An acute vasoocclusive episode (VOE) is a new onset of severe pain that persists for at least four hours for which there is no explanation other than vasoocclusion. VOEs are the primary source of acute pain requiring medical attention in SCD, and they account for most acute pain episodes experienced by patients with this condition. VOEs can be treated with parenteral opioids, ketorolac, or other nonsteroidal antiinflammatory drugs. As patients grow older and learn strategies for alleviating the pain of VOEs, they often manage these episodes at home, but VOEs are the most common manifestation of SCD and the most common SCD-related ED diagnosis.¹⁶ In a 2013 follow-up analysis of 264 adult patients with SCA in the Bethesda Sickle Cell Cohort study, approximately 40% reported no hospitalizations or ED treatments for VOEs within the past year, whereas 22% reported five or more hospitalizations or ED visits within that period, underscoring the tremendous variability of VOE severity that occurs in SCA.²⁰

The clinical management of VOEs focuses on rapid pain assessment and administration of appropriate analgesics. Infants and toddlers often present with dactylitis, or pain and swelling from infarctions in the hands and feet; these may be the first SCD-related complications they experience (see Figure 2).²¹ Other common locations for VOE pain in patients of all ages include the chest, abdomen, back, and long bones. SCD genotype, older age, higher hematocrit levels, and lower fetal Hb levels are risk factors for VOE.¹² Patients may have specific triggers for pain, such as extremes in temperature, dehydration, menstrual cycle changes, alcohol, or stress, but the majority of painful episodes have no identifiable cause. The effects of VOEs extend beyond the episodes themselves. Acute multisystem organ failure and death have also been reported during VOEs.^{22, 23} And patients with more frequent VOEs are shown to have a younger age at death.²⁰

Three subtypes of chronic pain have been identified in SCD²⁵:

chronic pain without contributing SCD complications, such as leg ulcers or AVN

As with other types of chronic pain, SCD pain can cause patients to experience central sensitization, hyperalgesia, and altered opioid metabolism. Chronic pain not only causes discomfort but may also precipitate mood changes, emotional disturbance, and behavioral dysfunction, thereby affecting numerous facets of the patient’s life as well as the lives of family members, friends, and colleagues.²⁶ In a six-month, prospective cohort study of 232 patients with SCD who were age 16 or older, 29% experienced pain almost daily while 14% experienced pain on 5% or fewer days.²⁷ This chronic pain was more frequent than VOEs and was often managed outside of a health care setting.

When the bone’s blood supply is interrupted, bone tissue may die, a condition referred to as AVN. In people with SCD, AVN may result from VOEs in the bone’s microcirculation that cause thrombosis, infarction, and ultimately, necrosis.²⁸ SCD severity and history of ACS may be risk factors for AVN,² which can occur in people of all ages and has been seen in children as young as five years.²⁹

Although the VOEs of SCD can occur in any organ, they are especially common in the bone marrow, particularly in the femoral or humeral head, where they can cause unilateral or bilateral AVN.²⁸ In one study, the overall cumulative incidence of femoral head AVN was 15% by age 30; the median age at diagnosis was 27, and nearly a quarter of the patients underwent hip replacement surgery at a median age of 36.² Often, however, patients do not report the pain of AVN or are unable to obtain orthopedic follow-up. If undetected or untreated, AVN can cause permanent gait abnormalities and limb-length discrepancies, significantly impairing mobility.

Priapism is an undesired, persistent, and often painful erection that can lead to erectile dysfunction, substantially impairing quality of life. In boys and men with SCD, priapism is a common complication. Researchers have calculated that the actuarial probability of male patients with SCA experiencing priapism was nearly 13% by age 10, more than 50% by age 15, and more than 89% by age 20.³⁰

In a survey of 130 male patients with SCD being treated at one of five UK or Nigerian hospitals, a history of priapism was reported by 46 (35%) of respondents.³ Within this group, 24 (52%) reported a history of severe, prolonged priapism (lasting more than 24 hours), which requires emergency treatment, and 33 (72%) reported a history of “stuttering” priapism—recurrent self-limited episodes, which are of much shorter duration. Stuttering episodes frequently heralded subsequent prolonged events, as only six of those reporting a history of severe priapism had no history of the stuttering type. In the group of 46 respondents, the mean age of priapism onset was 15, with 75% reporting their first episode before the age of 20 and 25% reporting a first episode before the age of 10. Sleep, sexual activity, and fever were frequent precipitating factors.³

ACS was the leading cause of death in the Dallas Newborn Cohort of patients with SCD⁹ and one of the most frequent causes of hospitalization in SCD.⁵ ACS is characterized by pleuritic chest pain, fever, rales on auscultation, and pulmonary infiltrates on chest X-ray.⁵ It can resemble other acute respiratory illnesses, including pneumonia, asthma exacerbation, or bronchiolitis.

Patient age affects presentation, etiology, and severity of ACS. Incidence is highest in children ages two to four years,⁵ but severity tends to be higher in adults, in whom studies have found mortality rates to be up to four times higher than in children.³¹ Children are more likely to present with wheezing, fever, and cough, whereas adults more often present with dyspnea, pain (commonly in the chest, ribs, sternum, arms, or legs), productive cough, and hemoptysis. ACS frequently occurs during hospitalization for VOE and following surgery.^{31, 32} In many cases, a cause is not evident or easily discernible. However, the most common etiologies are infection, followed by fat emboli from infarcted bone marrow. Following onset of symptoms, ACS can rapidly progress to respiratory failure, acute respiratory distress syndrome, or multisystem organ failure.

All patients with ACS should be hospitalized.¹⁵ Analgesia should be sufficient to reduce respiratory splinting and hypoventilation without causing atelectasis.³³ Guidelines on the clinical management of ACS were published in 2015.¹⁸ Among the recommendations in the guidelines are aggressive incentive spirometry (10 maximum inspirations) every two hours while the patient is awake to prevent atelectasis and the development of ACS during hospitalization for VOE.^{18, 19} Although iv fluid administration is frequently a component of VOE management, excessive fluids can cause pulmonary edema and precipitate ACS.¹⁸

Children and adults with SCD are at risk for cerebrovascular accidents such as ischemic stroke, hemorrhagic stroke, and silent stroke, also known as SCI. Analysis of clinical data on 4,082 SCD patients in the Cooperative Study of Sickle Cell Disease (CSSCD) provided the following prevalence estimates for cerebrovascular accidents in patients whose SCD genotype could be confirmed³⁴:

HbSS, 4.01%

The spleen is one of the first organs affected by SCD. In children with SCA, hyposplenism, a physiological reduction in spleen function, is usually evident within the first year of life.⁴⁰ Splenic dysfunction is believed to stem from vasoocclusion of the organ by sickled erythrocytes and subsequent ischemia, fibrosis, and progressive atrophy of the organ. The spleen is a major filter of the blood and plays an important role in immune defense as well as in vascular and blood homeostasis by removing senescent or altered red blood cells, microorganisms, and blood-borne antigens. Splenic damage puts patients at risk for immune dysfunction, vascular narrowing and occlusion, and severe bacterial infection. People with SCD remain at high risk for infection and sepsis throughout life.

All SCD genotypes put patients at increased risk for severe infection—particularly invasive bacterial infection—throughout life. This increased susceptibility is largely due to splenic and immune dysfunction. Young children with SCA in particular are at elevated risk for pneumonia, septicemia, and men- ingitis.^{44, 45} Incidence of these infections is lower in patients with HbSC and HbSβ⁺-thalassemia genotypes because splenic function is typically normal or only minimally impaired in infancy. The risk, however, is present in later childhood and adulthood.⁴⁶ Other infections are also common in SCD. VOE of the bone and subsequent necrosis predisposes patients to osteomyelitis.⁴⁷ Parvovirus B19, which is often asymptomatic in those without SCD, can trigger aplastic crisis and life-threatening anemia in people with SCD.⁴⁸ Risk of catheter-related infections is also higher in SCD. Infection is a common precipitant of VOE and the most common cause of ACS.³² Because of increased risks of infection, including infection with penicillin-resistant organisms, and incomplete vaccination in patients with SCD, any fever higher than 101.3°F (38.5°C) is considered a medical emergency requiring further evaluation.¹⁵

People with SCD suffer from a high incidence of social and behavioral health complications. Anxiety and depression have been reported to be as high as 7% and 28%, respectively, in these patients.⁵² Social and behavioral health complications can occur throughout life.

Severe disease may cause young children to miss school, limit college and job opportunities for young adults, and reduce career opportunities for older adults. Such losses present significant financial challenges, often limiting access to health care, insurance, and necessary medications. Interviews with 147 ED patients with SCD, conducted by social workers over a 14-month period, revealed that 27% and 17% of patients, respectively, experienced difficulties obtaining insurance coverage and meeting copay requirements for prescriptions.⁵³ Other issues that may affect patients’ ability to manage SCD effectively include navigating the time and transportation challenges involved in seeing numerous health care specialists while trying to work and take care of family responsibilities. It is not uncommon for patients to need to see an ophthalmologist, orthopedic surgeon, or nephrologist in addition to a sickle cell specialist and primary care provider.