement by using disease-specific tools to assess patients’ quality of life should be highly considered as the next frontier, especially during drug development trials. Likewise, evidence-based behavioral strategies such as self-management skills and cognitive behavioral therapy have application for complex chronic diseases such as SCD.

8. Five-year view

Specialized sickle cell–specific health-care delivery models such as day hospitals should become more common as they offer better patient outcomes through comprehensive and multidisciplinary care along with cost savings. The implementation and integration of SCD care models between stake holders such as third-party payers, hospitals, private sectors, and government agencies will likely improve sustainability and the health-care disparity gaps commonly reported by patients and health-care providers. Standardization of transition programs from pediatric to adult care will reduce the peak mortality and utilization rates in individuals aged 18–30 years living with SCD. The impact of iron overload may be mitigated by improved, noninvasive screening methods as well as new, patient-friendly formulations of iron chelators. Finally, a cure for SCD may be more accessible as gene therapy matures into a safe and viable method of repairing defective β-globin genes.

9. Key issues

• The lack of research studies focused on adults with SCD limits the effectiveness of adult treatment guidelines

• Coordination of care is essential for SCD management, and models such as the ‘medical home’ provide good examples

• Despite improvements, patients with SCD still face a higher risk of early death

• Substantial disparities exist in availability of treatment centers, federal funding, and assistance programs for patients with SCD compared with other genetic disorders

• Both race-specific and SCD-specific discrimination persist in the health-care system

• Pain, risk of comorbidities, SCD complications, and subsequent hospitalizations increase with age

• Patients with SCD transitioning from pediatric to adult care are less likely to receive appropriate care

• Transitioning patients are often under-informed about SCD and the transition process

Declaration of interests

P Adams-Graves is a speaker and consultant for Novartis Pharmaceuticals Corporation. L Bronte-Jordan is a speaker bureau member for Novartis Pharmaceuticals Corporation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Writing assistance was utilized in the production of this manuscript and performed by Jennifer Lee, PhD, of Phase Five Communications, who provided medical editorial assistance, which was funded by Novartis Pharmaceuticals Corporation.