Sickle cell disease (SCD) is an inherited hemolytic anemia that affects approximately 100,000 persons in the United States, mostly in the African-American population. It is responsible for lifelong medical complications in most affected individuals. Complications of SCD can be divided into those that are acute and those that are the result of the chronic repetitive vaso-occlusion of target organ systems (Table 89-1). This chapter focuses on the acute complications that the hospitalist is likely to encounter.

SCD refers to a group of hemolytic anemias in which hemoglobin S (HbS) is present in either a homozygous state (HbSS) or in a compound heterozygous state, as when combined with hemoglobin C (HbSC) or hemoglobin beta-thalassemia (HbS-beta thalassemia). The HbS mutation is the result of an amino acid substitution (valine is substituted for glutamic acid at position 6) in the beta globin of the hemoglobin heterotetramer. The mutation creates a hydrophobic region that, in the deoxygenated state, facilitates a non-covalent polymerization of HbS molecules into rigid strands. These HbS polymers damage the erythrocyte membrane and change the rheology of the erythrocyte in circulation, causing erythrocyte dehydration hemolytic anemia and vaso-occlusion.

The National Institutes of Health recommends that all infants be screened in the neonatal period for SCD¹ and all 50 states and the District of Columbia perform universal screening for SCD.² For this reason, most children with SCD are identified early and medical management is started even before the usual age of presentation. Because the sickle mutation affects beta globin, a component of adult hemoglobin rather than fetal hemoglobin (HbF), affected infants are usually asymptomatic for the first 6 months of life. Anemia and complications from SCD usually present toward the end of the first year of life, after the physiologic switch from fetal to adult hemoglobin.

Despite newborn screening and early identification, cases of previously undiagnosed SCD presenting with a medical complication do occur, and the clinician is advised to consider SCD in the differential of patients with non-immune hemolytic anemia. Although affected patients typically have moderate or severe anemia with hemoglobin values ranging from 7 to 9 g/dL, they generally are not overly symptomatic (e.g. weakness, fatigue) since the anemia is chronic and physiologically compensated. As the result of a markedly shortened red cell survival time, bone marrow production of new erythrocytes is brisk, as indicated by chronically elevated reticulocyte counts (usually 10% to 20%). Patients will often be slightly icteric due to chronic hemolysis, and may have splenomegaly and skull bone deformities due to extramedullary hematopoiesis.

Infants diagnosed by newborn screening should be referred to pediatric hematologists for confirmation of the diagnosis, parental education, genetic counseling, and long-term follow-up. Routine health maintenance visits to a pediatric hematologist are scheduled for every 3 months in the first 2 years of life, then every 6 months until 4 to 5 years of age, and annually thereafter. More frequent visits may be required for patients with increased educational needs, accumulated complications, and therapeutic monitoring (e.g. hydroxyurea and/or chronic transfusion therapy). “Well visits” allow the practitioner to obtain baseline clinical, laboratory, and radiological data that is important in the event of an acute complication and affords the opportunity for education and anticipatory guidance.

Acute and chronic complications are an important part of the management of SCD (Table 89-1). Although the hematologist manages conditions associated with chronic disease, the generalist may need to consider these complications and their impact when called upon to evaluate children with SCD. The discussion below focuses on the acute complications.

FEVER

Patients with SCD develop impaired spleen function in the first year of life and are functionally asplenic by 2 years of age. They are therefore at risk for invasive and overwhelming infections. Prior to the introduction of routine vaccination in many countries, encapsulated bacteria (e.g. Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis) were a significant threat.^3,4 Though less frequent now, pneumococcus remains a common cause of sepsis. Antibiotic prophylaxis should be initiated when the diagnosis of SCD is made (Table 89-2). Children with SCD should receive a complete routine immunization schedule, including Haemophilus influenzae type b series (Hib), pneumococcal conjugate vaccine (Prevnar [PCV13]) series, and a pneumococcal polysaccharide vaccine (Pneumovax [PPV23]) at age 2 with a booster 3 to 5 years later, to decrease the risk of bacteremia. Influenza vaccine should be administered to all sickle cell patients annually and the meningococcal polysaccharide vaccine should be administered to patients 2 years of age and older.⁴

Even with antibiotic prophylaxis and complete immunizations, all sickle cell patients should be considered high-risk for bacteremia and overwhelming sepsis. Prompt evaluation and empiric treatment of febrile SCD patients is necessary to reduce both mortality and morbidity of sepsis. Children with an obvious source of infection (e.g. otitis, gastroenteritis) should still receive full evaluation and appropriate empiric treatment until bacteremia has been excluded. The key to the proper management of febrile SCD patients (or any asplenic patient) involves rapid triage and assessment with administration of empiric parenteral antibiotics within 1 hour of presentation. The focused history, physical examination, and laboratory evaluation, including blood cultures, should be done promptly. If the patient has a central line or implanted port, blood cultures must be drawn off this line. Additional peripherally obtained cultures are not necessary. A chest radiograph is recommended for most patients, especially those with tachypnea, cough, hypoxemia, or thoracic pain, and considered for history of asthma or recurrent acute chest syndrome (ACS). Urinalysis and urine culture are recommended for all males <6 months and females <2 years. Throat culture with rapid antigen testing for group A β-hemolytic streptococci, analysis (including cell count, glucose, protein, and Gram stain) and culture of the cerebrospinal fluid, stool cultures, respiratory viral panels, and other studies should be obtained as clinically indicated.

All febrile patients with SCD require empiric parenteral antibiotic coverage for at least 24 hours. Ceftriaxone, given at 50 mg/kg IV/IM (maximum 2 grams/day), is the mainstay of empiric therapy.^5,6 Other third-generation cephalosporins may be used to complete coverage for the first 24 hours depending upon institutional guidelines or formulary. For patients allergic to cephalosporins, other broad-spectrum possibilities include clindamycin, and quinolones (e.g. levofloxacin). Vancomycin is usually reserved for those with signs of meningitis, a history of pneumococcal sepsis, or toxic appearance. Vancomycin should also be considered in areas with high local prevalence of resistant organisms^7,8 or if a central venous line is present. If a central venous line is present, antibiotics should be administered via this route. If a new infiltrate is identified on chest radiograph, a macrolide antibiotic should be added to the previously mentioned empiric antibiotics because of the high incidence of pneumonia caused by atypical organisms in this setting.⁹

Admission to hospital should be considered if there is any indication of possible complications or if high-risk features are present^10-12 (Table 89-3). If none of these features are present, one may consider discharge from the acute care setting if the patient is stable 1 hour after receiving empiric antibiotics.¹³ Patients should be counseled to return immediately for persistent fever longer than 48 hours, or worsening symptoms—especially respiratory decline, dehydration, lethargy, or pain. Clear instructions should also be given for follow-up in 24 hours with primary care physician, emergency department, or by phone so that pending cultures will be tracked.

CEREBROVASCULAR ACCIDENT

Vaso-occlusive stroke represents one of the most important causes of disability in the sickle cell population. Sickle cell patients are at increased risk of stroke starting in the late school-age period. Primary stroke affects approximately 10% of HbSS sickle cell patients before the end of their second decade of life.¹⁴ Risk factors for primary stroke include previous transient ischemic attack, low baseline hemoglobin, preceding acute chest syndrome, hypertension, and abnormal transcranial Doppler ultrasound (TCD) screen. TCD is a reliable screening test to identify patients with HbSS and HbS-beta thalassemia at highest risk of stroke. If the TCD is abnormal, these patients are prescribed chronic monthly transfusion therapy, with a goal of suppressing endogenous erythropoiesis and maintaining the sickle hemoglobin at less than 30% as measured by hemoglobin electrophoresis. This has been demonstrated to reduce the risk of recurrent stroke¹⁵ and to reduce the risk of primary stroke in those children with elevated TCD velocities.^16,17

Any acute neurological findings such as weakness, altered consciousness, seizure, or language/speech disturbance must prompt immediate evaluation for cerebral ischemia. The majority of childhood stroke in SCD is caused by a nonhemorrhagic vaso-occlusion, although infection, tumor, intoxication, and thromboembolic disease should be considered. Obtaining or reviewing neuroimaging should not delay the initiation of transfusion therapy, especially if symptoms have persisted for more than 24 hours. Computerized tomography (CT) findings may be normal in early ischemia. Highly sensitive MRI diffusion and T2-weighted-Fluid-Attenuated Inversion Recovery (FLAIR)-weighted images remain abnormal for several days after significant cerebral ischemia and MRA will often reveal static intracranial arterial vasculopathy.

Initial stabilization should include fluid hydration with crystalloid while samples for cross-matching are sent in preparation for red blood cell exchange transfusion. Correction of dehydration plus maintenance hydration alone may quickly reverse symptomatology, though should not be so aggressive as to risk the formation of cerebral edema. The goal of exchange transfusion is to reduce the proportion of sickle hemoglobin to below 30%. Exchange transfusion may be achieved through manual exchange techniques; however, simple transfusion may be a temporizing measure until adequate cross-matched blood and personnel are present to perform the exchange. Patients should be monitored for metabolic or electrolyte disturbances, such as hypocalcemia or hyperkalemia, arising from large transfusion, with prompt treatment as necessary. Automated exchange transfusion by erythrocytapheresis is the preferred method of treatment; however this requires specialized equipment, trained personnel, and central access in most children. Consultation with an experienced pediatric hematologist is important.

Other symptoms or signs should also be investigated and treated, such as EEG and anti-epileptics for seizure activity, and antipyretics for fever. Treatments with tissue–plasminogen activator (tPA), antiplatelet agents, and hypothermia have not been studied adequately in childhood and are generally not indicated in the acute setting.

Patients with recurrent neurological events should undergo further evaluation by MRA for moyamoya disease, a cerebrovascular disorder marked by progressive stenosis of cerebral arteries leading to development of a poorly defined network of fragile collateral vessels. Patients with significant cerebral vasculopathy have increased risk of recurrent stroke despite chronic transfusion therapy.¹⁸ Cohorts of patients with SCD and moyamoya have been treated with pial synangiosis or encephalo-duro-arteriosynangiosis (EDAS) with good outcomes.^19,20 In one series of 12 patients, EDAS resulted in a decrease from 16 strokes in 26.3 patient-years to no strokes in 38.3 patient-years.²⁰

ACUTE CHEST SYNDROME

ACS is a leading cause of morbidity and mortality in children with SCD.²¹ It is an acute illness characterized by fever, respiratory symptoms (one or more of tachypnea, cough, wheeze, or hypoxemia relative to baseline) and a new infiltrate on chest radiograph. Risk factors for the development of ACS include low HbF, elevated steady-state WBC counts,^9,22 comorbid asthma,²³ preceding vaso-occlusive pain crisis, and general anesthesia. The underlying pathophysiology is unclear, though infection, infarction, and pulmonary fat embolism have been implicated.⁹ Infectious agents most often identified are Chlamydia,²³ Mycoplasma,²⁴ and viruses with children showing a seasonal variation of presentation.²¹ Inadequately treated vaso-occlusive pain involving the sternum, ribs, trunk, or abdomen may lead to splinting respirations, decreased tidal volume, and the development of atelectasis, ventilation/perfusion mismatching, hypoxemia, and progression to ACS. ACS is the most common complication of surgery and anesthesia in patients with SCD,²⁵ likely related to high risk of cold exposure, hypoxia, acidosis, atelectasis, and psychological stress in the perioperative period. Use of incentive spirometry has been shown to decrease incidence of ACS in patients hospitalized with vaso-occlusive crisis²⁶ and should be used routinely in the care of all hospitalized sickle cell patients.