A lot of … clinical knowledge is not captured in research yet.… [W]e are still defining value in a context that really only looks at what the existing literature is.
—Sara v. G. (Open Session Panelist)
Sickle cell disease (SCD) is a multi-system disorder resulting from the complex interplay among hemolysis (the destruction of red blood cells [RBCs]), chronic inflammation, and systemic vascular damage. Its main presenting symptom is pain. Unpredictable, recurrent, and excruciating episodes of acute pain—often referred to as “pain crises”—and the various consequences of chronic pain are responsible for most of the psychosocial devastation of the disease and are also the primary reason for the use of health care (Borhade and Kondamudi, 2019). However, despite its importance, pain is perhaps the least understood complication of SCD and thus will be considered first in this chapter, separately from the disease’s other complications.
In addition to acute and chronic pain, SCD also has profound effects on every organ and system of the body, as discussed later in the chapter. Managing SCD requires paying attention to its complex pathophysiology and its nuanced effects on general medical comorbidities, which are becoming increasingly common as individuals survive into adulthood. The SCD population has benefited from research that generated evidence-based guidelines to prevent infections and strokes (which were the primary reason for early mortality in the 1970s and 1980s).
However, although it has been more than 70 years since the precise genetic defect responsible for this disorder was identified (Ingram, 2004), life expectancy for individuals with SCD remains more than 20 years less than that of the general population, according to research conducted at two academic medical centers (DeBaun et al., 2019). The characterization of the full range of morbidity and the identification of efficacious interventions for managing the disease have both come much more slowly than for other inherited disorders of childhood (e.g., hemophilia and cystic fibrosis). Biomarker development to guide clinical care and identify outcome measures for clinical trials has also proceeded at a slow pace, partly due to the complexity of the disease.
There is a desperate need for new and ongoing research to identify and widely implement modern, effective, and comprehensive management
approaches that will improve both longevity and the quality of life (QOL) in children and adults with SCD by preventing chronic complications and end-organ damage. Research is also required to identify and deploy strategies to mitigate the intense suffering and morbidity from SCD pain.
Pain is the prototypical symptom of SCD and the most common reason to seek acute or ambulatory care. It is associated with increased morbidity, mortality, and health care costs (Ballas et al., 2012a). Acute vaso-occlusive episodes (VOEs, also known as pain crises, pain episodes, or vaso-occlusive crises) are acute episodes of intense pain and are underpinned by a complex pathophysiology. VOEs are multifactorial and may stem from a variety of causes, and a high rate of VOEs is typically associated with early mortality from multi-organ damage. Individuals living with SCD also experience daily chronic pain. Pain may occur from chronic end-organ or nerve damage from SCD as a result of treatments (e.g., opioid-induced hyperalgesia [OIH]) or from non-SCD medical comorbidities, such as osteoarthritis, gout, or rheumatoid arthritis (Dampier et al., 2017).
Pain is, in a sense, an “invisible” complication of SCD. There are often no objective physical signs or biomarkers of either acute or chronic SCD pain. The lack of an objective tool to accurately predict and characterize pain in SCD and to guide clinicians to the appropriate therapeutic intervention remains a significant research gap, as discussed in Chapter 7 (Darbari and Brandow, 2017).
The complex pathophysiology of acute and chronic pain in SCD is poorly understood, which may be one of the reasons why its treatment remains suboptimal. There is insufficient understanding of the interplay among (1) the pathophysiology of pain in SCD, (2) the cumulative effects of recurrent pain episodes, (3) the individual variability in pain perception and coping, and (4) the influence of pain treatments (particularly the chronic exposure to opioids). As a growing number of individuals with SCD have now survived into adulthood, the cumulative burden of opioid-related side effects, including OIH, is emerging and will need to be further investigated.
Finally, but also importantly, socioeconomic factors relating to race and social milieu that are characteristic of the affected population complicate the experience and treatment of pain. Sociodemographic factors have been shown to influence pain perception, expression, and response to treatment (Clark et al., 1999). Individuals with SCD report higher levels of pain compared with cancer patients of either the same or a different race (Ezenwa et al., 2018). When individuals living with SCD perceive discrimination from physicians or nurses on account of their race or socioeconomic
The Epidemiology of Pain in SCD
Acute Pain in SCD
VOEs are characterized by severe and unpredictable acute pain. Diggs described the typical acute VOE as being of sudden onset; involving the lower back, joints, or extremities; either localized or migratory; and often continuous and throbbing (Ballas et al., 2012a; Diggs, 1956). The Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks–American Pain Society Pain Taxonomy (AAPT) initiative has recently established diagnostic criteria for acute SCD pain (Dampier et al., 2017). According to AAPT criteria, acute SCD pain is new-onset pain that lasts ≥ 2 hours but that has not been present for more than 10 days or two standard deviations above the mean length of an acute pain episode in adults with SCD (based on the Pain in Sickle Cell Epidemiology Study [PiSCES] cohort) (Field et al., 2019). This definition aims to distinguish acute pain from transient and chronic pain but may not adequately capture pain syndromes that represent a transition from acute to chronic pain.
Acute pain in SCD happens when the rapid breakdown of the sickled RBCs leads to increased inflammation by depleting the body of anti-inflammatory molecules that also help maintain blood vessel integrity. When the cells making up the lining of the blood vessels (i.e., the endothelium) are damaged, any inflammation makes it easier for sickled RBCs to obstruct the blood flow through the vessels. As a result there is an oxygen deficit to the downstream organs, which causes pain in tissues and nerves (Ballas et al., 2012a). The chronically heightened inflammatory state of SCD leads to activation of white blood cells, platelets, and endothelial cells as well as of the clotting pathways and, ultimately, multicellular adhesion or clumping, which results in vaso-occlusion (the obstruction of blood vessels) and ischemia–reperfusion injury, which is the damage created by reoxygenation after a period of oxygen deprivation (Kalogeris et al., 2012).
When an organ’s blood flow is compromised (ischemia), the resultant injury to the body’s pain-sensing (nociceptive) tissue results in acute pain (Ballas et al., 2012a). In the bone marrow, inflammation and death of cells (necrosis) occur, leading to pain that may be nociceptive, inflammatory, or neuropathic and is experienced acutely but can also persist, evolving into chronic pain (Charache and Page, 1967; Conran et al., 2009; Zhang et al., 2016).
Repetitive bouts of excruciating pain have a profoundly negative impact on all aspects of health-related quality of life (HRQOL) across the life
span (Dampier et al., 2011). Pain rates (measured in episodes per year) in SCD vary by age, with the highest rates in the 20- to 29-year-old cohort (Platt et al., 1991). A study by Brousseau et al. (2010) found that 21,112 patients had a total of 109,344 acute care encounters, which yields an acute care use rate of 2.59. This means that, on average, the individuals included in the study had approximately three acute care encounters per year; the majority of these were for pain (Brousseau et al., 2010).
Acute care use for pain is responsible for a large proportion of health care spending for SCD. Using data from 4,294 Florida Medicaid enrollees with SCD, Kauf et al. (2009) determined that the approximately 100,000 affected individuals in the United States use approximately $1.1 billion in medical care; this number is believed to be a conservative estimate (Kauf et al., 2009).
Patient-reported VOE pain has been found to be an independent predictor of mortality in individuals with SCD (Darbari et al., 2013). Frequent admissions (three or more per year) for acute painful events have been demonstrated to correlate with increased mortality (Elmariah et al., 2014). An investigation into the causes of death for 209 individuals with SCD revealed that 33 percent who were free of organ damage died during VOEs (Platt et al., 1994). These findings highlight the link between the symptom of pain and its underlying pathophysiology and related complications and their attendant morbidity and mortality.
Current treatment approaches are aimed at rapidly relieving pain and investigating and mitigating its triggers (Ballas et al., 2012a; Uwaezuoke et al., 2018). The most common triggers include dehydration, infection, extreme emotional distress, physical overexertion, and exposure to ambient temperature extremes (Ballas and Smith, 1992; Ballas et al., 2012a; Yale et al., 2000). Most individuals report that they can sense when a crisis is imminent and often resort to mindfulness-based and supportive management strategies, such as liberal oral hydration, rest, relaxation, massage of the affected area, or walking to increase circulation in an effort to abort the symptoms (Simmons et al., 2019; Williams et al., 2017). This is in line with the findings of multiple studies and anecdotal evidence that the majority of acute pain in SCD is managed at home, with acute care use occurring in only a minority (3–5 percent) of cases (Smith et al., 2008).
Once an individual presents to an acute care setting, the initial phase of the VOE treatment is focused on relieving the acute distress and intense pain by quickly offering effective analgesia. A typical approach is to provide parenteral opioids (typically through an intravenous injection), with or without non-steroidal anti-inflammatory drugs (NSAIDs), and supportive hydration (Puri et al., 2018; Uwaezuoke et al., 2018; Yale et al., 2000). After the initial relief of intense pain is achieved, the clinician maintains pain relief by frequent repeat dosing of analgesia while also treating the
underlying trigger, if identifiable, until the pain begins to resolve. Acute pain episodes may last from a few hours to a few days, to more than 1 week (Okwerekwu and Skirvin, 2018). As acute pain enters the resolving phase, it is important to gradually decrease the daily doses of opioids to avoid both rebound pain and withdrawal symptoms (Carroll, 2020). There are significant research gaps concerning the most effective way to apply the current understanding of the pathophysiology of SCD and knowledge of opioid pharmacogenomics to develop management strategies for acute pain in VOE (Puri et al., 2018).
The acute pain experience is characterized by the current episode of pain superimposed on the numerous prior acute pain episodes, plus the contribution of any chronic pain condition (Field et al., 2019). Thus, it is unrealistic to expect pain in SCD to be unidimensional in either presentation or response to treatment. The complexity and multifactorial nature of pain in SCD are difficult to dissect by patients, who may struggle to describe pain to health care providers, and by the providers, who may not completely understand it and thus inadequately treat it.
Chronic SCD Pain
In addition to acute pain, as individuals with SCD age they increasingly develop chronic pain. Chronic pain in SCD is defined as pain lasting more than 3 months, according to a National Institutes of Health (NIH) expert panel report (NHLBI, 2014). Among adolescents with SCD, this type of pain has been observed to change from intermittent acute pain that fully resolves between episodes to insidious daily pain with intermittent acute exacerbations, with the exacerbations perceived as becoming more intense over time (Smith and Scherer, 2010). The PiSCES study reported pain in 54.5 percent of 31,017 analyzed patient-days among adults with SCD; nearly 30 percent of the study participants reported experiencing pain on more than 95 percent of the days surveyed (Smith et al., 2008). The prospective Examining Sickle Cell Acute Pain in the Emergency vs. Day Hospital trial reported 68 percent of participants with chronic pain (Lanzkron et al., 2018), underscoring the high prevalence of this complication. Chronic pain in SCD often occurs in more than one location in the body (Franck et al., 2002), may have a neuropathic component (Wilkie et al., 2010), and often is accompanied by comorbid anxiety and depressive symptoms (Jonassaint et al., 2016).
The AAPT initiative attempted to better capture the multiple facets of chronic pain in SCD by developing an evidence-based classification system (Dampier et al., 2017). The new AAPT taxonomy defines chronic SCD pain as occurring on most days, lasting more than 6 months, and evidenced by at least one sign of pain sensitivity or chronic disease complication (e.g.,
a skin ulcer, splenic infarct, or bone infarction) associated with the location of the pain. The taxonomy defines three specific chronic pain subtypes: with contributory disease complications (e.g., gallstones, avascular necrosis, bone infracts), without contributory disease complications, and mixed (see Box 4-1). The new taxonomy can now be applied to address research gaps in the epidemiology, pathophysiology, and treatment of SCD chronic pain.
Neuropathic pain in SCD is not fully understood, but it likely arises from damage to the peripheral or central nervous systems (somatosensory system) during or following a VOE (Wilkie et al., 2010). As a result, it may be characterized by peripheral nociceptive sensitization or hypersensitivity that results in hyperalgesia and allodynia. Hyperalgesia is a heightened perception of severe pain generated by stimuli that are typically only mildly painful (Colloca et al., 2013; McMahon et al., 2013) and occurs in SCD with the onset of chronic pain. With allodynia, there is perception of severe pain from repeated stimuli that are usually painless; there is a need for additional research to understand its origin, prevention, and treatment in SCD (Ballas et al., 2012a).
Neuropathic pain occurs in 25–40 percent of individuals living with SCD (Brandow et al., 2014; Ezenwa et al., 2016); this is a significantly higher prevalence than in the general pain population although comparable to the prevalence in people with cancer (36–39 percent) (Brandow et al., 2014; Rayment et al., 2013). Patients describe neuropathic pain as numbness, tingling, and lancinating pain that is paroxysmal and often intense (Wilkie et al., 2010). Thermal pain sensitivity documented by quantitative sensory testing is indicative of neuropathic pain and has been reported in both children and adults (Brandow et al., 2013; Ezenwa et al., 2016; O’Leary et al., 2014). Despite the fact that neuropathic pain is a common archetype of chronic SCD pain, only 14 percent of adults with SCD and chronic pain in one study reported being prescribed adjuvant drugs that may target neuropathic pain pathways; the majority of the study participants received opioids only (Brandow et al., 2014; WHO, 2018; Wilkie et al., 2010).
Central sensitization (CS) refers to an increase in sensitivity to pain and in the responsiveness of neurons; it causes individuals with SCD to regularly experience clinical pain and other chronic pain syndromes (Ballas et al., 2012a; Campbell et al., 2016; Cataldo et al., 2015). Nociceptive signals from the periphery assault the central nervous system and alter the spinal cord and brain, causing chronic amplification of pain sensations (Woolf, 2011). One study reported CS in approximately 17–35 percent of chronic pain patients (Schliessbach et al., 2013); by contrast, CS is reportedly present in approximately 25–90 percent of individuals with SCD and chronic pain, according to two other studies (Campbell et al., 2016; Ezenwa et al., 2015). A higher degree of CS is associated with more clinical pain, more VOE pain, poor sleep, higher rates of pain catastrophizing, and negative
mood (Campbell et al., 2016). It is believed that chronic exposure to opioids can result in CS (Cohen et al., 2008; Hay et al., 2009). Additional predisposing factors include genetics (Smith et al., 2012), psychosocial and behavioral comorbidities (Finan et al., 2013; Smith and Scherer, 2010), and neuropsychological factors (Cruz-Almeida et al., 2013).
OIH refers to the paradoxical increased sensitivity to pain and heightened perception of pain that occurs after repeated/chronic exposure to opioids (Angst and Clark, 2006). With OIH even harmless stimuli can trigger an exaggerated pain response that worsens with increasing doses of opioids. This is an important differential diagnosis of exclusion; OIH is confirmed when pain perception and experience improve after ending opioid therapy (Lee et al., 2011; Ramasubbu and Gupta, 2011). While discontinuing opioids is a common approach in treating OIH, it should be undertaken with care because it may precipitate opioid withdrawal (Fishbain and Pulikal, 2019; Lee et al., 2011).
Opioid-Related Cyclical Withdrawal Syndrome
Unfortunately, the most common complication associated with opioids, opioid withdrawal syndrome (OWS), has been largely ignored in the management of SCD (Carroll et al., 2016). The committee was unable to find any published articles describing cyclic OWS and SCD, even though this clinical phenomenon is commonly experienced by individuals with SCD. OWS commonly occurs after VOE resolves and patients are transitioned to oral opiates without an appropriate taper or parenteral-to-oral dose adjustment. The resulting OWS may be interpreted as a new acute VOE, often leading to readmission and a vicious cycle of increased tolerance, higher opioid doses, and worse OWS.
Triggers and Psychological Impact of Pain
You can think of any life event, and I can tell you a story of how sickle cell disease impacted it.
—Tosin O. (Open Session Panelist)
Pain catastrophizing is the tendency to worry and obsess about pain, leading to feelings of helplessness that interfere with function and
adversely affect QOL (Van Damme et al., 2002). The PiSCES study reported a significantly higher degree of catastrophizing among adults with SCD than among those with other temporal chronic pain conditions (Citero et al., 2007) and also found an inverse relationship between mood and QOL (p < 0.001) (Citero et al., 2007). A study by Sil et al. (2016) showed that when a child and his or her parents express a large number of negative thoughts with a mindset of impending doom about the pain experience (pain catastrophizing), the child is more likely to also experience significant levels of functional disability (Sil et al., 2016). A failure to address thought patterns about pain can result in treatment failure.
Anxiety and Anticipatory Pain
The unpredictability and anticipation of SCD pain may trigger anxiety, as do repeated experiences of undertreatment of pain or inconsistent interactions with health care providers during acute pain exacerbations (Schlaeger et al., 2019). Some individuals may become anxious or stressed that they will have pain and miss an important activity, a life milestone (e.g., graduating from high school), or social activities with friends. Heightened anxiety is associated with increased pain sensitivity and can trigger VOEs. The relationship between anxiety and pain is discussed in more detail later in this chapter.
Treatment of Pain
Acute SCD Pain Management
The National Heart, Lung, and Blood Institute’s evidence-based consensus guidelines (NHLBI, 2014) provide a general philosophy for managing acute SCD pain. The guidelines recommend prompt oral or intravenous analgesia for rapid relief. The recommended drugs to treat acute VOE pain at home include oral mild to moderate opioids, such as hydrocodone, oxycodone, morphine, or hydromorphone. Once oral therapy has failed, the recommendation is to proceed to intravenous or subcutaneous administration of morphine or hydromorphone or intranasal or intravenous administration of fentanyl. Pain relief should be paired with a thorough assessment of the cause or trigger of the pain event—including infections, dehydration, or acidosis—and then prompt treatment of the identified triggers and any other complications identified. Ideally, the prompt treatment of acute SCD pain should take place in a dedicated SCD day hospital, observation unit, or infusion center with trained personnel who follow standardized treatment plans with individualized dosing, when possible.
Chronic SCD Pain Management
Management of SCD chronic pain in the United States has traditionally been unidimensional and involved opioid titration and rotation; there are very few studies to identify best practices for treating chronic pain. Without evidence-based recommendations for treating chronic pain in SCD, the committee borrowed best practices from the general chronic pain literature and the recent Centers for Disease Control and Prevention (CDC) guidelines for opioid prescribing to manage chronic pain. The guidelines recommend non-pharmacological therapies due to the lack of proven efficacy and demonstrated harm associated with long-term opioid therapy (Dowell et al., 2016). Additionally, existing guidelines prescribe a structured approach to the use of opioids for chronic pain, including realistic goal setting between provider and patient after discussion of risk and benefits of opioids, with regular reappraisal; use of the lowest effective dose of preferably short-acting opioids, with caution when escalating doses over recommended morphine equivalent per day limits; minimal use of long-acting opioids when possible; not co-prescribing opioids with other sedating medications (benzodiazepines); the use of risk mitigation strategies (including reviewing the state prescription drug monitoring database for controlled substance prescription history); urine drug testing; and supporting evidence-based treatment for substance use disorder (SUD) when identified (Dowell et al., 2016).
While these guidelines seem intuitive, they are outside of the usual scope of practice of hematologists who care for individuals with SCD. The complications associated with long-term exposure to opioids have been overlooked, and individuals with SCD are poorly informed about the potential contribution of chronic opioids to their current and prior medical comorbidities (Benyamin et al., 2008). Delayed puberty, gastrointestinal complaints, and OIH are examples of complications that patients and health care providers may not always recognize as opioid-related.
The management of SCD chronic pain remains an area of frustration and dissatisfaction for providers and people living with SCD. Insurance plans typically limit access to non-pharmacologic therapies, which are, as a consequence, often overlooked in SCD. With the obvious need to de-emphasize the use of opioids in chronic pain management, there have not been commensurate evidence-based recommendations for alternative approaches.
Oral acetaminophen has been widely used in multimodal pain management strategies in SCD with variable efficacy (Shah et al., 2019). Intravenous acetaminophen is rarely used because of cost considerations, but it has been found to reduce acute pain in children with SCD (Baichoo et al., 2019).
Non-steroidal anti-inflammatory drugs
While ketorolac and other NSAIDS have been routinely incorporated in the management of acute pain in SCD, studies about their effectiveness in controlling SCD pain have shown mixed results (Beiter et al., 2001; Hardwick et al., 1999; Perlin et al., 1994; Wright et al., 1992). Importantly, caution is paramount when using NSAIDs in SCD because kidney dysfunction may exist even in the presence of a normal serum creatinine and, therefore, remain undiagnosed. Acute kidney injury with ketorolac use has been reported in SCD (Baddam et al., 2017; Simckes et al., 1999).
Cannabis use is prevalent in SCD, with one small study showing that 18 percent of the study participants (all of whom had SCD) had positive urine test for cannabis alone and 5 percent tested positive in combination with cocaine/phencyclidine (Roberts et al., 2018). The majority of cannabis users with SCD report that cannabis helps them relax and alleviates insomnia (Howard et al., 2005). A minority state that they use cannabis only for non-medical reasons and recreationally. The regulatory framework around marijuana is becoming more lax in the United States, and marijuana for medical use can be obtained legally under certain qualifying conditions in 33 states and the District of Columbia (Procon.org, 2019); SCD is a qualifying medical condition in several U.S. states.
In spite of the increased availability of medical marijuana, evidence for its efficacy and safety in SCD is limited. A study conducted on patients with SCD using recreational cannabis showed that cannabis use was associated with increased hospitalizations (Ballas, 2017), but causality could not be inferred because sicker patients may have been more prone to using cannabis to relieve their symptoms. Studies in sickle mice show that cannabinoids may reduce pain by reducing mast cell activation and inflammation (Vincent et al., 2016), but controlled studies in people with SCD are lacking. Thus, efforts should be made to rapidly close the research gaps on the therapeutic effects and risks associated with marijuana and other cannabinoids in treating pain in SCD (NASEM, 2017).
Topical lidocaine has been associated with improved pain control in small studies (Rasolofo et al., 2013), but it is not generally approved by insurance plans and is rarely used for home management.
Intravenous ketamine is emerging as an alternative to morphine for acute pain management in SCD and may lead to lower opioid consumption (Lubega et al., 2018; Puri et al., 2019). However, neurological and psychiatric side effects are likely to limit its widespread use in the future.
Drugs targeting neuropathic pain
Neuropathic pain is difficult to treat and is usually refractory to opioid and non-opioid analgesics (e.g., acetaminophen, NSAIDS). Tricyclic antidepressants, gabapentin, and pregabalin have been extensively used to treat neuropathic pain in other diseases but are underused in SCD (Sharma and Brandow, 2020). In a pediatric administrative dataset, neuropathic pain-targeting drugs were prescribed to only 2.9 percent of children, and their use was associated with older age, female gender, and longer length of stay (Brandow et al., 2015).
Partial Agonist Opioids
Buprenorphine is a recently approved opioid with lower risk for misuse, withdrawal symptoms, and cravings for opioids as well as reduced risk of overdose. Recent data showed successful conversion to buprenorphine in patients with chronic pain and high opioid doses with a decrease in pain scores and acute care use, and increase in QOL measurements (Osunkwo et al., 2019).
SCD and the Opioid Epidemic
It is important to draw a clear distinction between the appropriate pain management used to address “acute-on-chronic” pain conditions like VOE in SCD and the overprescribing of pain medications that has led to the opioid epidemic in the United States. CDC has recently updated its opioid overuse prescribing guidelines to acknowledge that the pendulum has swung too far in the direction of restricting access, to the point that patients with a clear need for long-term opioids are being denied appropriate care (ASH, 2019; Meghani and Vapiwala, 2018). Because the opioid epidemic has become a major public health concern, the messaging to providers has tended to emphasize documenting the pain source, carrying out an appropriate workup, developing functional goals for pain, using a state registry to track controlled substance prescriptions, and monitoring prescriptions appropriately (Dowell et al., 2016). While all of these procedures are reasonable, the proliferation of high-profile provider indictments has resulted in a reluctance on the part of physicians to prescribe opioids for pain, further restricting access for vulnerable groups.
The committee believes that the unintended consequence of the new opioid-adverse climate could be a decreased access to opioids for SCD patients in need, such as those who are managing or recovering from acute VOE or have previously been maintained on daily opioids; pharmacies may not stock opioids in underserved communities perceived to have high rates of “opioid-using individuals” or risk of robbery, and some may require a 72-hour hold to allow time to investigate the appropriateness of
the prescription. This climate has reflected on patients’ perceptions of discrimination; people living with SCD have reported feeling increased stigma regarding their diagnosis and medication profile both within the hospital and at the pharmacy (Meghani and Vapiwala, 2018).
Non-Pharmacological Treatments of Pain in SCD
Various non-opioid-based treatments have been proposed for reducing acute pain and the duration of pain and for preventing pain in SCD; these treatments should be incorporated into a multidisciplinary pain control strategy whenever possible (Niscola et al., 2009). Because uncontrolled depression, anxiety, emotional trauma, and poor self-efficacy can worsen pain perception and control, behavioral and psychiatric comorbidities should be addressed as part of pain control strategies.
In acute VOEs, oxygen has been used to shorten the duration of VOE and to prevent complications, but its indiscriminate use in non-hypoxic settings could be detrimental (Helmerhorst et al., 2015). Importantly, while oxygen is helpful in treating acute hypoxemia, small studies have shown no additional benefit in terms of reducing the duration or severity of a VOE (Niscola et al., 2009). Large studies on this topic are lacking.
Topical heat and massage
There is low-quality evidence (i.e., primarily pilot studies with convenience samples) indicating that both heat and massage have moderate efficacy in pain control. Massage in adults and children living with SCD holds promise for reducing pain (Bodhise et al., 2004; Myers et al., 1999) and may lead to reduced use of pain medication and emergency department (ED) visits (Bodhise et al., 2004). The committee found one randomized controlled trial that evaluated massage in pediatric SCD (Lemanek et al., 2009); youth receiving the massage intervention had lower levels of pain, decreased anxiety and depression, and better overall functioning. More research is needed to understand the impact of massage in SCD.
Hydration has been a cornerstone of VOE prevention (Okomo and Meremikwu, 2007), but its benefits have been challenged in recent years because overhydration carries a risk of pulmonary edema, acute lung injury, and cardiac complications (Barabino et al., 2010; Gaartman et al., 2019). Intuitively, hypotonic solutions may ameliorate RBC dehydration in SCD and reduce sickle hemoglobin (HbS) polymerization and sickling, but recent publications have demonstrated that hypertonic fluid may have a negative impact on red cell deformability in in vitro microfluidic models
and result in poorer pain control in pediatric patients presenting to the ED for acute VOE pain (Carden et al., 2017, 2019). Large, controlled clinical studies are needed to determine the optimal intravenous fluid solution and the rate and volume of administration.
Using an incentive spirometer (a device that tracks and promotes slow, deep breathing) has been shown to reduce the risk of pulmonary complications in VOE (Bellet et al., 1995; Yawn et al., 2014); all hospitalized patients with VOE should be encouraged to use an incentive spirometer throughout the hospital stay.
Complementary and Alternative Medicine
Complementary and alternative medicine (CAM) is a catch-all category for treatments that reside outside traditional medical science, such as hypnosis, yoga, acupuncture, massage, and prayer. Mind–body techniques such as mindfulness mediate endogenous pain at the supraspinal level. Studies have found that individuals with SCD frequently use CAM, including prayer, acupuncture, dietary supplements, relaxation, massage, and exercise (Niscola et al., 2009; Thompson and Eriator, 2014).
Acupuncture involves placing needles into defined points on the body to relieve symptoms. There are reports of reduced pain with acupuncture in SCD (Bhushan et al., 2015; Sinha et al., 2019), while another study found no difference in SCD pain after acupuncture or control treatment (needles placed randomly) (Co et al., 1979). A recent study conducted at the NIH Clinical Center found that people living with SCD and receiving acupuncture while hospitalized or in the outpatient setting demonstrated reductions in pain (Lu et al., 2014). Recent evidence showed that children with SCD receiving acupuncture to treat acute SCD pain in an ED experienced decreased pain scores post-treatment (Tsai et al., 2018).
Further studies are needed to confirm the clinical benefit of acupuncture, particularly on different types of SCD pain (e.g., neuropathic) (Lu et al., 2014). It is also important to note that this treatment may not be covered by insurance plans, making it difficult for individuals to access (Sinha et al., 2019).
Yoga, a practice that incorporates physical positions, mindfulness, relaxation, and breathing exercises, has been shown to reduce chronic and acute pain in adults, although there are limited data concerning its use for the treatment of SCD pain. The only randomized controlled trial of yoga as a treatment for acute SCD pain for children hospitalized with VOE supported its feasibility, acceptability, and potential for reducing pain (Moody et al., 2017). However, the committee was unable to find similar studies for adults.
As discussed in Chapter 2, African Americans’ mistrust of the health care establishment and perceived discrimination by providers may lead to discounting care providers’ recommendations and resorting to using home or “folk” remedies. Quandt et al. (2015) found that older, rural African Americans were more likely to use both food- and non-food remedies than were older, rural whites and that these remedies were sometimes used in place of prescription medications. The authors note that these home remedies “can potentially interfere with biomedical treatments” (Quandt et al., 2015, p. 121), thereby warranting further research.
Behavioral treatment can modulate the pathway between nociceptive pain and emotional responses to pain in the limbic system, hypothalamus, and amygdala, thus potentially reducing the perception of pain.
Cognitive behavioral therapy
As discussed in Chapter 2, cognitive behavioral therapy (CBT) has been shown to be effective in the SCD population by addressing coping strategies and normalizing chronic pain. In CBT, individuals learn to differentiate emotional and behavioral reactions from a triggering event, such as pain (Anie and Green, 2015; Schatz et al., 2018). This method addresses thought distortions, working to de-catastrophize pain and address automatic negative thoughts associated with pain.
Mindfulness is a treatment that involves heightening one’s level of awareness by intentionally attending to the present in an accepting and non-judgmental way (Kabat-Zinn, 2009). Mind–body techniques, such as mindfulness meditation, mediate endogenous pain at the supraspinal level. Mindfulness-based interventions led to reduction in chronic pain (Reiner et al., 2013). A 4-week guided imagery intervention improved self-efficacy in children with SCD (Dobson and Byrne, 2014). A study of children and adults found that self-hypnosis over 18 months reduced pain frequency and improved sleep but did not affect rates of school absenteeism (Dinges et al., 1997). An ongoing, randomized trial of a telephone-delivered mindfulness intervention for adults with SCD is examining the impact of mindfulness on pain catastrophizing (Williams et al., 2017).
SCD affects multiple organs over the life span. The earliest complications develop at the age of 6 months and coincide with the almost complete replacement of fetal hemoglobin with adult hemoglobin in RBCs (Kanter and Kruse-Jarres, 2013). Some of the most common complications
in children are splenomegaly (an enlarged spleen), dactylitis (painful inflammation of fingers and toes), and jaundice. Some complications may appear in childhood and persist through adulthood, while others, especially those pertaining to organ failure, may manifest later in adulthood. SCD complications are best understood when grouped according to whether they are acute or chronic and based on the systems they affect. General medical comorbidities can have a negative effect on SCD outcomes, with the reverse being also true. Very little data have been published on the impact of general medical comorbidities in SCD, particularly among adults.
Table 4-1 summarizes the complications of SCD by the affected organ system, describing the signs and symptoms experienced acutely and chronically. The table also highlights the comorbidities that often occur as a cause or consequence of these complications and must be considered in the overall management of SCD. The table is followed by a brief description of available evidence on some of the most common complications. These complications are also discussed by Ballas et al. (2012b) and Ballas (2018).
System- or Organ-Specific Complications of SCD
SCD is a chronic hemolytic anemia and can lead to various cardiopulmonary and circulatory disorders. Cardiac hypertrophy (enlargement of the heart) develops early in life in response to chronic anemia. Diastolic dysfunction, possibly from myocardial fibrosis, is relatively common (Gladwin, 2017). Risk factors for increased cardiovascular mortality among individuals with SCD include systemic hypertension, pulmonary hypertension, heart attack, and possibly subclinical electrical instability (Haywood, 2009).
Central Nervous System
SCD causes acute and chronic neurological complications. Research conducted using data from patients enrolled in the Cooperative Study of Sickle Cell Disease shows that the chances of having a cerebrovascular accident (defined as transient ischemic attack, completed infarctive stroke, and hemorrhagic stroke) for the first time by age 20 years is 11 percent and by age 45 years is 24 percent for those with HbSS (i.e., the form of SCD in which a child inherits a sickle cell hemoglobin gene from each parent) (Ohene-Frempong et al., 1998).
Rates of silent strokes (ischemic lesions detectable by magnetic resonance imaging [MRI] that do not cause symptoms of acute stroke) are even higher: 21 percent in children (Pegelow et al., 2002) and more than 50 percent in adults (Kassim et al., 2016). Hemorrhagic strokes are also more prevalent in individuals
|Organ System||Manifestations (Signs/Symptom Burden)||Comorbid Conditions|
|Central Nervous System||
|Hematopoietic System (excluding spleen)||
TABLE 4-1 Continued
|Organ System||Manifestations (Signs/Symptom Burden)||Comorbid Conditions|
NOTE: CKD = chronic kidney disease; GERD = gastroesophageal reflux disease; NSAID = non-steroidal anti-inflammatory drug; SCT = sickle cell trait; VOE = vaso-occlusive episode.
a A prolonged QT interval is an electrical impulse that is measured by an electrocardiogram. The QT are the waves displayed on the paper results from the electrical impulses through the heart.
b Hemostatic activation refers to the hypercoagulable state that occurs downstream from the vaso-occlusive process in SCD (De Franceschi et al., 2011).
c Hydroxyurea, chronic transfusion therapy, and other disease-modifying therapies, when initiated early in life, may alter the natural history of SCD phenotype.
SOURCES: Adapted from Ballas et al., 2012b; Desai et al., 2014; Gale et al., 2015; Indik et al., 2016; Martins et al., 2012; Mehari and Klings, 2016; Osunkwo, 2011; Osunkwo et al., 2011; Powars et al., 1988; Wu et al., 2018.
with SCD. Among the chronic complications, cognitive impairment, particularly involving deficits in executive function, is highly prevalent in both children (Steen et al., 2005) and adults (Vichinsky et al., 2010).
Ninety percent of pediatric strokes can be prevented by transcranial Doppler (TCD) screening and prophylactic transfusion of children with high TCD velocities (Adams and Brambilla, 2005). However, screening and early interventions for other neurological complications in adults is not available.
It is well recognized that poor oral health is directly associated with increases in both cardiovascular and all-cause mortality (Jansson et al., 2002); this is also true for individuals with SCD. Individuals with SCD are prone to dental complications such as aseptic pulp necrosis, delay in dental eruption, mucosal damage due to anemia, dental nerve infarcts, and increased risk of caries and enamel erosion. Pain treatment with opioids contributes to these issues: gum and oral infection from poor dental hygiene and dry mouth from opioid use. The likelihood of hospitalization in adults with SCD increases with dental infections (Laurence et al., 2013). One study found that optimal dental care led to a statistically significant reduction in hospital admissions and total days hospitalized (Whiteman et al., 2016).
Weight gain, metabolic syndrome, and obesity are increasingly recognized comorbidities in the SCD population, particularly in those with the compound heterozygous genotypes SC/SB+ (Mandese et al., 2019; Ogunsile et al., 2019). There is a high prevalence of vitamin D deficiency, osteopenia, and osteoporosis in SCD. Renal osteodystrophy in SCD may confer worsening chronic pain and is often unrecognized and nonresponsive to opioids (Elsurer et al., 2013; Seck et al., 2012). Similarly, vitamin D deficiency and osteoporosis or osteopenia can result in pain (Catalano et al., 2017; Glaser and Kaplan, 1997; Osunkwo, 2011).
Fat Embolism Syndrome
Fat embolism syndrome is a life-threatening complication of SCD that occurs due to VOE-induced ischemic bone marrow infarction and the release of fat globules into the venous circulation (Dang et al., 2005); it may lead to multi-organ failure syndrome and death (Gangaraju et al., 2016). Fat embolism syndrome in SCD has a high overall mortality rate of
64 percent in a recent report (Tsitsikas et al., 2014). Mortality was reduced to 29 percent with exchange transfusion, as compared with 61 percent in those receiving a simple transfusion and 91 percent in the untransfused group (Tsitsikas et al., 2014).
Cholelithiasis (gallbladder stones) is common in SCD, and many patients undergo cholecystectomy at some point over their life span. However, there are limited data on whether elective cholecystectomy is warranted in people with SCD, particularly because patients with SCD are more susceptible to perioperative complications (Howard et al., 2013; Plummer et al., 2006; Solanki and McCurdy, 1979). Other hepatobiliary complications include acute intrahepatic cholestasis, sickle hepatopathy, and hepatic sequestration (the pooling of RBCs in the liver).
While there are limited reports of ischemia–reperfusion injury from sickling in the mesenteric vessels, chronic dyspepsia, decreased gastric and bowel motility, and gastroesophageal reflux disease are very common and may represent a form of autonomic dysfunction, particularly when coupled with the dysmotility side effect of opioids. NSAIDs for pain may also induce gastritis/esophagitis and upper and lower gastrointestinal bleeding (Gardner and Jaffe, 2015; Gardner and Jaffe, 2016).
Genitourinary and Reproductive System
The sexual and reproductive consequences of SCD are profound and poorly studied. There is an increased frequency of VOE during puberty, pregnancy, and menopause. Pregnancy remains high-risk and requires proactive co-management with high-risk obstetrics and attention to the risk of early fetal demise, pre- and post-eclampsia, preterm labor, deep vein thrombosis, and intrauterine growth restriction (IUGR). Women with SCD are at higher risk of maternal and fetal mortality and are more likely to undergo Cesarean sections than those without SCD (Hassell, 2005; Kuo and Caughey, 2016).
Fetal growth problems, such as IUGR and small for gestational age and prematurity, affect offspring with unclear long-term impacts (Oteng-Ntim et al., 2015). Women with RBC alloimmunization are at risk for having babies with hemolytic disease of the newborn, and those exposed to opioids are at increased risk for neonatal abstinence syndrome (Nnoli et al., 2018).
Up to 48 percent of male individuals with SCD experience recurrent episodes of priapism (sustained, undesired, painful erections); the peak incidence is during puberty and young adulthood with the hormonal surges in testosterone, but it may be seen as young as age 7 (Arduini and Trovo de Marqui, 2018). The long-term consequences of recurrent or stuttering priapism may include the early development of erectile dysfunction, penile fibrosis, and impotence (Mantadakis et al., 1999).
Anemia, defined by a decreased hemoglobin concentration, is a hallmark of SCD and is almost invariably present in individuals with homozygous HbS (sickle cell anemia, or SCA). The symptoms of severe anemia include pallor, fatigue, decreased exercise tolerance, shortness of breath, and decreased cognitive function. The severity of anemia has been associated with serious complications such as stroke in children with SCD. Hemolysis (the premature destruction of RBCs) causes a cascade of downstream effects that cause chronic inflammation, as well as abnormalities in blood cells and the vessel wall function (Gordeuk et al., 2016). There is a large body of evidence that links the severity of hemolysis to severe complications, including pulmonary hypertension and chronic kidney disease (CKD) (Kato et al., 2017; Nouraie et al., 2013; Taylor et al., 2008).
Immune System and Spleen
Infarction of the spleen early in life causes autosplenectomy (i.e., the progressive transformation of the spleen into fibrous scar tissue) and functional asplenia (i.e., the absence of protection of the spleen from certain bacteria) (Brousse et al., 2014). Children who have undergone autosplenectomy are susceptible to infections from S. pneumoniae and other bacteria and may die from bacterial sepsis (Brousse et al., 2014). The institution of penicillin prophylaxis and immunizations against H. influenzae and S. pneumoniae early in life in children with SCD have proven to be very effective preventive strategies.
Most acute presentations of SCD involve bone pain, which may occur during acute hypoxic ischemic injury to a significant portion of a bone (Ballas et al., 2012b). If the injury persists over time, evolution to bony infarcts occurs. In the epiphysis, this is referred to as osteonecrosis (Vanderhave et al., 2018). Avascular necrosis is painful, may have significant function-limiting effects, and requires joint replacement in late stages
Ocular consequences of SCD include retinopathy (damage to the retina) that typically occurs in the peripheral retinal vascular bed, as compared with diabetic retinopathy, which is more likely to affect the central bed. Adequately diagnosing sickle retinopathy requires training; individuals with SCD are advised to get annual or biennial screening ophthalmological exams beginning at age 10 and to receive early timed intervention if retinopathy is identified (Yawn et al., 2014). Other ocular complications include bony infarcts of the orbital and facial bones and orbital hematomas, which can lead to vision-threatening complications.
Pulmonary complications are leading causes of death in SCD. Acute chest syndrome (ACS) is a major acute pulmonary complication that, without prompt intervention, carries high mortality (Novelli and Gladwin, 2016). Pulmonary hypertension is a chronic complication that affects predominantly adult individuals with homozygous HbS (prevalence of 6–10 percent) (Fonseca et al., 2012; Mehari et al., 2012; Parent et al., 2011). Pulmonary hypertension is an independent risk factor for death in SCD, with a 6-year mortality rate of approximately 40 percent (Mehari et al., 2012). Transthoracic echocardiography is an important screening tool for symptomatic individuals with SCD; abnormal blood flow across the tricuspid valve indicates an increased mortality risk in SCD (Gladwin et al., 2004) and risk-stratifies patients for additional pulmonary hypertension testing. Research is under way to determine the optimal screening strategies in individuals with SCD and the best therapeutic approaches for those with pulmonary hypertension confirmed by cardiac catheterization.
Asthma and airway hyperreactivity are significant comorbidities in SCD, particularly in children, and are associated with worse disease outcomes (Field et al., 2011). Finally, restrictive lung deficits are also more common in individuals with SCD.
The kidney is compromised early in life with both glomerular and tubular damage. Individuals with SCD experience early mortality once end-stage renal disease ensues (McClellan et al., 2012) and may require renal
Renal medullary carcinoma is a rare, aggressive tumor that occurs in individuals with sickle cell trait (SCT) or SCD (less frequently) at a higher-than-average rate (Blas et al., 2019). Guidelines for diagnosis and management are needed, as well as an international registry and biorepository (Blas et al., 2019).
Screening for microalbuminuria identifies individuals with SCD at risk of developing CKD and is recommended by current guidelines.
Non-Organ-Specific Complications of SCD
Many SCD complications are not restricted to any one organ system, and the impact of the disease on QOL can be profound but hard to define and compartmentalize. Table 4-2 presents an overview of SCD complications that are not confined to one organ system and their related acute and chronic manifestations and comorbidities.
Behavioral Health in SCD
There were many days where I took the main medication just hoping that I would not wake up. I would not wake up to face another day of emotional pain. And the judgment that came from the community.
—Jenn. N. (Open Session Panelist)
Researchers investigating the mental health impacts of living with SCD have focused primarily on the diagnoses of depression and anxiety as related to pain and pain coping behavior. Anie (2005) reported that the most common variables assessed included anxiety, depression, coping, neurological complications, and QOL. These studies are limited and allow for only correlative results as they differ in their sample size, the choice of a control group, and how each outcome was assessed. In individuals with SCD, pain affects psychological and behavioral health and creates challenges (Benton et al., 2011; Thomas et al., 1998).
Depression and anxiety
As with other chronic diseases, depressive symptoms are frequently reported among youth and adults with SCD (Anie, 2005; Levenson, 2008; Lukoo et al., 2015). Jonassaint et al. (2016) found that across 12 SCD studies, the prevalence rates for depression were 2–57 percent. The PiSCES study also found high rates of depression, with 27.6 percent of 308 adults reporting depressive symptoms (Sogutlu et al., 2011).
|SCD-Related Complications||Manifestations (Signs/Symptom Burden)||Comorbid Conditions|
TABLE 4-2 Continued
|SCD-Related Complications||Manifestations (Signs/Symptom Burden)||Comorbid Conditions|
|Sudden Death Syndrome||
NOTE: CS = central sensitization; DVT = deep vein thrombosis; PTSD = posttraumatic stress disorder; ROD = renal osteodystrophy; SCD = sickle cell disease; SUD = substance use disorder; VOE = vaso-occlusive crisis.
One early study (Jenerette et al., 2005) used the Beck Depression Inventory (BDI) Fast Screen for 232 adults living with SCD. The SCD sample had higher levels of depression (26 percent) and depressive symptoms (32 percent) than the overall U.S. population (9.5 percent). The authors attributed their findings to the stigma of SCD.
Reports from the PiSCES project indicated that both adults and children with SCD experienced worse HRQOL than the general population, particularly in the domains of bodily pain, vitality, social function, and general health (Anie et al., 2002; Kater et al., 1999; McClish et al., 2005; Thomas and Taylor, 2002). In a prospective study using the BDI, involving 142 patients, results indicated that QOL scores were significantly but inversely related to depression, with high depression scores associated with worse QOL scores (Adam et al., 2017). Health care system usage and inpatient costs were also significantly higher for patients with high scores on the BDI; the adjusted total costs were nearly twice as high for the depressed group as for the non-depressed group.
Studies have found a reciprocal relationship between depressive symptoms and pain in SCD (Jonassaint et al., 2016). Depressed mood and negative thinking influence an individual’s ability to cope with pain, and pain increases the risk of experiencing depression. People with SCD who report depressive symptoms also appear to have more frequent and severe pain. In the PiSCES study, depression was associated with increased reports of days with pain (71.1 versus 49.6 percent for the non-depressed group) and with increased pain impact during “non-crisis days” (judged according to distress, interference with normal activities, and overall mean pain scores) as compared with the non-depressed group (Levenson et al., 2008). Hasan et al. (2003) found that depressive symptoms were associated with more frequent ED visits and admissions for VOEs. In a systematic review of depression and health care use, Jonassaint et al. (2016) found that people with SCD who had depressive symptoms were more likely to have high health care use (2.8 times greater risk). This population also had more hospitalizations per year (Jonassaint et al., 2016).
The frequency of pain in a child and parent catastrophizing about that pain emerged as predictors of clinically significant depressive symptoms in children (Goldstein-Leever et al., 2018). Bakri et al. (2014) demonstrated the negative effects of repeated hospitalizations on the behavior of children with SCD, reporting increased rates of anxiety/depression, somatic complaint, withdrawn or aggressive behavior, and internalizing symptoms.
A similar relationship has been found between anxiety and pain in SCD. Adults with SCD have a prevalence rate of anxiety around 6.5 percent (Levenson et al., 2008). In the PiSCES study, people with SCD and anxiety symptoms also reported an increased use of opioids during crisis and non-crisis days (Levenson et al., 2008). This pattern is also present in children
For some individuals, living with SCD is akin to experiencing recurrent episodes of psychological trauma. Individuals with SCD report experiencing a constant fear of death or feeling that the current trip to the ED will be their last because of the unpredictability of the acute exacerbations. Many people living with SCD settle into an “automatic survival mode,” with hypervigilance and hyperreactivity to sound, speech, and movements, and this leads to a chronic fatigue and exhaustion similar to posttraumatic stress disorder (PTSD), which is caused by an intense, disturbing emotional response to a traumatic experience that involved actual or threatened death or serious injury or harm. PTSD has on occasion been reported in the SCD literature (Alao and Soderberg, 2002; Hofmann et al., 2007).
Although it seems intuitive that a relationship exists between SCD status and depression, it is difficult to confirm the etiology of that link. The existing research is imbalanced and has gaps and numerous associated methodological challenges, including the measurement of depression and the use of a control group. Clearly, this is an area in need of further research.
Insomnia and other sleep disorders
People living with SCD commonly experience significant sleep problems. For instance, children have a higher prevalence of sleep-disordered breathing, which can contribute to learning difficulties, behavioral problems, higher blood pressure, and reduced growth (Valrie et al., 2007). Children also experience difficulty falling asleep, low blood oxygen levels at night, night awakenings, longer periods before rapid eye movement (REM) sleep, short REM sleep duration, urinary incontinence, and subsequent daytime sleepiness (Valrie et al., 2013). As adults, they are very likely to experience sleep-disordered breathing, with more than 70 percent reporting some sleep disturbance symptoms (Wallen et al., 2014). Additionally, adults with SCD have late sleep onset and decreased sleep duration and spend more time awake during the night (increased sleep fragmentation), with almost the entire sample (97 percent) reporting poor sleep (Wallen et al., 2014). Although sleep-disordered breathing is a significant health concern for individuals with SCD (Sharma et al., 2015), little physiological sleep research has been carried out, and the available interventions are limited.
The physiologic effects of SCD increase the risk for a range of neurologic complications (e.g., stroke, silent cerebral infarct [SCI], microstructural white matter abnormalities), resulting in significant cognitive deficits (Kawadler et al., 2016; Prussien et al., 2019; Schatz
et al., 2002). Children with SCD, with and without prior history of stroke or SCI, have higher rates of developmental disabilities. Specifically, among all African American children, 0.6 percent of the observed developmental disabilities (e.g., intellectual disabilities, cerebral palsy, and hearing and visual impairment) can be attributed to SCD. Furthermore, the increased risk for developmental disabilities in individuals with SCD is mostly due to stroke (Ashley-Koch et al., 2001).
Intelligence quotient (IQ) is the most commonly assessed aspect of cognition in the literature, and IQ is most often lower in people with SCD than in controls (e.g., siblings and peers) (Prussien et al., 2019). The most significant childhood IQ deficits are associated with stroke and SCI, but SCD patients with normal-appearing MRI tests may also have IQ deficits. Findings from a meta-regression of studies conducted in a pediatric SCD population indicated that there are significant differences of approximately 10, 6, and 7 points in IQ for children living with SCD with stroke (compared with those with SCI), SCI (compared with those with no SCI), and normal-appearing MRI (compared with children with no SCD and normal MRI), respectively (Kawadler et al., 2016). Cognitive deficits have been observed across a range of domains (e.g., memory, learning, language, visuospatial abilities) (Berkelhammer et al., 2007); however, the most significant and consistent deficits are in executive abilities (Hood et al., 2019), attention (Daly et al., 2012), and processing speed (Stotesbury et al., 2017).
The etiology, risk factors, and trajectory of cognitive impairment in individuals with SCD without a history of stroke or SCI is a major gap in knowledge.
Substance use disorders/opioid use disorders
There is significant ambiguity and hesitancy surrounding the application of the terms SUD and “opioid use disorder” (OUD) in the context of SCD. This is partly due to the concerns about increasing stigma in an already stigmatized population and the fear that applying these terms will reduce access to optimal treatment for pain, which typically requires opioids. Nevertheless, it is important that appropriate terminology and diagnostic criteria be applied equally to all populations to avoid undertreatment, overtreatment, and inappropriate treatment; further worsen clinical outcomes; and reduce access to evidence-based care.
Unfortunately, there are relatively few publications that address the epidemiology of SUD or, more specifically, OUD in SCD. These are mostly case reports (Alao et al., 2003; Biedrzycki et al., 2009; Boulmay and Lottenberg, 2009; Kotila et al., 2015). In a large study on the epidemiology of pain in SCD, 31.4 percent of participants were identified as having an alcohol SUD (Levenson et al., 2007). Another study reported a 36 percent prevalence of cannabis use in SCD (Howard et al., 2005).
The assumption by providers and the general public is that the use of relatively high-dose opioids is universally associated with SUD in individuals with SCD. Because of this suspicion, the typical response of many clinicians is to withhold opioids, particularly in the acute setting, without a detailed assessment/evaluation of SUD. This response leads to significant conflict between patients and providers/health care systems, in addition to increased pain, suffering, complications from poorly treated pain, and the potential emergence of pseudo-addiction and related behaviors (Kotila et al., 2015).
In a disease where pain is characteristically severe and exposure to opioids is nearly universal, it is expected that some individuals with SCD will meet the criteria for SUD/OUD. Data from a large U.S. study show that 40 percent of SCD patients used opioids over a 12-month period (Han et al., 2018). However, opioid use has been constant and stable over time for the general population (2008–2013) (Ruta and Ballas, 2016). There was a 31.4 percent self-reported rate of SUD for alcohol in the PiSCES study (Levenson et al., 2007). Marijuana use is common in SCD, with one study finding that in a sample of 58 individuals living with SCD, 42 percent reported marijuana use in the past 2 years (Roberts et al., 2018). Deaths from opioid overdose in people living with SCD are markedly lower than in other non-cancer pain conditions, including low back pain, migraine, and fibromyalgia (Ruta and Ballas, 2016). All individuals should be assessed for the risk of SUD and provided access to optimal treatment for SUD and mental health disorders, if necessary.
Fatigue is described as “an overwhelming, debilitating, and sustained sense of exhaustion that decreases one’s ability to carry out daily activities, including the ability to work effectively and to function at one’s usual level in family or social roles” (Dantzer et al., 2014, p. 39) and is now recognized both in the general population and cancer literature as a significant morbidity. People with SCD frequently report chronic fatigue that is out of proportion to the degree of anemia and that can be debilitating, especially with older age. Fatigue negatively affects QOL and contributes to high rates of debilitation (Badawy et al., 2018a; Irvine et al., 1991). Fatigue in SCD causes poor vocation attainment, functional outcomes, relapses, and depression (Ameringer and Smith, 2011; Anderson et al., 2015).
There is limited understanding of the etiology of fatigue in SCD and no intervention studies that describe treatments to mitigate it.
Medical Comorbidities and SCD
Comorbidities compound SCD-related complications and adversely affect QOL. For example, asthma increases the risk of ACS, and obstructive
sleep apnea increases the risk of stroke. Type 2 diabetes and hypertension are common comorbidities in adults (Zhou et al., 2019).
It is unclear whether children and adults with SCD have an increased risk of cancer. Recent data from California suggest that children and adults with SCD are at an increased risk for developing hematologic malignancies but may be at lower risk for solid tumors (Brunson et al., 2017). This study reported a more than two-fold increased risk of leukemia, but the influence of long-term therapies, such as hydroxyurea (HU), could not be investigated.
Sudden Death in SCD
VOE is the most common presentation associated with death in those with SCD (Rizio et al., 2020). Death can be sudden and unexpected, often occurring at home following a recent discharge from the hospital (approximately 40 percent) or within 24 hours of presentation to the hospital (28 percent) (Manci et al., 2003; Niraimathi et al., 2016). Infection is a leading cause of death (33–48 percent) (Manci et al., 2003). Other causes of death include overt organ failure, ACS, and stroke (Platt et al., 1994).
Evidence of bone marrow fat emboli is common in many autopsy cases of sudden death. In a large autopsy study, there was significantly more organ injury than recognized before death, so the clinical presentation often does not reflect the severity of hidden chronic end-organ damage (Manci et al., 2003).
Traditionally, SCD was considered a disease of childhood, and health care management approaches were focused on reducing the overwhelmingly high infant and child mortality from infections (Davis et al., 1997). The premise for the creation of Comprehensive Sickle Cell Centers of Excellence, which began with the National Sickle Cell Anemia Control Act of 1972, was the provision of early diagnosis and supportive care (Bonds, 2005; Manley, 1984; Scott, 1979). Embedded in the field of pediatrics, the centers focused primarily on newborn screening (NBS), preventing death from infection by implementing evidence-based penicillin prophylaxis guidelines, and administering vaccinations against pneumococcal infection. An additional focus was mitigating the pain and suffering associated with acute complications of the disease.
Now that more than 98 percent of children with SCD are surviving into adulthood (Quinn et al., 2010), a new model of care that addresses the underlying pathophysiology, its changes with age, and its concomitant medical and psychosocial comorbidities is critically needed (and will be discussed in Chapter 5).
Prevention of Complications of SCD
Pneumococcal and Infection Prophylaxis
Splenic dysfunction occurs early in childhood; 84 percent of infants develop asplenia by 12 months of age (Thompson, 2011) and 94 percent of children by 5 years of age. Asplenia increases the risk of infection, particularly with encapsulated organisms, such as S. pneumoniae, H. influenzae type b, and Salmonella species (Pearson, 1977).
In 1986 prophylactic oral penicillin therapy was evaluated in children with SCD and shown to decrease mortality and the number and frequency of infections during childhood (by 84 percent) (Gaston et al., 1986). Since then, penicillin prophylaxis by 4 months of age has been recommended as the standard of care. A 1995 study of 400 patients with SCD evaluated discontinuing penicillin therapy in children over 5 years old who had taken penicillin for at least 2 years and also received pneumococcal 23-valent vaccination (Falletta et al., 1995). The equivalency of infection rates on and off penicillin between the study groups led to the recommendations that some people with SCD may be able to discontinue penicillin therapy safely after age 5, while continuing to be monitored for infection (Falletta et al., 1995).
Immunizations with conjugate vaccines against S. pneumoniae and H. influenza type b have also been critically important at significantly reducing bacteremia in SCD (Gaston et al., 1986; John et al., 1984; Knight-Madden and Serjeant, 2001); the introduction of pneumococcal vaccines led to a drop of the incidence of invasive pneumococcal disease by 90.8 percent in children less than 2 years old and 93.4 percent in children older than 5 years (Halasa et al., 2007).
Transcranial Doppler and Stroke Prevention
Robust data also exist for primary stroke prevention using TCD as a high-quality screening tool (Krejza et al., 2010) and preventative chronic transfusions for persons identified as high risk (Bernaudin et al., 2011; Enninful-Eghan et al., 2010; Fullerton et al., 2004). Analysis of data from The Stroke Prevention Trial in Sickle Cell Anemia also showed that participants with normal internal carotid artery or middle cerebral artery velocity had a higher risk of stroke (10 times greater) if they had an elevated anterior cerebral artery velocity compared with those with normal anterior cerebral artery velocity (Kwiatkowski et al., 2006). Discontinuing chronic transfusion led to a resurgence of stroke risk and subsequent strokes within 1 year (Adams and Brambilla, 2005), so there remains a strong evidence-based recommendation of continuing transfusions to prevent stroke recurrence in children with SCD (NHLBI, 1997).
HU, a drug originally developed to treat malignancies and myeloproliferative disorders, was tested for the treatment of SCD because of the discovery that patients on HU experienced increases in the production of fetal hemoglobin (HbF) (Charache et al., 1992; Platt et al., 1984). Higher HbF levels are partially protective against hemoglobin S polymerization, sickling, hemolysis, and their downstream effects. In addition, HU reduces leukocyte and platelet counts, thereby reducing cellular adhesion, and it acts as a nitric oxide donor. In 1995 the Multicenter Study of Hydroxyurea (MSH) found that HU led to a 44 percent reduction in the median number of VOEs and ACS episodes and also reduced transfusion requirements in patients with SCA (Charache et al., 1995). HU also reduced the number of severe VOEs requiring hospitalization and doubled both the time to first crisis and the time to second crisis (Charache et al., 1995). The MSH study led to the adoption of HU as a recommended therapeutic intervention for adults with SCA who have three or more moderate to severe VOEs in a 12-month period (Yawn et al., 2014). In the MSH trial there were no increased adverse effects compared with placebo, other than reversible myelosuppression (a decrease in bone marrow activity) (Charache et al., 1995). Longer-term data on HU in adults have confirmed its utility in mitigating acute SCD complications. A recent Cochrane review of 17 studies, including eight randomized controlled trials with 899 adults and children of all genotypes, found statistically significant improvements in VOE frequency, duration, and intensity and fewer hospital admissions, occurrences of ACS, and blood transfusions in the HU-treated groups (Nevitt et al., 2017). There remains insufficient evidence on the long-term benefits of HU in preventing chronic organ damage and on optimal dosing strategies, long-term risks (including effects on reproduction and fertility), and benefits in the hemoglobin SC genotype (Nevitt et al., 2017).
In 2011 the Pediatric Hydroxyurea Phase III Clinical Trial randomly assigned infants with HbSS or HbSb0-thalassemia, regardless of clinical severity, to receive placebo or HU for 2 years (McGann et al., 2012). The infants on HU had significant reductions in VOEs, dactylitis, and gastroenteritis as well as a reduced need for transfusions; HU was well tolerated, with no severe adverse events (Wang et al., 2011). The 12-month open label Hydroxyurea European Sickle Cell Disease Cohort study (ADDMEDICA SASA, 2015) assessed a new formulation of HU in pediatric patients. HU use increased HbF in the study population and reduced the percentage of patients with at least one VOE, one episode of ACS, and one hospitalization or transfusion after the 12-month period (FDA, 2017). In 2017 the U.S. Food and Drug Administration (FDA) approved the use of HU in pediatric patients (FDA, 2017).
No significant long-term toxicities have been detected in SCD cohorts followed for up to 15–20 years (Hankins et al., 2015; Steinberg et al., 2010), but concerns remain about more prolonged exposure, particularly in children; HU is a known carcinogen and teratogen in animals, albeit at higher doses than those used in patients (Sakano et al., 2001; Ziegler-Skylakakis et al., 1985). While women who have accidentally continued to take HU during pregnancy have not experienced embryonal toxicity and leukemogenesis has not been detected in SCD cohorts, continued surveillance for long-term toxicity remains important.
HU has been hailed as a “wonder drug” (Yurkiewicz, 2014) because of its multipronged mechanism of action and its efficacy and tolerable toxicity. Yet its adoption by the SCD community has proceeded at a slow pace, with providers under-prescribing the drug and patients remaining wary about its potential side effects, particularly with long-term use. Thus, the effectiveness of HU outside of clinical trials has been limited by poor adherence (Loiselle et al., 2016; Walsh et al., 2014). Research found that older adult individuals living with SCD are less likely to be using HU than individuals under age 30 (Sinha et al., 2018). Thus, HU education targeting older adults is clearly needed and may improve survival.
L-Glutamine and Other Emerging Therapies
FDA approved L-glutamine in 2017 to reduce acute complications in adults and children 5 years and older (Nevitt et al., 2017). L-glutamine is believed to enhance the capacity of the RBCs to handle oxidative stress. The Phase III study of L-glutamine in SCD involved 230 people 5–58 years old who received the treatment as a powder to be mixed with food or drink (Niihara et al., 2018). The outcomes demonstrated a 25 percent reduction in median VOEs compared with placebo and a 33 percent reduction in median hospitalizations compared with placebo. Adverse effects were minor and included low-grade nausea, noncardiac chest pain, fatigue, and musculoskeletal pain (Niihara et al., 2018). Approximately two-thirds of participants were also on HU, suggesting that L-glutamine may provide additional and potentially synergistic clinical benefits. L-glutamine is available in a powder formulation that needs to be mixed in with beverage or food, which may lead to poor adherence (Quinn, 2018). (Newly approved and emerging therapies are discussed in Chapter 7.)
RBC transfusions remain a cornerstone of supportive care for both acute and chronic life-threatening SCD complications. Transfusions provide non-sickle RBCs that correct the severe anemia from hemolysis and
decrease the proportion of HbS-containing RBCs. Together, these effects improve oxygen-carrying capacity and reduce the hypoxic perfusion deficit from vaso-occlusion.
Exchange transfusion is an effective way to improve the total hemoglobin while rapidly reducing HbS. Exchange transfusions can be either manual (Porter and Huehns, 1987) or done with an automated cell separator (Janes et al., 1997; Kuo et al., 2012; Lawson et al., 1999; Tsitsikas et al., 2016). Exchange transfusions necessitate exposure to multiple blood units from different donors and often require a large-bore, double lumen central venous catheter.
Prophylactic transfusions are critically important in the prevention of stroke and post-operative complications in SCD, and they improve the outcomes of severe complications such as ACS (Emre et al., 1995; Velasquez et al., 2009) and multi-organ failure syndrome. An ongoing, multi-center, international clinical trial (NCT04084080) is exploring whether exchange transfusions improve morbidity and mortality in patients with high-risk disease (defined by high tricuspid regurgitant velocity [TRV], the combination of moderately high TRV and high plasma N-terminal prohormone of brain natriuretic peptide, or the presence of CKD).
While potentially life-saving, transfusions in SCD patients may lead to significant complications, including iron overload, alloimmunization (the formation of antibodies against antigens present on the transfused RBCs) and hemolytic reactions, and infections. Iron overload is highly prevalent in SCD, with one study showing iron deposition in the liver, endocrine organs, cardiac muscle, and bones in 30 percent of 141 adults with SCD who died over a 25-year period; 7 percent of those deaths were attributed to iron overload (Darbari et al., 2006). In a larger cohort of 387 young adults with SCD, 45 percent of the 22 deaths were related to iron overload (Aduloju et al., 2008). Increased rates of alloimmunization have emerged (Rosse et al., 1990; Vichinsky et al., 1990) due to the wide genotypic variation in RBC phenotype among most blood donors, who are mostly Caucasian, and persons with SCD, who are predominantly of African American descent, causing a high risk of hemolytic transfusion reactions (Vichinsky et al., 1990).
Current guidelines recommend transfusing donor RBCs that are phenotypically antigen-matched to the patient for ABO, RhD, and the C, E, and K antigens in order to mitigate the risk of alloimmunization. For individuals with alloantibodies, blood group genotyping has helped decrease the risk of further alloimmunization (Ribeiro et al., 2009). Hemolytic transfusion reactions are harmful and potentially life-threatening complications of transfusions that occur in 4–10 percent of recipients (Mekontso Dessap et al., 2016; Narbey et al., 2017; Vidler et al., 2015). Occasionally, bystander hemolysis of native RBCs can also occur following transfusion, leading to a life-threatening hyperhemolytic crisis. This may present with severe anemia,
severe hemolysis, and respiratory distress with ACS (50 percent of cases) (Habibi et al., 2016).
Person-Centered Management Approaches of SCD
SCD is a complex multi-system disorder, and its management requires a comprehensive, person-centric, multidisciplinary, and interdisciplinary approach, with disease self-management at its core. Unfortunately, this model of care remains out of reach for most persons affected by SCD.
Whole-person SCD care includes both management of the effects of the disease—starting from primary, secondary, and tertiary prevention—and attention to psychosocial and QOL concerns. Whole-person care is critical to ensuring improved QOL, higher care quality (as reflected, for example, in the reduced use of acute care), increased patient satisfaction, and a reduced cost of care per patient. Okpala et al. (2002) recently suggested that to optimize clinical outcomes for individuals with SCD, care should be delivered by a multidisciplinary team that engages medical and nonmedical support services; care should include education for individuals living with SCD and their parents, genetic counseling, social services (e.g., vocational support provided by community-based organizations), infection prevention, dietary advice, psychotherapy, subspecialist medical care, maternal and child health, orthopedic and general surgery, pain control, physiotherapy, dental and eye care, drug dependency services, specialized nursing care, and the often-forgotten primary care. While the hematologist has historically been the primary driver of care coordination, given the current dearth of hematologists with SCD expertise, that role will need to be subsumed by any willing and committed provider who has received the proper training in SCD (Okpala et al., 2002).
Developing adequate self-management skills is essential for individuals to effectively manage a complex disease; disease self-management leads to increased medication adherence, improved pain management, and better health outcomes (Matthie et al., 2015; Nicholas et al., 2012). Recently, guidelines have been created with input from people living with SCD to improve disease knowledge in the SCD community (Cronin et al., 2018).
New tools for improving self-management and increasing health literacy can be found in the growing field of technology-based applications (mHealth or eHealth). Mobile or Internet-based methods allow for increased
engagement and quick dissemination of knowledge remotely, without the need for face-to-face visits with health care providers. mHealth aims to increase coping skills and adherence while decreasing the stigma and bias that may result from direct provider interactions. Studies have shown that mobile technologies are effective not only in high-income countries such as the United States but also in low- and middle-income countries (Abaza and Marschollek, 2017).
Although the committee was unable to find any studies that have extensively examined mHealth for SCD, a recent review found that mHealth applications showed feasibility and moderate improvement of medication adherence and coping with pain (Badawy et al., 2018b). However, most of the studies in the review were small and lacked clearly defined clinical outcomes, so further work is needed to better adapt mHealth technology to different SCD populations. In addition, an in-depth review of mHealth tools is necessary to ensure that data security and patient confidentiality are preserved. CDC has developed the Living Well With Sickle Cell Disease Self-Care Toolkit to provide SCD education, prevention tips, and self-management tools (e.g., pain diaries) (CDC, 2019).
While intense, episodic exercise may pose risks to patients with SCD (Campbell et al., 2009; Chirico et al., 2016), research has demonstrated that regular, moderate exercise training can be beneficial and may contribute to overall wellness and improved QOL. Data indicate that regular training reduces oxidative stress and thereby decreases the risks of developing chronic and acute complications (Connes et al., 2011). More and larger studies are needed to determine the best exercise training routines for providing functional benefits.
Another healthy lifestyle recommendation is to optimize water intake to maintain adequate hydration (NHLBI, 2002; Okomo and Meremikwu, 2017) because people living with SCD are more prone to dehydration. Westcott et al. (2017) found that only 31.8 percent of young adults with SCD were meeting fluid intake guidelines.
Optimizing nutritional intake is also paramount, although studies about the effects of specific micronutrients and macronutrients and dietary regimens in SCD are limited.
Screening for specific cognitive deficits in individuals with SCD may help predict later academic outcomes and stroke risk (Schatz et al., 2018) and may make it possible to deploy targeted cognitive interventions. Memory training
programs are a non-pharmacological approach to improving academic outcomes. One study demonstrated that individuals with SCD who completed a working memory training program exhibited improved visual and working memory compared with non-completers (Hardy et al., 2016). Additionally, a small cohort of children with SCD with cerebral infarcts who completed weekly combined tutoring and memory/learning strategies had improved memory and academic achievement compared with controls at 2 years of age (King et al., 2004).
Attention is another cognitive domain of focus in SCD. Although the current literature is limited, children with SCD in the United States have rates of attention deficit hyperactivity disorder prevalence that are between 19 and 40 percent (Acquazzino et al., 2017; Benton et al., 2011; Lance et al., 2015), which are much higher than the general pediatric population (approximately 10 percent) (Xu et al., 2018). Thus, specific treatments to improve attention may also be beneficial in SCD.
One to 3 million Americans have SCT, with the prevalence of SCT in the United States being 8–10 percent in African Americans and lower in many other racial/ethnic groups, including Hispanics, South Asians, Southern Europeans, and Middle Easterners.
SCT is not considered a disease and does not typically cause the multi-organ complications associated with SCD (Naik and Haywood, 2015). Following certain extreme triggers, however, individuals with SCT may experience medical problems, including an increased risk for prevalent and incident chronic renal disease, pulmonary embolism, and rhabdomyolysis (Naik et al., 2018).
Recent epidemiological studies have identified three primary areas that require further research to understand the clinical implications of SCT. The first is exercise-related complications, which include exertional rhabdomyolysis, heat-associated collapse, and sudden death. A retrospective review of 2.1 million military personnel from 1977 to 1981 found that 12 of 28 unexplained sudden deaths were in individuals with SCT, with a relative risk (RR) of death that was 39.8 (95% confidence interval [CI], 17–90; p < 0.001) times higher among recruits with SCT than among peers without SCT (Kark et al., 1987). A more recent retrospective review of 273 deaths in the National Collegiate Athletic Association from 2004 to 2008 found 13 deaths categorized as exertion related, 5 in athletes with SCT, with an RR of 29 (Harmon et al., 2012). All exercise-related deaths in individuals with SCT were associated with extreme exertion and intense exercise, and both studies failed to adjust for confounders. Thus, prospective well-designed cohort studies to better elucidate the true RR of exertional death in SCT are urgently needed.
Individuals with SCD may develop renal abnormalities; rates of hematuria (blood in the urine) are higher than in the general population, and hyposthenuria (an impaired urine concentrating ability) is common. Epidemiological studies have lent support to the notion that SCT may predispose one to CKD. In a pooled analysis of 15,975 self-identified African Americans from five prospective population-based cohort studies—the Atherosclerosis Risk in Communities, Jackson Heart Study, Women’s Health Initiative, Multi-Ethnic Study of Atherosclerosis, and Coronary Artery Risk Development in Young Adults—239 of the 2,233 individuals with CKD were found to have SCT, with a pooled adjusted odds ratio of 1.57 (95% CI 1.34–1.84) for CKD with SCT compared with those without SCT (Naik et al., 2014).
Further studies are required to better establish the relationship between SCT and CKD and the effect of SCT on the development of diabetic, hypertensive, and other risk-variant renal disease.
With universal NBS and mandatory screening of various adult populations for SCT, it is a moral obligation to conduct high-quality research to inform genetic counseling and personal and policy decisions, which must be conducted in a way that minimizes stigma. Robust, well-designed epidemiologic studies to answer critical questions about SCT are critical.
The American College of Obstetricians and Gynecologists recommends screening with a hemoglobin electrophoresis and complete blood count if there is suspicion for hemoglobinopathy based on ethnic background (ACOG, 2017). Some groups have recommended that, after screening, couples at risk for having a child with SCD should be offered genetic counseling and prenatal diagnosis testing (ACOG, 2007; Pecker and Naik, 2018).
In the United States, NBS for hemoglobinopathies was initiated in the 1990s to identify newborns with SCD and transfer them to SCD treatment centers for confirmatory testing and early interventions. Unfortunately, no national approach for informing families and providing information about the genetic and medical implications of SCT was in place at the time of NBS implementation and only limited progress has been made in this arena.
Pain is the hallmark of SCD and is a predictor of mortality and QOL in individuals affected by the disease. The pathophysiology of acute and chronic pain in SCD is complex, which is the main reason why treatment remains suboptimal. The treatment of pain is further complicated by racial, cognitive, and socioeconomic factors.
in the body and results in end-organ damage and symptoms that may be organ-related or constitutional, such as fatigue.
Individuals living with SCD may also experience various psychological symptoms, such as depression and anxiety, that often go undetected and therefore untreated. There is a strong link between psychological comorbidities and both acute and chronic pain. Neurocognitive deficits can also influence pain perception, ability to cope with pain, and response to treatment.
Evidence-based treatment strategies remain sparse for the prevention and management of the numerous complications of SCD. Current preventive strategies rest on infection prevention by vaccination and early penicillin prophylaxis and primary stroke prevention with chronic transfusion therapy. HU as a disease-modifying therapy has had a profound impact in reducing the rates of VOE and ACS. Transfusions also remain an important tool in the care of patients with SCD. Stem cell transplantation offers a cure, and new therapies have been recently approved or are under development (see Chapter 7). However, all treatments carry side effects, and poor medication adherence, partly stemming from mistrust of the medical environment, remains a significant concern.
A whole-person care approach has been proposed as the optimal means of providing care to individuals with SCD, with attention to lifestyle modification, behavioral interventions, and interventions aimed at alleviating cognitive deficits.
It is important that individuals with SCT receive the appropriate genetic counseling so that they understand the implications of their diagnosis. Further research is needed to fully understand the potential health-related complications associated with SCT.
Conclusion 4-1: Pain is the hallmark of SCD and is a predictor of mortality and quality of life in individuals affected by the disease. The pathophysiology of acute and chronic pain in SCD is complex and has not been completely elucidated, which has led to suboptimal care.
Conclusion 4-2: In addition to pain, complications associated with SCD are numerous. The disease affects almost every organ in the body and results in end-organ damage. Individuals living with SCD may experience various psychological symptoms, such as depression and anxiety, and most may go untreated. Therefore, it is critical to include a discussion of the critical role of addressing mental health in SCD.
Conclusion 4-3: There are limited data on the natural history of SCD and on how to address the growing disease burden in aging individuals with SCD.
Conclusion 4-4: There remains limited understanding of the health impact of SCT, particularly in certain high-risk groups, such as athletes and Army recruits. There are limited resources and no systematic strategies to track and counsel individuals who have been identified as SCT carriers at NBS.
Abaza, H., and M. Marschollek. 2017. mHealth application areas and technology combinations: A comparison of literature from high and low/middle income countries. Methods of Information in Medicine 56(7):e105–e122.
ACOG (American College of Obstetrics and Gynecology). 2007. ACOG practice bulletin no. 78: Hemoglobinopathies in pregnancy. Obstetrics & Gynecology 109(1):229–237.
ACOG. 2017. Carrier screening for genetic conditions. Committee opinion no. 691. Obstetrics & Gynecology 129:e41–e55.
Acquazzino, M. A., M. Miller, M. Myrvik, R. Newby, and J. P. Scott. 2017. Attention deficit hyperactivity disorder in children with sickle cell disease referred for an evaluation. Journal of Pediatric Hematology/Oncology 39(5):350–354.
Adam, S. S., C. M. Flahiff, S. Kamble, M. J. Telen, S. D. Reed, and L. M. De Castro. 2017. Depression, quality of life, and medical resource utilization in sickle cell disease. Blood Advances 1(23):1983–1992.
Adams, R. J., and D. Brambilla. 2005. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. New England Journal of Medicine 353(26):2769–2778.
ADDMEDICA SASA. 2015. European Sickle Cell Disease Cohort—Hydroxyurea (ESCORT–HU). https://clinicaltrials.gov/ct2/show/NCT02516579 (accessed April 4, 2019).
Aduloju, S., S. Palmer, and J. R. Eckman. 2008. Mortality in sickle cell patient transitioning from pediatric to adult program: 10 years Grady comprehensive sickle cell center experience. Blood 112(11):1426.
Alao, A. O., and M. Soderberg. 2002. Sickle cell disease and posttraumatic stress disorder. International Journal of Psychiatry in Medicine 32(1):97–101.
Alao, A. O., N. Westmoreland, and S. Jindal. 2003. Drug addiction in sickle cell disease: Case report. International Journal of Psychiatry in Medicine 33(1):97–101.
Ameringer, S., and W. R. Smith. 2011. Emerging biobehavioral factors of fatigue in sickle cell disease. Journal of Nursing Scholarship 43(1):22–29.
Anderson, L. M., T. M. Allen, C. D. Thornburg, and M. J. Bonner. 2015. Fatigue in children with sickle cell disease: Association with neurocognitive and social–emotional functioning and quality of life. Journal of Pediatric Hematology/Oncology 37(8):584–589.
Angst, M. S., and J. D. Clark. 2006. Opioid-induced hyperalgesia: A qualitative systematic review. Anesthesiology 104(3):570–587.
Anie, K. A. 2005. Psychological complications in sickle cell disease. British Journal of Haematology 129(6):723–729.
Anie, K. A., and J. Green. 2015. Psychological therapies for sickle cell disease and pain. Cochrane Database of Systematic Reviews(2):CD001916.
Anie, K. A., A. Steptoe, and D. H. Bevan. 2002. Sickle cell disease: Pain, coping and quality of life in a study of adults in the UK. British Journal of Health Psychology 7(Part 3):331–344.
Arduini, G. A. O., and A. B. Trovo de Marqui. 2018. Prevalence and characteristics of priapism in sickle cell disease. Hemoglobin 42(2):73–77.
ASH (American Society of Hematology). 2019. CDC issues key clarification on guideline for prescribing opioids for chronic pain. https://www.hematology.org/Newsroom/PressReleases/2019/9537.aspx (accessed November 19, 2019).
Ashley-Koch, A., C. C. Murphy, M. J. Khoury, and C. A. Boyle. 2001. Contribution of sickle cell disease to the occurrence of developmental disabilities: A population-based study. Genetics in Medicine 3(3):181–186.
Badawy, S. M., L. Barrera, S. Cai, and A. A. Thompson. 2018a. Association between participants’ characteristics, patient-reported outcomes, and clinical outcomes in youth with sickle cell disease. BioMed Research International 2018:8296139.
Badawy, S. M., R. M. Cronin, J. Hankins, L. Crosby, M. DeBaun, A. A. Thompson, and N. Shah. 2018b. Patient-centered eHealth interventions for children, adolescents, and adults with sickle cell disease: Systematic review. Journal of Medical Internet Research 20(7):e10940.
Baddam, S., I. Aban, L. Hilliard, T. Howard, D. Askenazi, and J. D. Lebensburger. 2017. Acute kidney injury during a pediatric sickle cell vaso-occlusive pain crisis. Pediatric Nephrology 32(8):1451–1456.
Baichoo, P., A. Asuncion, and G. El-Chaar. 2019. Intravenous acetaminophen for the management of pain during vaso-occlusive crises in pediatric patients. Pharmacy and Therapeutics 44(1):5–8.
Bakri, M. H., E. A. Ismail, G. O. Elsedfy, M. A. Amr, and A. Ibrahim. 2014. Behavioral impact of sickle cell disease in young children with repeated hospitalization. Saudi Journal of Anaesthesia 8(4):504–509.
Ballas, S. K. 2017. The use of cannabis by patients with sickle cell disease increased the frequency of hospitalization due to vaso-occlusive crises. Cannabis Cannabinoid Research 2(1):197–201.
Ballas, S. K. 2018. Comorbidities in aging patients with sickle cell disease. Clinical Hemorheology and Microcirculation 68(2–3):129–145.
Ballas, S. K., and E. D. Smith. 1992. Red blood cell changes during the evolution of the sickle cell painful crisis. Blood 79(8):2154–2163.
Ballas, S. K., K. Gupta, and P. Adams-Graves. 2012a. Sickle cell pain: A critical reappraisal. Blood 120(18):3647–3656.
Ballas, S. K., M. R. Kesen, M. F. Goldberg, G. A. Lutty, C. Dampier, I. Osunkwo, W. C. Wang, C. Hoppe, W. Hagar, D. S. Darbari, and P. Malik. 2012b. Beyond the definitions of the phenotypic complications of sickle cell disease: An update on management. Scientific World Journal 2012:949535.
Barabino, G. A., M. O. Platt, and D. K. Kaul. 2010. Sickle cell biomechanics. Annual Review of Biomedical Engineering 12:345–367.
Beiter, J. L., Jr., H. K. Simon, C. R. Chambliss, T. Adamkiewicz, and K. Sullivan. 2001. Intravenous ketorolac in the emergency department management of sickle cell pain and predictors of its effectiveness. Archives of Pediatrics & Adolescent Medicine 155(4):496–500.
Bellet, P. S., K. A. Kalinyak, R. Shukla, M. J. Gelfand, and D. L. Rucknagel. 1995. Incentive spirometry to prevent acute pulmonary complications in sickle cell diseases. New England Journal of Medicine 333(11):699–703.
Benton, T. D., R. Boyd, J. Ifeagwu, E. Feldtmose, and K. Smith-Whitley. 2011. Psychiatric diagnosis in adolescents with sickle cell disease: A preliminary report. Current Psychiatry Reports 13(2):111–115.
Benyamin, R., A. M. Trescot, S. Datta, R. Buenaventura, R. Adlaka, N. Sehgal, S. E. Glaser, and R. Vallejo. 2008. Opioid complications and side effects. Pain Physician 11(2 Suppl):S105–S120.
Berkelhammer, L. D., A. L. Williamson, S. D. Sanford, C. L. Dirksen, W. G. Sharp, A. S. Margulies, and R. A. Prengler. 2007. Neurocognitive sequelae of pediatric sickle cell disease: A review of the literature. Child Neuropsychology 13(2):120–131.
Bernaudin, F., S. Verlhac, C. Arnaud, A. Kamdem, S. Chevret, I. Hau, L. Coic, E. Leveille, E. Lemarchand, E. Lesprit, I. Abadie, N. Medejel, F. Madhi, S. Lemerle, S. Biscardi, J. Bardakdjian, F. Galacteros, M. Torres, M. Kuentz, C. Ferry, G. Socie, P. Reinert, and C. Delacourt. 2011. Impact of early transcranial Doppler screening and intensive therapy on cerebral vasculopathy outcome in a newborn sickle cell anemia cohort. Blood 117(4):1130–1140; quiz 1436.
Bhushan, D., K. Conner, J. M. Ellen, and E. M. S. Sibinga. 2015. Adjuvant acupuncture for youth with sickle cell pain: A proof of concept study. Medical Acupuncture 27(6):461–466.
Biedrzycki, O. J., D. Bevan, and S. Lucas. 2009. Fatal overdose due to prescription fentanyl patches in a patient with sickle cell/beta-thalassemia and acute chest syndrome: A case report and review of the literature. American Journal of Forensic Medicine and Pathology 30(2):188–190.
Blas, L., J. Roberti, J. Petroni, L. Reniero, and F. Cicora. 2019. Renal medullary carcinoma: A report of the current literature. Current Urology Reports 20(1):4.
Bodhise, P. B., M. Dejoie, Z. Brandon, S. Simpkins, and S. K. Ballas. 2004. Non-pharmacologic management of sickle cell pain. Hematology 9(3):235–237.
Bonds, D. R. 2005. Three decades of innovation in the management of sickle cell disease: The road to understanding the sickle cell disease clinical phenotype. Blood Review 19(2):99–110.
Borhade, M. B., and N. P. Kondamudi. 2019. Sickle cell crisis. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK526064 (accessed April 4, 2019).
Boulmay, B., and R. Lottenberg. 2009. Cocaine abuse complicating acute painful episodes in sickle cell disease. Southern Medical Journal 102(1):87–88.
Boyle, S. M., B. Jacobs, F. A. Sayani, and B. Hoffman. 2016. Management of the dialysis patient with sickle cell disease. Seminars in Dialysis 29(1):62–70.
Brandow, A. M., C. L. Stucky, C. A. Hillery, R. G. Hoffmann, and J. A. Panepinto. 2013. Patients with sickle cell disease have increased sensitivity to cold and heat. American Journal of Hematology 88(1):37–43.
Brandow, A. M., R. A. Farley, and J. A. Panepinto. 2014. Neuropathic pain in patients with sickle cell disease. Pediatric Blood & Cancer 61(3):512–517.
Brandow, A. M., R. A. Farley, M. Dasgupta, R. G. Hoffmann, and J. A. Panepinto. 2015. The use of neuropathic pain drugs in children with sickle cell disease is associated with older age, female sex, and longer length of hospital stay. Journal of Pediatric Hematology and Oncology 37(1):10–15.
Brousse, V., P. Buffet, and D. Rees. 2014. The spleen and sickle cell disease: The sick(led) spleen. British Journal of Haematology 166(2):165–176.
Brousseau, D. C., P. L. Owens, A. L. Mosso, J. A. Panepinto, and C. A. Steiner. 2010. Acute care utilization and rehospitalizations for sickle cell disease. JAMA 303(13):1288–1294.
Brunson, A., T. H. M. Keegan, H. Bang, A. Mahajan, S. Paulukonis, and T. Wun. 2017. Increased risk of leukemia among sickle cell disease patients in california. Blood 130(13):1597–1599.
Campbell, A., C. P. Minniti, M. Nouraie, M. Arteta, S. Rana, O. Onyekwere, C. Sable, G. Ensing, N. Dham, L. Luchtman-Jones, G. J. Kato, M. T. Gladwin, O. L. Castro, and V. R. Gordeuk. 2009. Prospective evaluation of haemoglobin oxygen saturation at rest and after exercise in paediatric sickle cell disease patients. British Journal of Haematology 147(3):352–359.
Campbell, C. M., G. Moscou-Jackson, C. P. Carroll, K. Kiley, C. Haywood, Jr., S. Lanzkron, M. Hand, R. R. Edwards, and J. A. Haythornthwaite. 2016. An evaluation of central sensitization in patients with sickle cell disease. Journal of Pain 17(5):617–627.
Carden, M. A., M. Fay, Y. Sakurai, B. McFarland, S. Blanche, C. DiPrete, C. H. Joiner, T. Sulchek, and W. A. Lam. 2017. Normal saline is associated with increased sickle red cell stiffness and prolonged transit times in a microfluidic model of the capillary system. Microcirculation 24(5):28106307.
Carden, M. A., D. C. Brousseau, F. A. Ahmad, J. Bennett, S. Bhatt, A. Bogie, K. Brown, T. C. Casper, L. L. Chapman, C. E. Chumpitazi, D. Cohen, C. Dampier, A. M. Ellison, H. Grasemann, R. W. Hickey, L. L. Hsu, S. Leibovich, E. Powell, R. Richards, S. Sarnaik, D. L. Weiner, and C. R. Morris. 2019. Normal saline bolus use in pediatric emergency departments is associated with poorer pain control in children with sickle cell anemia and vaso-occlusive pain. American Journal of Hematology 94(6):689–696.
Carroll, C. P. 2020. Opioid treatment for acute and chronic pain in patients with sickle cell disease. Neuroscience Letters 714:134534.
Carroll, C. P., S. Lanzkron, C. Haywood, Jr., K. Kiley, M. Pejsa, G. Moscou-Jackson, J. A. Haythornthwaite, and C. M. Campbell. 2016. Chronic opioid therapy and central sensitization in sickle cell disease. American Journal of Preventive Medicine 51(1 Suppl 1):S69–S77.
Catalano, A., G. Martino, N. Morabito, C. Scarcella, A. Gaudio, G. Basile, and A. Lasco. 2017. Pain in osteoporosis: From pathophysiology to therapeutic approach. Drugs & Aging 34(10):755–765.
Cataldo, G., S. Rajput, K. Gupta, and D. A. Simone. 2015. Sensitization of nociceptive spinal neurons contributes to pain in a transgenic model of sickle cell disease. Pain 156(4):722–730.
CDC (Centers for Disease Control and Prevention). 2019. Living well with sickle cell disease self-care toolkit. https://www.cdc.gov/ncbddd/sicklecell/documents/LivingWell-With-Sickle-Cell-Disease_Self-CareToolkit.pdf (accessed January 9, 2019).
Charache, S., and D. L. Page. 1967. Infarction of bone marrow in the sickle cell disorders. Annals of Internal Medicine 67(6):1195–1200.
Charache, S., G. J. Dover, R. D. Moore, S. Eckert, S. K. Ballas, M. Koshy, P. F. Milner, E. P. Orringer, G. Phillips, Jr., and O. S. Platt. 1992. Hydroxyurea: Effects on hemoglobin F production in patients with sickle cell anemia. Blood 79(10):2555–2565.
Charache, S., M. L. Terrin, R. D. Moore, G. J. Dover, F. B. Barton, S. V. Eckert, R. P. McMahon, and D. R. Bonds. 1995. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. New England Journal of Medicine 332(20):1317–1322.
Chirico, E. N., C. Faes, P. Connes, E. Canet-Soulas, C. Martin, and V. Pialoux. 2016. Role of exercise-induced oxidative stress in sickle cell trait and disease. Sports Medicine 46(5):629–639.
Citero, V. A., J. L. Levenson, D. K. McClish, V. E. Bovbjerg, P. L. Cole, B. A. Dahman, L. T. Penberthy, I. P. Aisiku, S. D. Roseff, and W. R. Smith. 2007. The role of catastrophizing in sickle cell disease—The PiSCES project. Pain 133(1–3):39–46.
Clark, R., N. B. Anderson, V. R. Clark, and D. R. Williams. 1999. Racism as a stressor for African Americans. A biopsychosocial model. American Psychologist 54(10):805–816.
Co, L. L., T. H. Schmitz, H. Havdala, A. Reyes, and M. P. Westerman. 1979. Acupuncture: An evaluation in the painful crises of sickle cell anaemia. Pain 7(2):181–185.
Cohen, S. P., P. J. Christo, S. Wang, L. Chen, M. P. Stojanovic, C. H. Shields, C. Brummett, and J. Mao. 2008. The effect of opioid dose and treatment duration on the perception of a painful standardized clinical stimulus. Regional Anesthesia & Pain Medicine 33(3):199–206.
Colloca, L., M. Flaten, and K. Meissner (eds.). 2013. Placebo and pain. New York: Academic Press.
Connes, P., R. Machado, O. Hue, and H. Reid. 2011. Exercise limitation, exercise testing and exercise recommendations in sickle cell anemia. Clinical Hemorheology and Microcirculation 49(1–4):151–163.
Conran, N., C. F. Franco-Penteado, and F. F. Costa. 2009. Newer aspects of the pathophysiology of sickle cell disease vaso-occlusion. Hemoglobin 33(1):1–16.
Cronin, R. M., T. L. Mayo-Gamble, S. J. Stimpson, S. M. Badawy, L. E. Crosby, J. Byrd, E. J. Volanakis, A. A. Kassim, J. L. Raphael, V. M. Murry, and M. R. DeBaun. 2018. Adapting medical guidelines to be patient-centered using a patient-driven process for individuals with sickle cell disease and their caregivers. BMC Hematology 18(1):12.
Cruz-Almeida, Y., C. D. King, B. R. Goodin, K. T. Sibille, T. L. Glover, J. L. Riley, A. Sotolongo, M. S. Herbert, J. Schmidt, B. J. Fessler, D. T. Redden, R. Staud, L. A. Bradley, and R. B. Fillingim. 2013. Psychological profiles and pain characteristics of older adults with knee osteoarthritis. Arthritis Care & Research 65(11):1786–1794.
Daly, B., M. C. Kral, R. T. Brown, D. Elkin, A. Madan-Swain, M. Mitchell, L. Crosby, D. Dematteo, A. Larosa, and S. Jackson. 2012. Ameliorating attention problems in children with sickle cell disease: A pilot study of methylphenidate. Journal of Developmental and Behavioral Pediatrics 33(3):244–251.
Dampier, C., P. LeBeau, S. Rhee, S. Lieff, K. Kesler, S. Ballas, Z. Rogers, W. Wang, and Comprehensive Sickle Cell Centers Clinical Trial Consortium site investigators. 2011. Health-related quality of life in adults with sickle cell disease (SCD): A report from the Comprehensive Sickle Cell Centers Clinical Trial Consortium. American Journal of Hematology 86(2):203–205.
Dampier, C., T. M. Palermo, D. S. Darbari, K. Hassell, W. Smith, and W. Zempsky. 2017. AAPT diagnostic criteria for chronic sickle cell disease pain. Journal of Pain 18(5):490–498.
Dang, N. C., C. Johnson, M. Eslami-Farsani, and L. J. Haywood. 2005. Bone marrow embolism in sickle cell disease: A review. American Journal of Hematology 79(1):61–67.
Dantzer, R., C. J. Heijnen, A. Kavelaars, S. Laye, and L. Capuron. 2014. The neuroimmune basis of fatigue. Trends in Neuroscience 37(1):39–46.
Darbari, D. S., and A. M. Brandow. 2017. Pain-measurement tools in sickle cell disease: Where are we now? Hematology: American Society of Hematology Education Program 2017(1):534–541.
Darbari, D. S., P. Kple-Faget, J. Kwagyan, S. Rana, V. R. Gordeuk, and O. Castro. 2006. Circumstances of death in adult sickle cell disease patients. American Journal of Hematology 81(11):858–863.
Darbari, D. S., Z. Wang, M. Kwak, M. Hildesheim, J. Nichols, D. Allen, C. Seamon, M. Peters-Lawrence, A. Conrey, M. K. Hall, G. J. Kato, and J. G. Taylor IV. 2013. Severe painful vaso-occlusive crises and mortality in a contemporary adult sickle cell anemia cohort study. PLOS ONE 8(11):e79923.
Davis, H., K. C. Schoendorf, P. J. Gergen, and R. M. Moore, Jr. 1997. National trends in the mortality of children with sickle cell disease, 1968 through 1992. American Journal of Public Health 87(8):1317–1322.
De Franceschi, L., M. D. Cappellini, and O. Olivieri. 2011. Thrombosis and sickle cell disease. Seminars in Thrombosis and Hemostasis 37(3):226–236.
DeBaun, M. R., D. L. Ghafuri, M. Rodeghier, P. Maitra, S. Chaturvedi, A. Kassim, and K. I. Ataga. 2019. Decreased median survival of adults with sickle cell disease after adjusting for left truncation bias: A pooled analysis. Blood 133(6):615–617.
Desai, A. A., A. R. Patel, H. Ahmad, J. V. Groth, T. Thiruvoipati, K. Turner, C. Yodwut, P. Czobor, N. Artz, R. F. Machado, J. G. N. Garcia, and R. M. Lang. 2014. Mechanistic insights and characterization of sickle cell disease-associated cardiomyopathy. Circulation: Cardiovascular Imaging 7(3):430–437.
Diggs, L. W. 1956. The crisis in sickle cell anemia: Hematologic studies. American Journal of Clinical Pathology 26(10):1109–1118.
Dinges, D. F., W. G. Whitehouse, E. C. Orne, P. B. Bloom, M. M. Carlin, N. K. Bauer, K. A. Gillen, B. S. Shapiro, K. Ohene-Frempong, C. Dampier, and M. T. Orne. 1997. Self-hypnosis training as an adjunctive treatment in the management of pain associated with sickle cell disease. International Journal of Clinical and Experimental Hypnosis 45(4):417–432.
Dobson, C. E., and M. W. Byrne. 2014. Original research: Using guided imagery to manage pain in young children with sickle cell disease. American Journal of Nursing 114(4):26–36; test 37, 47.
Dowell, D., T. M. Haegerich, and R. Chou. 2016. CDC guideline for prescribing opioids for chronic pain—United States, 2016. MMWR Recommendations and Reports 65(1):1–49.
Elmariah, H., M. E. Garrett, L. M. De Castro, J. C. Jonassaint, K. I. Ataga, J. R. Eckman, A. E. Ashley-Koch, and M. J. Telen. 2014. Factors associated with survival in a contemporary adult sickle cell disease cohort. American Journal of Hematology 89(5):530–535.
Elsurer, R., B. Afsar, and E. Mercanoglu. 2013. Bone pain assessment and relationship with parathyroid hormone and health-related quality of life in hemodialysis. Renal Failure 35(5):667–672.
Emre, U., S. T. Miller, M. Gutierez, P. Steiner, S. P. Rao, and M. Rao. 1995. Effect of transfusion in acute chest syndrome of sickle cell disease. Journal of Pediatrics 127(6):901–904.
Enninful-Eghan, H., R. H. Moore, R. Ichord, K. Smith-Whitley, and J. L. Kwiatkowski. 2010. Transcranial Doppler ultrasonography and prophylactic transfusion program is effective in preventing overt stroke in children with sickle cell disease. Journal of Pediatrics 157(3):479–484.
Ezenwa, M. O., R. E. Molokie, D. J. Wilkie, M. L. Suarez, and Y. Yao. 2015. Perceived injustice predicts stress and pain in adults with sickle cell disease. Pain Management Nursing 16(3):294–306.
Ezenwa, M. O., R. E. Molokie, Z. J. Wang, Y. Yao, M. L. Suarez, C. Pullum, J. M. Schlaeger, R. B. Fillingim, and D. J. Wilkie. 2016. Safety and utility of quantitative sensory testing among adults with sickle cell disease: Indicators of neuropathic pain? Pain Practice 16(3):282–293.
Ezenwa, M. O., Y. Yao, R. E. Molokie, Z. J. Wang, M. W. Mandernach, M. L. Suarez, and D. J. Wilkie. 2017. Coping with pain in the face of healthcare injustice in patients with sickle cell disease. Journal of Immigrant and Minority Health 19(6):1449–1456.
Ezenwa, M. O., R. E. Molokie, Z. J. Wang, Y. Yao, M. L. Suarez, B. Dyal, K. Abudawood, and D. J. Wilkie. 2018. Differences in sensory pain, expectation, and satisfaction reported by outpatients with cancer or sickle cell disease. Pain Management Nursing 19(4):322–332.
Falletta, J. M., G. M. Woods, J. I. Verter, G. R. Buchanan, C. H. Pegelow, R. V. Iyer, S. T. Miller, C. T. Holbrook, T. R. Kinney, E. Vichinsky, D. L. Becton, W. Wang, H. S. Johnstone, D. L. Wethers, G. H. Reaman, M. R. DeBaun, N. J. Grossman, K. Kalinyak, J. H. Jorgensen, A. Bjornson, M. D. Thomas, and C. Reid. 1995. Discontinuing penicillin prophylaxis in children with sickle cell anemia. Prophylactic penicillin study II. Journal of Pediatrics 127(5):685–690.
FDA (U.S. Food and Drug Administration). 2017. FDA approves hydroxyurea for treatment of pediatric patients with sickle cell anemia. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-hydroxyurea-treatment-pediatric-patients-sickle-cell-anemia (accessed April 4, 2019).
Field, J. J., J. Stocks, F. J. Kirkham, C. L. Rosen, D. J. Dietzen, T. Semon, J. Kirkby, P. Bates, S. Seicean, M. R. DeBaun, S. Redline, and R. C. Strunk. 2011. Airway hyperresponsiveness in children with sickle cell anemia. Chest 139(3):563–568.
Field, J. J., S. K. Ballas, C. M. Campbell, L. E. Crosby, C. Dampier, D. S. Darbari, D. K. McClish, W. R. Smith, and W. T. Zempsky. 2019. AAAPT diagnostic criteria for acute sickle cell disease pain. Journal of Pain 20(7):746–759.
Finan, P. H., B. R. Goodin, and M. T. Smith. 2013. The association of sleep and pain: An update and a path forward. Journal of Pain 14(12):1539–1552.
Fishbain, D. A., and A. Pulikal. 2019. Does opioid tapering in chronic pain patients result in improved pain or same pain vs increased pain at taper completion? A structured evidence-based systematic review. Pain Medicine 20(11):2179–2197.
Fonseca, G. H., R. Souza, V. M. Salemi, C. V. Jardim, and S. F. Gualandro. 2012. Pulmonary hypertension diagnosed by right heart catheterisation in sickle cell disease. European Respiratory Journal 39(1):112–118.
Franck, L. S., M. Treadwell, E. Jacob, and E. Vichinsky. 2002. Assessment of sickle cell pain in children and young adults using the adolescent pediatric pain tool. Journal of Pain and Symptom Management 23(2):114–120.
Fullerton, H. J., R. J. Adams, S. Zhao, and S. C. Johnston. 2004. Declining stroke rates in Californian children with sickle cell disease. Blood 104(2):336–339.
Gaartman, A., A. Sayedi, C. Van Tuijn, H. Heijboer, T. Netelenbos, B. Biemond, and E. Nur. 2019. Complications of extra fluid therapy (hyperhydration) in sickle cell patients during vaso-occlusive painful crisis. Paper presented at ASH Annual Meeting, December 7, Orange County Convention Center.
Gale, H. I., B. N. Setty, P. G. Sprinz, G. Doros, D. D. Williams, T. C. Morrison, T. A. Kalajian, P. Tu, S. N. Mundluru, M. N. Mehta, and I. Castro-Aragon. 2015. Implications of radiologic–pathologic correlation for gallbladder disease in children and young adults with sickle cell disease. Emergency Radiology 22(5):543–551.
Gangaraju, R., V. V. Reddy, and M. B. Marques. 2016. Fat embolism syndrome secondary to bone marrow necrosis in patients with hemoglobinopathies. Southern Medical Journal 109(9):549–553.
Gardner, C. S., and T. A. Jaffe. 2015. CT of gastrointestinal vasoocclusive crisis complicating sickle cell disease. American Journal of Roentgenology 204(5):994–999.
Gardner, C. S., and T. A. Jaffe. 2016. Acute gastrointestinal vaso-occlusive ischemia in sickle cell disease: CT imaging features and clinical outcome. Abdominal Radiology 41(3):466–475.
Gaston, M. H., J. I. Verter, G. Woods, C. Pegelow, J. Kelleher, G. Presbury, H. Zarkowsky, E. Vichinsky, R. Iyer, J. S. Lobel, S. Diamond, C. T. Holbrook, F. M. Gill, K. Ritchey, and J. M. Falletta. 1986. Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial. New England Journal of Medicine 314(25):1593–1599.
Gérardin, C., A. Moktefi, C. Couchoud, A. Duquesne, N. Ouali, P. Gataut, A. Karras, D. Anglicheau, C. Lefaucheur, L. Figueres, L. Albano, A. Lionet, M. Novion, M.-J. Ziliotis, M. Louis, A. Del Bello, M. Matignon, K. Dahan, A. Habibi, F. Galacteros, P. Bartolucci, P. Grimbert, and V. Audard. 2019. Survival and specific outcome of sickle cell disease patients after renal transplantation. British Journal of Haematology 187(5):676–680.
Gladwin, M. T. 2017. Cardiovascular complications in patients with sickle cell disease. Hematology: American Society of Hematology—Education Program 2017(1):423–430.
Gladwin, M. T., V. Sachdev, M. L. Jison, Y. Shizukuda, J. F. Plehn, K. Minter, B. Brown, W. A. Coles, J. S. Nichols, I. Ernst, L. A. Hunter, W. C. Blackwelder, A. N. Schechter, G. P. Rodgers, O. Castro, and F. P. Ognibene. 2004. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. New England Journal of Medicine 350(9):886–895.
Glaser, D. L., and F. S. Kaplan. 1997. Osteoporosis. Definition and clinical presentation. Spine 22(24 Suppl):12s–16s.
Goldstein-Leever, A., L. L. Cohen, C. Dampier, and S. Sil. 2018. Parent pain catastrophizing predicts child depressive symptoms in youth with sickle cell disease. Pediatric Blood & Cancer 65(7):e27027.
Gordeuk, V. R., O. L. Castro, and R. F. Machado. 2016. Pathophysiology and treatment of pulmonary hypertension in sickle cell disease. Blood 127(7):820–828.
Habibi, A., A. Mekontso-Dessap, C. Guillaud, M. Michel, K. Razazi, M. Khellaf, B. Chami, D. Bachir, C. Rieux, G. Melica, B. Godeau, F. Galacteros, P. Bartolucci, and F. Pirenne. 2016. Delayed hemolytic transfusion reaction in adult sickle-cell disease: Presentations, outcomes, and treatments of 99 referral center episodes. American Journal of Hematology 91(10):989–994.
Halasa, N. B., S. M. Shankar, T. R. Talbot, P. G. Arbogast, E. F. Mitchel, W. C. Wang, W. Schaffner, A. S. Craig, and M. R. Griffin. 2007. Incidence of invasive pneumococcal disease among individuals with sickle cell disease before and after the introduction of the pneumococcal conjugate vaccine. Clinical Infectious Diseases 44(11):1428–1433.
Han, J., J. Zhou, S. L. Saraf, V. R. Gordeuk, and G. S. Calip. 2018. Characterization of opioid use in sickle cell disease. Pharmacoepidemiology and Drug Safety 27(5):479–486.
Hankins, J. S., M. B. McCarville, A. Rankine-Mullings, M. E. Reid, C. L. Lobo, P. G. Moura, S. Ali, D. P. Soares, K. Aldred, D. W. Jay, B. Aygun, J. Bennett, G. Kang, J. C. Goldsmith, M. P. Smeltzer, J. M. Boyett, and R. E. Ware. 2015. Prevention of conversion to abnormal transcranial Doppler with hydroxyurea in sickle cell anemia: A Phase III international randomized clinical trial. American Journal of Hematology 90(12):1099–1105.
Hardwick, W. E., Jr., T. G. Givens, K. W. Monroe, W. D. King, and D. Lawley. 1999. Effect of ketorolac in pediatric sickle cell vaso-occlusive pain crisis. Pediatric Emergency Care 15(3):179–182.
Hardy, S. J., K. K. Hardy, J. C. Schatz, A. L. Thompson, and E. R. Meier. 2016. Feasibility of home-based computerized working memory training with children and adolescents with sickle cell disease. Pediatric Blood & Cancer 63(9):1578–1585.
Harmon, K. G., J. A. Drezner, D. Klossner, and I. M. Asif. 2012. Sickle cell trait associated with a RR of death of 37 times in National Collegiate Athletic Association football athletes: A database with 2 million athlete-years as the denominator. British Journal of Sports Medicine 46(5):325–330.
Hasan, S. P., S. Hashmi, M. Alhassen, W. Lawson, and O. Castro. 2003. Depression in sickle cell disease. Journal of the National Medical Association 95(7):533–537.
Hassell, K. 2005. Pregnancy and sickle cell disease. Hematology/Oncology Clinics of North America 19(5):vii–viii, 903–916.
Hay, J. L., J. M. White, F. Bochner, A. A. Somogyi, T. J. Semple, and B. Rounsefell. 2009. Hyperalgesia in opioid-managed chronic pain and opioid-dependent patients. Journal of Pain 10(3):316–322.
Haywood, C., Jr., M. Diener-West, J. Strouse, C. P. Carroll, S. Bediako, S. Lanzkron, J. Haythornthwaite, G. Onojobi, and M. C. Beach. 2014. Perceived discrimination in health care is associated with a greater burden of pain in sickle cell disease. Journal of Pain and Symptom Management 48(5):934–943.
Haywood, L. J. 2009. Cardiovascular function and dysfunction in sickle cell anemia. Journal of the National Medical Association 101(1):24–30.
Helmerhorst, H. J., M. J. Schultz, P. H. van der Voort, E. de Jonge, and D. J. van Westerloo. 2015. Bench-to-bedside review: The effects of hyperoxia during critical illness. Critical Care 19:284.
Hofmann, M., M. de Montalembert, B. Beauquier-Maccotta, P. de Villartay, and B. Golse. 2007. Posttraumatic stress disorder in children affected by sickle-cell disease and their parents. American Journal of Hematology 82(2):171–172.
Hood, A. M., A. A. King, M. E. Fields, A. L. Ford, K. P. Guilliams, M. L. Hulbert, J. M. Lee, and D. A. White. 2019. Higher executive abilities following a blood transfusion in children and young adults with sickle cell disease. Pediatric Blood & Cancer 66(10):e27899.
Howard, J., K. A. Anie, A. Holdcroft, S. Korn, and S. C. Davies. 2005. Cannabis use in sickle cell disease: A questionnaire study. British Journal of Haematology 131(1):123–128.
Howard, J., M. Malfroy, C. Llewelyn, L. Choo, R. Hodge, T. Johnson, S. Purohit, D. C. Rees, L. Tillyer, I. Walker, K. Fijnvandraat, M. Kirby-Allen, E. Spackman, S. C. Davies, and L. M. Williamson. 2013. The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: A randomised, controlled, multicentre clinical trial. Lancet 381(9870):930–938.
Indik, J. H., V. Nair, R. Rafikov, I. S. Nyotowidjojo, J. Bisla, M. Kansal, D. S. Parikh, M. Robinson, A. Desai, M. Oberoi, A. Gupta, T. Abbasi, Z. Khalpey, A. R. Patel, R. M. Lang, S. C. Dudley, B. R. Choi, J. G. Garcia, R. F. Machado, and A. A. Desai. 2016. Associations of prolonged QTC in sickle cell disease. PLOS ONE 11(10):e0164526.
Ingram, V. M. 2004. Sickle-cell anemia hemoglobin: The molecular biology of the first “molecular disease”—The crucial importance of serendipity. Genetics 167(1):1–7.
Irvine, D. M., L. Vincent, N. Bubela, L. Thompson, and J. Graydon. 1991. A critical appraisal of the research literature investigating fatigue in the individual with cancer. Cancer Nursing 14(4):188–199.
Janes, S., M. Pocock, E. Bishop, and D. Bevan. 1997. Automated red cell exchange in sickle cell disease. British Journal of Haematology 97:256–258.
Jansson, L., S. Lavstedt, and L. Frithiof. 2002. Relationship between oral health and mortality rate. Journal of Clinical Periodontology 29(11):1029–1034.
Jenerette, C., M. Funk, and C. Murdaugh. 2005. Sickle cell disease: A stigmatizing condition that may lead to depression. Issues in Mental Health Nursing 26(10):1081–1101.
John, A. B., A. Ramlal, H. Jackson, G. H. Maude, A. W. Sharma, and G. R. Serjeant. 1984. Prevention of pneumococcal infection in children with homozygous sickle cell disease. BMJ 288(6430):1567–1570.
Jonassaint, C. R., V. L. Jones, S. Leong, and G. M. Frierson. 2016. A systematic review of the association between depression and health care utilization in children and adults with sickle cell disease. British Journal of Haematology 174(1):136–147.
Kabat-Zinn, J. 2009. Wherever you go, there you are: Mindfulness meditation in everyday life. New York: Hachette Books.
Kalogeris, T., C. P. Baines, M. Krenz, and R. J. Korthuis. 2012. Cell biology of ischemia/reperfusion injury. International Review of Cell and Molecular Biology 298:229–317.
Kanter, J., and R. Kruse-Jarres. 2013. Management of sickle cell disease from childhood through adulthood. Blood Reviews 27(6):279–287.
Kark, J. A., D. M. Posey, H. R. Schumacher, and C. J. Ruehle. 1987. Sickle-cell trait as a risk factor for sudden death in physical training. New England Journal of Medicine 317(13):781–787.
Kassim, A. A., S. Pruthi, M. Day, M. Rodeghier, M. C. Gindville, M. A. Brodsky, M. R. DeBaun, and L. C. Jordan. 2016. Silent cerebral infarcts and cerebral aneurysms are prevalent in adults with sickle cell anemia. Blood 127(16):2038–2040.
Kater, A. P., H. Heijboer, M. Peters, T. Vogels, M. H. Prins, and H. S. Heymans. 1999. Quality of life in children with sickle cell disease in Amsterdam area. Nederlands Tijdschrift voor Geneeskunde 143(41):2049–2053.
Kato, G. J., M. H. Steinberg, and M. T. Gladwin. 2017. Intravascular hemolysis and the pathophysiology of sickle cell disease. Journal of Clinical Investigation 127(3):750–760.
Kauf, T. L., T. D. Coates, L. Huazhi, N. Mody-Patel, and A. G. Hartzema. 2009. The cost of health care for children and adults with sickle cell disease. American Journal of Hematology 84(6):323–327.
Kawadler, J. M., J. D. Clayden, C. A. Clark, and F. J. Kirkham. 2016. Intelligence quotient in paediatric sickle cell disease: A systematic review and meta-analysis. Developmental Medicine and Child Neurology 58(7):672–679.
King, A., D. White, M. Armstrong, R. McKinstry, M. Noetzel, and M. R. Debaun. 2004. An educational remediation program benefits children with sickle cell disease and cerebral infarcts. Pediatric Research 56(4):668.
Knight-Madden, J., and G. R. Serjeant. 2001. Invasive pneumococcal disease in homozygous sickle cell disease: Jamaican experience 1973–1997. Journal of Pediatrics 138(1):65–70.
Kotila, T. R., O. E. Busari, V. Makanjuola, and O. R. Eyelade. 2015. Addiction or pseudoaddiction in sickle cell disease patients: Time to decide—A case series. Annals of Ibadan Postgraduate Medicine 13(1):44–47.
Krejza, J., R. Chen, G. Romanowicz, J.L. Kwiatkowski, R. Ichord, M. Arkuszewski, R. Zimmerman, K. Ohene-Frempong, L. Desiderio, and E.R. Melhem. 2010. Sickle cell disease and transcranial Doppler imaging: Inter-hemispheric differences in blood flow Doppler parameters. Stroke 42:81–86.
Kuo, K., and A. B. Caughey. 2016. Contemporary outcomes of sickle cell disease in pregnancy. American Journal of Obstetrics and Gynecology 215(4):e501–e505.
Kuo, K. H. M., R. Ward, J. Howard, and P. Telfer. 2012. A comparison of chronic manual and automated red blood cell exchange transfusion in sickle cell disease patients from two comprehensive care centres in the United Kingdom. Blood 120(21):3430.
Kwiatkowski, J. L., S. Granger, D. J. Brambilla, R.C. Brown, S. T. Miller, R. J. Adams, and STOP Trial Investigators. 2006. Elevated blood flow velocity in the anterior cerebral artery and stroke risk in sickle cell disease: Extended analysis from the STOP trial. British Journal of Haematology 134(3):333–339.
Lance, E. I., A. M. Comi, M. V. Johnston, J. F. Casella, and B. K. Shapiro. 2015. Risk factors for attention and behavioral issues in pediatric sickle cell disease. Clinical Pediatrics 54(11):1087–1093.
Lanzkron, S., J. Little, J. Field, J. R. Shows, H. Wang, R. Seufert, J. Brooks, R. Varadhan, C. Haywood, Jr., M. Saheed, C. Y. Huang, B. Griffin, S. Frymark, A. Piehet, D. Robertson, M. Proudford, A. Kincaid, C. Green, L. Burgess, M. Wallace, and J. Segal. 2018. Increased acute care utilization in a prospective cohort of adults with sickle cell disease. Blood Advances 2(18):2412–2417.
Laurence, B., C. Haywood, Jr., and S. Lanzkron. 2013. Dental infections increase the likelihood of hospital admissions among adult patients with sickle cell disease. Community Dental Health 30(3):168–172.
Lawson, S., S. Oakley, N. A. Smith, and D. Bareford. 1999. Red cell exchange in sickle cell disease. Clinical and Laboratory Haematology 21:99–102.
Lee, M., S. M. Silverman, H. Hansen, V. B. Patel, and L. Manchikanti. 2011. A comprehensive review of opioid-induced hyperalgesia. Pain Physician 14(2):145–161.
Lemanek, K. L., M. Ranalli, and C. Lukens. 2009. A randomized controlled trial of massage therapy in children with sickle cell disease. Journal of Pediatric Psychology 34(10):1091–1096.
Levenson, J. L. 2008. Psychiatric issues in adults with sickle cell disease. Primary Psychiatry 15(5):45–49.
Levenson, J. L., D. K. McClish, B. A. Dahman, L. T. Penberthy, V. E. Bovbjerg, I. P. Aisiku, S. D. Roseff, and W. R. Smith. 2007. Alcohol abuse in sickle cell disease: The PiSCES project. American Journal on Addiction 16(5):383–388.
Levenson, J. L., D. K. McClish, B. A. Dahman, V. E. Bovbjerg, V. D. A. Citero, L. T. Penberthy, I. P. Aisiku, J. D. Roberts, S. D. Roseff, and W. R. Smith. 2008. Depression and anxiety in adults with sickle cell disease: The PiSCES project. Psychosomatic Medicine 70(2):192–196.
Loiselle, K., J. L. Lee, L. Szulczewski, S. Drake, L. E. Crosby, and A. L. Pai. 2016. Systematic and meta-analytic review: Medication adherence among pediatric patients with sickle cell disease. Journal of Pediatric Psychology 41(4):406–418.
Lu, K., M. C. Cheng, X. Ge, A. Berger, D. Xu, G. J. Kato, and C. P. Minniti. 2014. A retrospective review of acupuncture use for the treatment of pain in sickle cell disease patients: Descriptive analysis from a single institution. Clinical Journal of Pain 30(9):825–830.
Lubega, F. A., M. S. DeSilva, D. Munube, R. Nkwine, J. Tumukunde, P. K. Agaba, M. T. Nabukenya, F. Bulamba, and T. S. Luggya. 2018. Low dose ketamine versus morphine for acute severe vaso occlusive pain in children: A randomized controlled trial. Scandinavian Journal of Pain 18(1):19–27.
Lukoo, R. N., R. M. Ngiyulu, G. L. Mananga, J. L. Gini-Ehungu, P. M. Ekulu, P. M. Tshibassu, and M. N. Aloni. 2015. Depression in children suffering from sickle cell anemia. Journal of Pediatric Hematology/Oncology 37(1):20–24.
Manci, E. A., D. E. Culberson, Y. M. Yang, T. M. Gardner, R. Powell, J. Haynes, Jr., A. K. Shah, V. N. Mankad, and investigators of the Cooperative Study of Sickle Cell Disease. 2003. Causes of death in sickle cell disease: An autopsy study. British Journal of Haematology 123(2):359–365.
Mandese, V., E. Bigi, P. Bruzzi, G. Palazzi, B. Predieri, L. Lucaccioni, M. Cellini, and L. Iughetti. 2019. Endocrine and metabolic complications in children and adolescents with sickle cell disease: An Italian cohort study. BMC Pediatrics 19(1):56.
Manley, A. F. 1984. Legislation and funding for sickle cell services, 1972–1982. American Journal of Pediatric Hematology/Oncology 6(1):67–71.
Mantadakis, E., J. D. Cavender, Z. R. Rogers, D. H. Ewalt, and G. R. Buchanan. 1999. Prevalence of priapism in children and adolescents with sickle cell anemia. Journal of Pediatric Hematology/Oncology 21(6):518–522.
Martins, W. A., H. F. Lopes, F. M. Consolim-Colombo, F. Gualandro Sde, E. Arteaga-Fernandez, and C. Mady. 2012. Cardiovascular autonomic dysfunction in sickle cell anemia. Autonomic Neuroscience 166(1–2):54–59.
Matthie, N., C. Jenerette, and S. McMillan. 2015. Role of self-care in sickle cell disease. Pain Management Nursing 16(3):257–266.
McClellan, A. C., J. C. Luthi, J. R. Lynch, J. M. Soucie, R. Kulkarni, A. Guasch, E. D. Huff, D. Gilbertson, W. M. McClellan, and M. R. DeBaun. 2012. High one year mortality in adults with sickle cell disease and end-stage renal disease. British Journal of Haematology 159(3):360–367.
McClish, D. K., L. T. Penberthy, V. E. Bovbjerg, J. D. Roberts, I. P. Aisiku, J. L. Levenson, S. D. Roseff, and W. R. Smith. 2005. Health related quality of life in sickle cell patients: The PiSCES project. Health and Quality of Life Outcomes 3:50.
McGann, P. T., J. M. Flanagan, T. A. Howard, S. D. Derlinger, J. He, A. S. Kulharya, B. W. Thompson, and R. E. Ware. 2012. Genotoxicity associated with hydroxyurea exposure in infants with sickle cell anemia: Results from the BABY-HUG Phase III clinical trial. Pediatric Blood Cancer 59(2):254–257.
McMahon, S., M. Koltzenburg, I. Tracey, and D. Turk. 2013. Wall & Melzack’s textbook of pain, 6th ed. Philadelphia, PA: Saunders.
Meghani, S. H., and N. Vapiwala. 2018. Bridging the critical divide in pain management guidelines from the CDC, NCCN, and ASCO for cancer survivors. JAMA Oncology 4(10):1323–1324.
Mehari, A., and E. S. Klings. 2016. Chronic pulmonary complications of sickle cell disease. Chest 149(5):1313–1324.
Mehari, A., M. T. Gladwin, X. Tian, R. F. Machado, and G. J. Kato. 2012. Mortality in adults with sickle cell disease and pulmonary hypertension. JAMA 307(12):1254–1256.
Mekontso Dessap, A., F. Pirenne, K. Razazi, S. Moutereau, S. Abid, C. Brun-Buisson, B. Maitre, M. Michel, F. Galacteros, P. Bartolucci, and A. Habibi. 2016. A diagnostic nomogram for delayed hemolytic transfusion reaction in sickle cell disease. American Journal of Hematology 91(12):1181–1184.
Moody, K., B. Abrahams, R. Baker, R. Santizo, D. Manwani, V. Carullo, D. Eugenio, and A. Carroll. 2017. A randomized trial of yoga for children hospitalized with sickle cell vasoocclusive crisis. Journal of Pain and Symptom Management 53(6):1026–1034.
Myers, C. D., M. E. Robinson, T. H. Guthrie, S. P. Lamp, and R. Lottenberg. 1999. Adjunctive approaches for sickle cell chronic pain. Alternative Health Practitioner 5(3):203–212.
Myrvik, M. P., A. D. Campbell, M. M. Davis, and J. L. Butcher. 2012. Impact of psychiatric diagnoses on hospital length of stay in children with sickle cell anemia. Pediatric Blood & Cancer 58(2):239–243.
Myrvik, M. P., L. M. Burks, R. G. Hoffman, M. Dasgupta, and J. A. Panepinto. 2013. Mental health disorders influence admission rates for pain in children with sickle cell disease. Pediatric Blood & Cancer 60(7):1211–1214.
Naik, R. P., and C. Haywood, Jr. 2015. Sickle cell trait diagnosis: Clinical and social implications. Hematology: American Society of Hematology—Education Program 2015:160–167.
Naik, R. P., V. K. Derebail, M. E. Grams, N. Franceschini, P. L. Auer, G. M. Peloso, B. A. Young, G. Lettre, C. A. Peralta, R. Katz, H. I. Hyacinth, R. C. Quarells, M. L. Grove, A. G. Bick, P. Fontanillas, S. S. Rich, J. D. Smith, E. Boerwinkle, W. D. Rosamond, K. Ito, S. Lanzkron, J. Coresh, A. Correa, G. E. Sarto, N. S. Key, D. R. Jacobs, S. Kathiresan, K. Bibbins-Domingo, A. V. Kshirsagar, J. G. Wilson, and A. P. Reiner. 2014. Association of sickle cell trait with chronic kidney disease and albuminuria in African Americans. JAMA 312(20):2115–2125.
Naik, R. P., K. Smith-Whitley, K. L. Hassell, N. I. Umeh, M. de Montalembert, P. Sahota, C. Haywood, Jr., J. Jenkins, M. A. Lloyd-Puryear, C. H. Joiner, V. L. Bonham, and G. J. Kato. 2018. Clinical outcomes associated with sickle cell trait: A systematic review. Annals of Internal Medicine 169(9):619–627.
Narbey, D., A. Habibi, P. Chadebech, A. Mekontso-Dessap, M. Khellaf, J. D. Lelievre, B. Godeau, M. Michel, F. Galacteros, R. Djoudi, P. Bartolucci, and F. Pirenne. 2017. Incidence and predictive score for delayed hemolytic transfusion reaction in adult patients with sickle cell disease. American Journal of Hematology 92(12):1340–1348.
NASEM (National Academies of Sciences, Engineering, and Medicine). 2017. The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. Washington, DC: The National Academies Press.
Nevitt, S. J., A. P. Jones, and J. Howard. 2017. Hydroxyurea (hydroxycarbamide) for sickle cell disease. Cochrane Database of Systematic Reviews 4:CD002202.
NHLBI (National Heart, Lung, and Blood Institute). 1997. Clinical alert: Periodic transfusions lower stroke risk in children with sickle cell anemia. https://www.nlm.nih.gov/databases/alerts/sickle97.html (accessed November 19, 2019).
NHLBI. 2002. The management of sickle cell disease. https://www.nhlbi.nih.gov/files/docs/guidelines/sc_mngt.pdf (accessed April 4, 2020).
NHLBI. 2014. Evidence-based management of sickle cell disease: Expert panel report. https://www.nhlbi.nih.gov/sites/default/files/media/docs/sickle-cell-disease-report%20020816_0.pdf (accessed June 18, 2019).
Nicholas, M. K., A. Asghari, M. Corbett, R. J. Smeets, B. M. Wood, S. Overton, C. Perry, L. E. Tonkin, and L. Beeston. 2012. Is adherence to pain self-management strategies associated with improved pain, depression and disability in those with disabling chronic pain? European Journal of Pain 16(1):93–104.
Niihara, Y., S. T. Miller, J. Kanter, S. Lanzkron, W. R. Smith, L. L. Hsu, V. R. Gordeuk, K. Viswanathan, S. Sarnaik, I. Osunkwo, E. Guillaume, S. Sadanandan, L. Sieger, J. L. Lasky, E. H. Panosyan, O. A. Blake, T. N. New, R. Bellevue, L. T. Tran, R. L. Razon, C. W. Stark, L. D. Neumayr, E. P. Vichinsky, for the investigators of the Phase 3 Trial of l-Glutamine in Sickle Cell Disease. 2018. A Phase 3 trial of L-glutamine in sickle cell disease. New England Journal of Medicine 379(3):226–235.
Niraimathi, M., R. Kar, S. E. Jacob, and D. Basu. 2016. Sudden death in sickle cell anaemia: Report of three cases with brief review of literature. Indian Journal of Hematology & Blood Transfusion 32(Suppl 1):258–261.
Niscola, P., F. Sorrentino, L. Scaramucci, P. de Fabritiis, and P. Cianciulli. 2009. Pain syndromes in sickle cell disease: An update. Pain Medicine 10(3):470–480.
Nnoli, A., N. S. Seligman, K. Dysart, J. K. Baxter, and S. K. Ballas. 2018. Opioid utilization by pregnant women with sickle cell disease and the risk of neonatal abstinence syndrome. Journal of the National Medical Association 110(2):163–168.
Nouraie, M., J. S. Lee, Y. Zhang, T. Kanias, X. Zhao, Z. Xiong, T. B. Oriss, Q. Zeng, G. J. Kato, J. S. Gibbs, M. E. Hildesheim, V. Sachdev, R. J. Barst, R. F. Machado, K. L. Hassell, J. A. Little, D. E. Schraufnagel, L. Krishnamurti, E. Novelli, R. E. Girgis, C. R. Morris, E. B. Rosenzweig, D. B. Badesch, S. Lanzkron, O. L. Castro, J. C. Goldsmith, V. R. Gordeuk, M. T. Gladwin, and Walk-PHASST investigators and patients. 2013. The relationship between the severity of hemolysis, clinical manifestations and risk of death in 415 patients with sickle cell anemia in the U.S. and Europe. Haematologica 98(3):464–472.
Novelli, E. M., and M. T. Gladwin. 2016. Crises in sickle cell disease. Chest 149(4):1082–1093.
Ogunsile, F. J., S. M. Bediako, J. Nelson, C. Cichowitz, T. Yu, C. Patrick Carroll, K. Stewart, R. Naik, C. Haywood, Jr., and S. Lanzkron. 2019. Metabolic syndrome among adults living with sickle cell disease. Blood Cells, Molecules, and Disease 74:25–29.
Ohene-Frempong, K., S. J. Weiner, L. A. Sleeper, S. T. Miller, S. Embury, J. W. Moohr, D. L. Wethers, C. H. Pegelow, and F. M. Gill. 1998. Cerebrovascular accidents in sickle cell disease: Rates and risk factors. Blood 91(1):288–294.
Okomo, U., and M. M. Meremikwu. 2007. Fluid replacement therapy for acute episodes of pain in people with sickle cell disease. Cochrane Database of Systematic Reviews 2:CD005406.
Okomo, U., and M. M. Meremikwu. 2017. Fluid replacement therapy for acute episodes of pain in people with sickle cell disease. Cochrane Database of Systematic Reviews 7:CD005406.
Okpala, I., V. Thomas, N. Westerdale, T. Jegede, K. Raj, S. Daley, H. Costello-Binger, J. Mullen, C. Rochester-Peart, S. Helps, E. Tulloch, M. Akpala, M. Dick, S. Bewley, M. Davies, and I. Abbs. 2002. The comprehensiveness care of sickle cell disease. European Journal of Haematology 68(3):157–162.
Okwerekwu, I., and J. A. Skirvin. 2018. Sickle cell disease pain management. U.S. Pharmacist 43(3):12–18.
O’Leary, J. D., M. W. Crawford, I. Odame, G. D. Shorten, and P. A. McGrath. 2014. Thermal pain and sensory processing in children with sickle cell disease. Clinical Journal of Pain 30(3):244–250.
Osunkwo, I. 2011. Complete resolution of sickle cell chronic pain with high dose vitamin D therapy: A case report and review of the literature. Journal of Pediatric Hematology/Oncology 33(7):549–551.
Osunkwo, I., E. I. Hodgman, K. Cherry, C. Dampier, J. Eckman, T. R. Ziegler, S. Ofori-Acquah, and V. Tangpricha. 2011. Vitamin D deficiency and chronic pain in sickle cell disease. British Journal of Haematology 153(4):538–540.
Osunkwo, I., P. Veeramreddy, J. Arnall, R. Crawford, J. Symanowski, R. Olaosebikan, S. Sanikommu, S. Newby, S. Wyatt, J. Sebaaly, and K. Rector. 2019. Use of buprenorphine/naloxone in ameliorating acute care utilization and chronic opioid use in adults with sickle cell disease. Paper presented at ASH Annual Meeting, Valencia BC, Orange County Convention Center.
Oteng-Ntim, E., B. Ayensah, M. Knight, and J. Howard. 2015. Pregnancy outcome in patients with sickle cell disease in the UK—A national cohort study comparing sickle cell anaemia (HbSS) with HbSC disease. British Journal of Haematology 169(1):129–137.
Parent, F., D. Bachir, J. Inamo, F. Lionnet, F. Driss, G. Loko, A. Habibi, S. Bennani, L. Savale, S. Adnot, B. Maitre, A. Yaici, L. Hajji, D. S. O’Callaghan, P. Clerson, R. Girot, F. Galacteros, and G. Simonneau. 2011. A hemodynamic study of pulmonary hypertension in sickle cell disease. New England Journal of Medicine 365(1):44–53.
Pearson, H. A. 1977. Sickle cell anemia and severe infections due to encapsulated bacteria. Journal of Infectious Diseases 136 (Suppl 1):S25–S30.
Pecker, L. H., and R. P. Naik. 2018. The current state of sickle-cell trait: Implications for reproductive and genetic counseling. Blood 132(22):2331–2338.
Pegelow, C. H., E. A. Macklin, F. G. Moser, W. C. Wang, J. A. Bello, S. T. Miller, E. P. Vichinsky, M. R. DeBaun, L. Guarini, R. A. Zimmerman, D. P. Younkin, D. M. Gallagher, and T. R. Kinney. 2002. Longitudinal changes in brain magnetic resonance imaging findings in children with sickle cell disease. Blood 99(8):3014–3018.
Perlin, E., H. Finke, O. Castro, S. Rana, J. Pittman, R. Burt, C. Ruff, and D. McHugh. 1994. Enhancement of pain control with ketorolac tromethamine in patients with sickle cell vaso-occlusive crisis. American Journal of Hematology 46(1):43–47.
Platt, O. S., S. H. Orkin, G. Dover, G. P. Beardsley, B. Miller, and D. G. Nathan. 1984. Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia. Journal of Clinical Investigation 74(2):652–656.
Platt, O. S., B. D. Thorington, D. J. Brambilla, P. F. Milner, W. F. Rosse, E. Vichinsky, and T. R. Kinney. 1991. Pain in sickle cell disease. Rates and risk factors. New England Journal of Medicine 325(1):11–16.
Platt, O. S., D. J. Brambilla, W. F. Rosse, P. F. Milner, O. Castro, M. H. Steinberg, and P. P. Klug. 1994. Mortality in sickle cell disease. Life expectancy and risk factors for early death. New England Journal of Medicine 330(23):1639–1644.
Plummer, J. M., N. D. Duncan, D. I. Mitchell, A. H. McDonald, M. Reid, and M. Arthurs. 2006. Laparoscopic cholecystectomy for chronic cholecystitis in Jamaican patients with sickle cell disease: Preliminary experience. West Indian Medical Journal 55(1):22–24.
Porter, J. B., and E. R. Huehns. 1987. Transfusion and exchange transfusion in sickle cell anaemias, with particular reference to iron metabolism. Acta Haematologica 78(2–3):198–205.
Powars, D., J. A. Weidman, T. Odom-Maryon, J. C. Niland, and C. Johnson. 1988. Sickle cell chronic lung disease: Prior morbidity and the risk of pulmonary failure. Medicine 67(1):66–76.
Procon.org. 2019. Legal medical marijuana states and DC. https://medicalmarijuana.procon.org/legal-medical-marijuana-states-and-dc (accessed November 19, 2019).
Prussien, K. V., L. C. Jordan, M. R. DeBaun, and B. E. Compas. 2019. Cognitive function in sickle cell disease across domains, cerebral infarct status, and the lifespan: A meta-analysis. Journal of Pediatric Psychology 44(8):948–958.
Puri, L., K. A. Nottage, J. S. Hankins, and D. L. Anghelescu. 2018. State of the art management of acute vaso-occlusive pain in sickle cell disease. Paediatric Drugs 20(1):29–42.
Puri, L., K. J. Morgan, and D. L. Anghelescu. 2019. Ketamine and lidocaine infusions decrease opioid consumption during vaso-occlusive crisis in adolescents with sickle cell disease. Current Opinion in Supportive and Palliative Care 13(4):402–407.
Quandt, S. A., J. C. Sandberg, J. G. Grzywacz, K. P. Altizer, and T. A. Arcury. 2015. Home remedy use among African American and white older adults. Journal of the National Medical Association 107(2):121–129.
Quinn, C. T. 2018. L-glutamine for sickle cell anemia: More questions than answers. Blood 132(7):689–693.
Quinn, C. T., Z. R. Rogers, T. L. McCavit, and G. R. Buchanan. 2010. Improved survival of children and adolescents with sickle cell disease. Blood 115(17):3447–3452.
Ramasubbu, C., and A. Gupta. 2011. Pharmacological treatment of opioid-induced hyperalgesia: A review of the evidence. Journal of Pain and Palliative Care Pharmacotherapy 25(3):219–230.
Rasolofo, J., M. Poncelet, V. Rousseau, and P. Marec-Berard. 2013. Analgesic efficacy of topical lidocaine for vaso-occlusive crisis in children with sickle cell disease. Archives de Pédiatrie 20(7):762–767.
Rayment, C., M. J. Hjermstad, N. Aass, S. Kaasa, A. Caraceni, F. Strasser, E. Heitzer, R. Fainsinger, and M. I. Bennett. 2013. Neuropathic cancer pain: Prevalence, severity, analgesics and impact from the European Palliative Care Research Collaborative Computerised Symptom Assessment Study. Palliative Medicine 27(8):714–721.
Reiner, K., L. Tibi, and J. D. Lipsitz. 2013. Do mindfulness-based interventions reduce pain intensity? A critical review of the literature. Pain Medicine 14(2):230–242.
Ribeiro, K. R., M. H. Guarnieri, D. C. da Costa, F. F. Costa, J. Pellegrino, Jr., and L. Castilho. 2009. DNA array analysis for red blood cell antigens facilitates the transfusion support with antigen-matched blood in patients with sickle cell disease. Vox Sanguinis 97(2):147–152.
Rizio, A. A., M. Bhor, X. Lin, K. L. McCausland, M. K. White, J. Paulose, S. Nandal, R. I. Halloway, and L. Bronte-Hall. 2020. The relationship between frequency and severity of vaso-occlusive crises and health-related quality of life and work productivity in adults with sickle cell disease. Quality of Life Research, January 13 [Epub ahead of print].
Roberts, J. D., J. Spodick, J. Cole, J. Bozzo, S. Curtis, and A. Forray. 2018. Marijuana use in adults living with sickle cell disease. Cannabis and Cannabinoid Research 3(1):162–165.
Rosse, W. F., D. Gallagher, T. R. Kinney, O. Castro, H. Dosik, J. Moohr, W. Wang, and P. S. Levy. 1990. Transfusion and alloimmunization in sickle cell disease. The cooperative study of sickle cell disease. Blood 76(7):1431–1437.
Ruta, N. S., and S. K. Ballas. 2016. The opioid drug epidemic and sickle cell disease: Guilt by association. Pain Medicine 17(10):1793–1798.
Sakano, K., S. Oikawa, K. Hasegawa, and S. Kawanishi. 2001. Hydroxyurea induces site-specific DNA damage via formation of hydrogen peroxide and nitric oxide. Japanese Journal of Cancer Research 92(11):1166–1174.
Schatz, J., R. L. Finke, J. M. Kellett, and J. H. Kramer. 2002. Cognitive functioning in children with sickle cell disease: A meta-analysis. Journal of Pediatric Psychology 27(8):739–748.
Schatz, J., A. M. Schlenz, K. E. Smith, and C. W. Roberts. 2018. Predictive validity of developmental screening in young children with sickle cell disease: A longitudinal follow-up study. Developmental Medicine & Child Neurology 60(5):520–526.
Schlaeger, J., M. Ezenwa, Y. Yao, M. Suarez, V. Angulo, D. Shuey, Z. Wang, R. Molokie, and D. Wikie. 2019. Association of pain, anxiety, depression, and fatigue with sensitization in outpatient adults with sickle cell disease. Journal of Pain 20(4):S24–S25.
Schliessbach, J., A. Siegenthaler, K. Streitberger, U. Eichenberger, E. Nuesch, P. Juni, L. ArendtNielsen, and M. Curatolo. 2013. The prevalence of widespread central hypersensitivity in chronic pain patients. European Journal of Pain 17(10):1502–1510.
Scott, R. B. 1979. Reflections on the current status of the national sickle cell disease program in the United States. Journal of the National Medical Association 71(7):679–681.
Seck, S. M., M. Dahaba, E. F. Ka, M. M. Cisse, S. Gueye, and A. O. Tal. 2012. Mineral and bone disease in black African hemodialysis patients: A report from Senegal. Nephro-Urology Monthly 4(4):613–616.
Shah, N., M. Bhor, L. Xie, S. Arcona, R. Halloway, J. Paulose, and H. Yuce. 2019. Evaluation of vaso-occlusive crises in United States sickle cell disease patients: A retrospective claims-based study. Journal of Health Economics and Outcomes Research 6(3):106–117.
Sharma, D., and A. M. Brandow. 2020. Neuropathic pain in individuals with sickle cell disease. Neuroscience Letters 714:134445.
Sharma, S., J. T. Efird, C. Knupp, R. Kadali, D. Liles, K. Shiue, P. Boettger, and S. F. Quan. 2015. Sleep disorders in adult sickle cell patients. Journal of Clinical Sleep Medicine 11(3):219–223.
Sil, S., C. Dampier, and L. L. Cohen. 2016. Pediatric sickle cell disease and parent and child catastrophizing. Journal of Pain 17(9):963–971.
Simckes, A. M., S. S. Chen, A. V. Osorio, R. E. Garola, and G. M. Woods. 1999. Ketorolac-induced irreversible renal failure in sickle cell disease: A case report. Pediatric Nephrology 13(1):63–67.
Simmons, L. A., H. Williams, S. Silva, F. Keefe, and P. Tanabe. 2019. Acceptability and feasibility of a mindfulness-based intervention for pain catastrophizing among persons with sickle cell disease. Pain Management Nursing 20(3):261–269.
Sinha, C. B., N. Bakshi, D. Ross, and L. Krishnamurti. 2018. From trust to skepticism: An in-depth analysis across age groups of adults with sickle cell disease on their perspectives regarding hydroxyurea. PLOS ONE 13(6):e0199375.
Sinha, C. B., N. Bakshi, D. Ross, and L. Krishnamurti. 2019. Management of chronic pain in adults living with sickle cell disease in the era of the opioid epidemic: A qualitative study. JAMA Network Open 2(5):e194410.
Smith, S. B., D. W. Maixner, R. B. Fillingim, G. Slade, R. H. Gracely, K. Ambrose, D. V. Zaykin, C. Hyde, S. John, K. Tan, W. Maixner, and L. Diatchenko. 2012. Large candidate gene association study reveals genetic risk factors and therapeutic targets for fibromyalgia. Arthritis & Rheumatology 64(2):584–593.
Smith, W. R., and M. Scherer. 2010. Sickle-cell pain: Advances in epidemiology and etiology. Hematology: American Society of Hematology—Education Program 2010:409–415.
Smith, W. R., L. T. Penberthy, V. E. Bovbjerg, D. K. McClish, J. D. Roberts, B. Dahman, I. P. Aisiku, J. L. Levenson, and S. D. Roseff. 2008. Daily assessment of pain in adults with sickle cell disease. Annals of Internal Medicine 148(2):94–101.
Sogutlu, A., J. L. Levenson, D. K. McClish, S. D. Rosef, and W. R. Smith. 2011. Somatic symptom burden in adults with sickle cell disease predicts pain, depression, anxiety, health care utilization, and quality of life: The PiSCES project. Psychosomatics 52(3):272–279.
Solanki, D. L., and P. R. McCurdy. 1979. Cholelithiasis in sickle cell anemia: A case for elective cholecystectomy. American Journal of the Medical Sciences 277(3):319–324.
Steen, R. G., C. Fineberg-Buchner, G. Hankins, L. Weiss, A. Prifitera, and R. K. Mulhern. 2005. Cognitive deficits in children with sickle cell disease. Journal of Child Neurology 20(2):102–107.
Steinberg, M. H., W. F. McCarthy, O. Castro, S. K. Ballas, F. D. Armstrong, W. Smith, K. Ataga, P. Swerdlow, A. Kutlar, L. DeCastro, M. A. Waclawiw, and investigators of the Multicenter Study of Hydroxyurea in Sickle Cell and MSH Patients’ Follow-Up. 2010. The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: A 17.5 year follow-up. American Journal of Hematology 85(6):403–408.
Stotesbury, H., J. Kawadler, P. Balfour, M. Koelbel, and F. J. Kirkham. 2017. Cognitive deficits in sickle cell disease; links with nocturnal oxygen desaturation in adolescents, but not children. Developmental Medicine and Child Neurology Conference: 43rd Annual Conference of the British Paediatric Neurology Association, BPNA 2017. United Kingdom. 2059(Suppl 2011):2037–2038.
Taylor, J. G., V. G. Nolan, L. Mendelsohn, G. J. Kato, M. T. Gladwin, and M. H. Steinberg. 2008. Chronic hyper-hemolysis in sickle cell anemia: Association of vascular complications and mortality with less frequent vasoocclusive pain. PLOS ONE 3(5):e2095.
Thomas, V. J., and L. M. Taylor. 2002. The psychosocial experience of people with sickle cell disease and its impact on quality of life: Qualitative findings from focus groups. British Journal of Health Psychology 7(Part 3):345–363.
Thomas, V. N., J. Wilson-Barnett, and F. Goodhart. 1998. The role of cognitive-behavioural therapy in the management of pain in patients with sickle cell disease. Journal of Advanced Nursing 27(5):1002–1009.
Thompson, A. A. 2011. Primary prophylaxis in sickle cell disease: Is it feasible? Is it effective? Hematology: American Society of Hematology–Education Program 2011:434–439.
Thompson, W. E., and I. Eriator. 2014. Pain control in sickle cell disease patients: Use of complementary and alternative medicine. Pain Medicine 15(2):241–246.
Tsai, S. L., E. Reynoso, D. W. Shin, and J. W. Tsung. 2018. Acupuncture as a nonpharmacologic treatment for pain in a pediatric emergency department. Pediatric Emergency Care, September 21 [Epub ahead of print].
Tsitsikas, D. A., G. Gallinella, S. Patel, H. Seligman, P. Greaves, and R. J. Amos. 2014. Bone marrow necrosis and fat embolism syndrome in sickle cell disease: Increased susceptibility of patients with non-SS genotypes and a possible association with human parvovirus B19 infection. Blood Reviews 28(1):23–30.
Tsitsikas, D. A., B. Sirigireddy, R. Nzouakou, A. Calvey, J. Quinn, J. Collins, F. Orebayo, N. Lewis, S. Todd, and R. J. Amos. 2016. Safety, tolerability, and outcomes of regular automated red cell exchange transfusion in the management of sickle cell disease. Journal of Clinical Apheresis 31(6):545–550.
Uwaezuoke, S. N., A. C. Ayuk, I. K. Ndu, C. I. Eneh, N. R. Mbanefo, and O. U. Ezenwosu. 2018. Vaso-occlusive crisis in sickle cell disease: Current paradigm on pain management. Journal of Pain Research 11:3141–3150.
Valrie, C. R., K. M. Gil, R. Redding-Lallinger, and C. Daeschner. 2007. Brief report: Sleep in children with sickle cell disease: An analysis of daily diaries utilizing multilevel models. Journal of Pediatric Psychology 32(7):857–861.
Valrie, C. R., M. H. Bromberg, T. Palermo, and L. E. Schanberg. 2013. A systematic review of sleep in pediatric pain populations. Journal of Developmental and Behavioral Pediatrics 34(2):120–128.
Van Damme, S., G. Crombez, P. Bijttebier, L. Goubert, and B. Van Houdenhove. 2002. A confirmatory factor analysis of the pain catastrophizing scale: Invariant factor structure across clinical and non-clinical populations. Pain 96(3):319–324.
Vanderhave, K. L., C. A. Perkins, B. Scannell, and B. K. Brighton. 2018. Orthopaedic manifestations of sickle cell disease. Journal of the American Academy of Orthopaedic Surgeons 26(3):94–101.
Velasquez, M. P., M. M. Mariscalco, S. L. Goldstein, and G. E. Airewele. 2009. Erythrocytapheresis in children with sickle cell disease and acute chest syndrome. Pediatric Blood & Cancer 53(6):1060–1063.
Vichinsky, E. P., A. Earles, R. A. Johnson, M. S. Hoag, A. Williams, and B. Lubin. 1990. Alloimmunization in sickle cell anemia and transfusion of racially unmatched blood. New England Journal of Medicine 322(23):1617–1621.
Vichinsky, E. P., L. D. Neumayr, J. I. Gold, M. W. Weiner, R. R. Rule, D. Truran, J. Kasten, B. Eggleston, K. Kesler, L. McMahon, E. P. Orringer, T. Harrington, K. Kalinyak, L. M. De Castro, A. Kutlar, C. J. Rutherford, C. Johnson, J. D. Bessman, L. B. Jordan, and F. D. Armstrong. 2010. Neuropsychological dysfunction and neuroimaging abnormalities in neurologically intact adults with sickle cell anemia. JAMA 303(18):1823–1831.
Vidler, J. B., K. Gardner, K. Amenyah, A. Mijovic, and S. L. Thein. 2015. Delayed haemolytic transfusion reaction in adults with sickle cell disease: A 5-year experience. British Journal of Haematology 169(5):746–753.
Vincent, L., D. Vang, J. Nguyen, B. Benson, J. Lei, and K. Gupta. 2016. Cannabinoid receptor-specific mechanisms to alleviate pain in sickle cell anemia via inhibition of mast cell activation and neurogenic inflammation. Haematologica 101(5):566–577.
Wallen, G. R., C. P. Minniti, M. Krumlauf, E. Eckes, D. Allen, A. Oguhebe, C. Seamon, D. S. Darbari, M. Hildesheim, L. Yang, J. D. Schulden, G. J. Kato, and J. G. Taylor 6th. 2014. Sleep disturbance, depression and pain in adults with sickle cell disease. BMC Psychiatry 14(207):207.
Walsh, K. E., S. L. Cutrona, P. L. Kavanagh, L. E. Crosby, C. Malone, K. Lobner, and D. G. Bundy. 2014. Medication adherence among pediatric patients with sickle cell disease: A systematic review. Pediatrics 134(6):1175–1183.
Wang, W. C., R. E. Ware, S. T. Miller, R. V. Iyer, J. F. Casella, C. P. Minniti, S. Rana, C. D. Thornburg, Z. R. Rogers, R. V. Kalpatthi, J. C. Barredo, R. C. Brown, S. A. Sarnaik, T. H. Howard, L. W. Wynn, A. Kutlar, F. D. Armstrong, B. A. Files, J. C. Goldsmith, M. A. Waclawiw, X. Huang, and B. W. Thompson. 2011. A multicenter randomised controlled trial of hydroxyurea (hydroxycarbamide) in very young children with sickle cell aneamia. Lancet 377(9778):1663–1672.
Westcott, E. 2017. Healthy behaviors of adolescents and young adults with sickle cell disease. Electronic Thesis or Dissertation. University of Cincinnati. https://etd.ohiolink.edu (accessed November 19, 2019).
While, A. E., and J. Mullen. 2004. Living with sickle cell disease: The perspective of young people. British Journal of Nursing 13(6):320–325.
Whiteman, L. N., C. Haywood, Jr., S. Lanzkron, J. J. Strouse, A. H. Batchelor, A. Schwartz, and R. W. Stewart. 2016. Effect of free dental services on individuals with sickle cell disease. Southern Medical Journal 109(9):576–578.
WHO (World Health Organization). 2018. WHO guidelines for the pharmacological and radiotherapeutic management of cancer pain in adults and adolescents. Geneva, Switzerland: World Health Organization.
Wilkie, D. J., R. Molokie, D. Boyd-Seal, M. L. Suarez, Y. O. Kim, S. Zong, H. Wittert, Z. Zhao, Y. Saunthararajah, and Z. J. Wang. 2010. Patient-reported outcomes: Descriptors of nociceptive and neuropathic pain and barriers to effective pain management in adult outpatients with sickle cell disease. Journal of the National Medical Association 102(1):18–27.
Williams, H., S. Silva, L. A. Simmons, and P. Tanabe. 2017. A telephonic mindfulness-based intervention for persons with sickle cell disease: Study protocol for a randomized controlled trial. Trials 18(1):218.
Woolf, C. J. 2011. Central sensitization: Implications for the diagnosis and treatment of pain. Pain 152(3 Suppl):S2–S15.
Wright, S. W., R. L. Norris, and T. R. Mitchell. 1992. Ketorolac for sickle cell vaso-occlusive crisis pain in the emergency department: Lack of a narcotic-sparing effect. Annals of Emergency Medicine 21(8):925–928.
Wu, Z., Z. Malihi, A. W. Stewart, C. M. Lawes, and R. Scragg. 2018. The association between vitamin D concentration and pain: A systematic review and meta-analysis. Public Health Nutrition 21(11):2022–2037.
Xu, G., L. Strathearn, B. Liu, B. Yang, and W. Bao. 2018. Twenty-year trends in diagnosed attention-deficit/hyperactivity disorder among U.S. children and adolescents, 1997–2016. JAMA Network Open 1(4):e181471.
Yale, S. H., N. Nagib, and T. Guthrie. 2000. Approach to the vaso-occlusive crisis in adults with sickle cell disease. American Family Physician 61(5):1349–1356.
Yawn, B. P., G. R. Buchanan, A. N. Afenyi-Annan, S. K. Ballas, K. L. Hassell, A. H. James, L. Jordan, S. M. Lanzkron, R. Lottenberg, W. J. Savage, P. J. Tanabe, R. E. Ware, M. H. Murad, J. C. Goldsmith, E. Ortiz, R. Fulwood, A. Horton, and J. John-Sowah. 2014. Management of sickle cell disease: Summary of the 2014 evidence-based report by expert panel members. JAMA 312(10):1033–1048.
Yurkiewicz, I. 2014. These agents prevent disease. Why aren’t we using them? Scientific American. December 31. https://blogs.scientificamerican.com/unofficial-prognosis/these-agents-prevent-disease-why-aren-t-we-using-them (accessed April 4, 2020).
Zhang, D., C. Xu, D. Manwani, and P. S. Frenette. 2016. Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology. Blood 127(7):801–809.
Zhou, J., J. Han, E. A. Nutescu, W. L. Galanter, S. M. Walton, V. R. Gordeuk, S. L. Saraf, and G. S. Calip. 2019. Similar burden of type 2 diabetes among adult patients with sickle cell disease relative to African Americans in the U.S. population: A six-year population-based cohort analysis. British Journal of Haematology 185(1):116–127.
Ziegler-Skylakakis, K., L. R. Schwarz, and U. Andrae. 1985. Microsome- and hepatocytemediated mutagenicity of hydroxyurea and related aliphatic hydroxamic acids in V79 Chinese hamster cells. Mutation Research 152(2–3):225–231.
This page intentionally left blank.