Am Fam Physician. 2000;62(6):1309-1314
This is part II of a two-part article on sickle cell disease in childhood. Part I, “Laboratory Diagnosis, Pathophysiology and Health Maintenance,” appeared in the September 1 issue (Am Fam Physician 2000;62:1013–20, 1027–8).
Treatment advances over the past 25 years have significantly decreased morbidity and mortality in children with sickle cell disease. Aggressive management of fever, early diagnosis of acute chest syndrome, judicious use of transfusions and proper treatment of pain can improve quality of life and prognosis for these children. Prophylactic hydroxyurea therapy has been shown to reduce the incidence and severity of pain crises in adults with sickle cell disease and has been effective in limited studies conducted in children. Research into stem cell transplantation provides hope that a cure for sickle cell disease may be possible.
Complications of sickle cell disease occur suddenly and can rapidly become severe. Infection, acute splenic sequestration crisis, aplastic crisis, acute chest syndrome, stroke, cholelithiasis, renal disease and pain are the major complications of this disease in children. Some complications lend themselves to simple management, whereas others, including aseptic necrosis of the hip, priapism and leg ulcers, require prompt referral for specialized treatment1–3 (Table 1). A child with sickle cell disease who is acutely ill is usually best managed in a facility that can provide pediatric tertiary care.
| Primary care management | Consultation recommended |
|---|---|
| Fever with or without focus: prompt treatment with broad-spectrum antibiotics after cultures have been obtained; use a cephalosporin with or without vancomycin (Vancocin) | Persistent fever or a temperature of 39.4ºC (103ºF) or higher |
| Signs of toxicity or meningitis | |
| Pain: oral hydration, acetaminophen (e.g., Tylenol) with or without codeine, ibuprofen (Advil, Motrin), orally or parenterally administered morphine | Persistent pain in an extremity accompanied by acute signs of classic inflammation, increased temperature or positive blood culture |
| Chest pain accompanied by persistently decreased oxygen saturation and/or radiographic findings | |
| Severe or persistent headaches | |
| Respiratory symptoms with essentially normal oxygen saturation and negative chest radiograph: liberal administration of oxygen, incentive spirometer, bronchodilators | Low oxygen saturation |
| Abnormal findings on the chest radiograph | |
| Dyspnea | |
| Increased anemia: close observation and frequent evaluation of the complete blood cell count and reticulocyte count | Anemia accompanied by enlarging spleen, rapid worsening of anemia, or hematocrit less than 25 percent of baseline |
| Gross hematuria | First episode |
| Microscopic hematuria or proteinuria | Persistent hematuria or proteinuria |
| Right upper quadrant abdominal pain without cholecystitis or obstruction: symptomatic therapy | Recurrent abdominal pain with or without severe or increasing icterus |
| Asymptomatic gallstones: no treatment needed | Increased icterus |
| Aseptic necrosis | |
| Central nervous system symptoms, including severe headaches and deteriorating school performance | |
| Leg ulcers | |
| Priapism |
Infection
Children with any type of sickle cell disease are susceptible to overwhelming sepsis. Therefore, blood cultures should be obtained, and therapy with a cephalosporin (e.g., cefotaxime [Claforan], ceftriaxone [Rocephin] or cefuroxime [Ceftin]) should be started in a child with significant temperature elevation. Vancomycin (Vancocin) should be added to antimicrobial therapy in children who live in communities with a high incidence of penicillin-resistant pneumococci.4
The differential diagnosis of localized infections, particularly bone and lung infections, can be difficult. Pain and swelling over an extremity are usually due to bone infarct or sickling in the periosteum. Osteomyelitis should also be considered, particularly in a child with marked signs of inflammation, a white blood cell count greater than 28,000 per mm3 (28 × 106 per L) with or without band cells, a markedly elevated sedimentation rate or a significant temperature elevation. Bone scans can help make the diagnosis.
Salmonella species are the most common cause of osteomyelitis in children with sickle cell disease.5 Staphylococcus aureus is the second most common organism. Pneumococcus species are occasionally isolated in infants. Antibiotics should be selected to treat these organisms.
Acute Splenic Sequestration Crisis
The diagnosis of acute splenic sequestration crisis is based on sudden enlargement of the spleen accompanied by a precipitous fall in the hematocrit and a rise in the reticulocyte count. Enlargement of the spleen from entrapped blood can be so rapid and severe that it causes circulatory compromise. Early diagnosis and immediate intervention with intravenously administered fluids and judicious transfusion can be lifesaving.6
Acute splenic sequestration crisis is most common in children with homozygous sickle cell disease (hemoglobin SS disease) who are less than three years of age, but it can occur in any type of sickle cell disease. Children with homozygous sickle cell disease have usually infarcted their spleens before four years of age. However, children with variant disease can have acute splenic sequestration crisis at any time during childhood.6
After the first or second crisis, elective splenectomy should be performed when the child is stable.6
Aplastic Crisis
Erythrocyte production by the bone marrow may pause temporarily in children with sickle cell disease. In one study of 308 children with sickle cell anemia, all 91 cases of aplastic crisis were caused by human parvovirus B19 infection.7 The infection is self-limited and may cause only mild, nonspecific symptoms.
The hematocrit may fall significantly enough to warrant transfusion. Blood transfusion is usually recommended in the child whose hematocrit is 20 to 25 percent below baseline, or less than 18 percent.
At the time of aplasia, the child with sickle cell disease is highly contagious. If the diagnosis of aplastic crisis is made, the child should be strictly isolated from all vulnerable groups, such as pregnant women, immunocompromised children and all children with hemolytic anemias.
Acute Chest Syndrome
The appearance of a new pulmonary infiltrate on the chest radiograph of a child with sickle cell disease is termed “acute chest syndrome.” The syndrome can develop because of infection, infarction or a combination of the two. Infectious causes include gram-positive or gram-negative bacteria, atypical bacteria and viruses. Acute chest syndrome can also be caused by fat emboli that have moved to the lungs from bone infarcts.8
Acute chest syndrome is usually accompanied or preceded by pain in the chest or extremities, fever, respiratory distress and/or low oxygen saturation. The white blood cell count is generally high. Although the chest radiograph may be normal initially, subsequent radiographs will reveal an infiltrate, which may extend rapidly, involving one or more lobes as well as the pleura.
Because sudden clinical deterioration is common, the child with acute chest syndrome should be hospitalized and closely observed, often in a pediatric intensive care unit. The child should be treated with oxygen and simple or exchange transfusions if needed. Antibiotic therapy should include a cephalosporin (e.g., cefuroxime) to cover the usual organisms found in pediatric pulmonary disease and a macrolide antibiotic because of the frequency of Mycoplasma or Chlamydia species.
Overhydration and excessive use of narcotic analgesia should be avoided to decrease the risk of pulmonary edema and respiratory depression. An incentive spirometer should be used in the child with chest signs and symptoms.9
Stroke
About 10 percent of children with sickle cell disease have strokes. Most of these strokes are infarcts in the distribution of the internal carotid artery or the middle or anterior cerebral arteries. The peak incidence is between four and six years of age.10
Although strokes usually occur without warning, they are occasionally preceded by severe headaches or deterioration of school performance. The sudden appearance of a limp in a child with sickle cell disease warrants careful evaluation for a neurologic cause.
Strokes can be diagnosed by computed tomography or magnetic resonance imaging (MRI). Studies have recently shown that “silent” lesions on MRI studies (even in the absence of clinical signs) or high flow values on transcranial Doppler ultrasound examinations are associated with a high risk of stroke; treatment of such findings may be warranted.11 These imaging studies should be obtained and read by personnel and physicians with specific expertise in pediatric sickle cell disease.
Monthly transfusions are the main treatment currently available for stroke. Transfusions have inherent risks, including infection, allosensitization and iron overload.
Gallbladder Disease
Because children with sickle cell disease have chronic hemolysis, they are prone to develop pigmented gallstones. Laparoscopic cholecystectomy should be considered if a child has severe recurrent right upper quadrant pain or an episode of cholecystitis, common duct obstruction or pancreatitis. The procedure is usually well tolerated.12
Preoperative transfusion should be performed to raise the hematocrit to 30 to 32 percent. Lowering the relative percentage of hemoglobin S with transfusions is not necessary for cholecystectomy or any other major surgery.13
Renal Complications
The kidney is prone to damage from sickle cells. Children with sickle cell disease and sickle cell trait are unable to concentrate urine appropriately and therefore have a high incidence of enuresis.14
Hematuria can occur in children with any type of sickle cell disease and, occasionally, in those with sickle cell trait.14 The bleeding is usually mild, but it can be severe enough to necessitate blood transfusion.
The child who presents with gross blood in the urine should undergo a genitourinary work-up to rule out other causes. Bed rest and hydration usually suffice to control symptoms.14
Starting in the second decade of life, the child with sickle cell disease may show signs of chronic kidney damage. If urinalyses show persistent microscopic hematuria or significant proteinuria, a pediatric hematologist and/or a pediatric nephrologist should be consulted.
Pain
The pain episode is the most distressing symptom in patients with sickle cell disease. Pain can be severe and debilitating, and it often interferes with school performance or employment. The American Pain Society has recently published specific guidelines for the management of sickle cell pain.15
The patient with sickle cell disease is no more or less prone to addiction to narcotics than any other patient. Because sickle cell pain is episodic and severe, the patient should be treated with as much narcotic as required. In time, the patient may develop tolerance to medication and therefore require relatively large doses; however, once the pain has begun to subside, the narcotic can be discontinued gradually without withdrawal symptoms and without the need for more medication until the next event.
Ibuprofen (Advil, Motrin) or acetaminophen (e.g., Tylenol) with or without codeine often controls pain in a child younger than six years. The older child may require a more potent narcotic analgesic. Massage and local application of heat are helpful ancillary measures.
If the pain is so severe that parenteral narcotic therapy is required, morphine is preferred over meperidine (Demerol)16 because morphine can be given subcutaneously if venous access is a problem and because meperidine may cause seizures after a few days of administration. Ketorolac (Toradol), a non-steroidal anti-inflammatory drug usually given parenterally, has been shown to be quite effective, and it can lessen the requirement for intravenously administered narcotics.17
In the older child or adolescent, narcotic administration by patient-controlled analgesia is advantageous because it allows titration of the medication to the severity of pain and gives the patient a sense of empowerment.18 It is important to use an age-appropriate pain scale to assess the patient's pain. The pain scale can serve as an objective guide for medication regulation.
If oral intake is poor, intravenous hydration should be given, but the patient should be monitored carefully. Depending on oral intake and hydration status, intravenous fluids should be no more than 1.5 times greater than the maintenance volume.
Prophylactic hydroxyurea (Hydrea) therapy lessens the incidence and severity of pain episodes in many adults with sickle cell disease. It can also decrease the incidence of acute chest syndrome.19 Trials of hydroxyurea in children have been limited, although a few short studies have shown this agent to be well tolerated, nontoxic and often effective.20–22 Like adults, children who receive hydroxyurea require careful follow-up and dosage adjustment based on frequent laboratory determinations.
Recent Advances
Gene therapy continues to be studied as a way to inactivate the sickle gene, to increase expression of the gene for hemoglobin F or to introduce genes whose products can inhibit the polymerization of hemoglobin S.
Bone marrow transplantation can be curative, but it still presents problems. Long-term follow-up is lacking, and the procedure is expensive and not widely available. Another serious barrier to the use of bone marrow transplantation is the frequent lack of a human leukocyte antigen–matched sibling as donor in the individual case.23
The use of cord-blood stem cells might avoid some of the problems of bone marrow transplantation.24 Nonablative marrow infusion, rather than total marrow replacement, also shows promise. Other treatment modalities currently being studied include arginine butyrate to enhance fetal hemoglobin production25; poloxamer 188, a nonionic surfactant, to reduce the length of pain crises26; and nitric oxide, to manage acute chest syndrome.27
In another 20 years, sickle cell disease may join the ranks of chronic illnesses that, when properly treated, do not interfere with the activity, growth and mental development of affected children. Even before practical breakthroughs in gene therapy are achieved, collaborative studies may demonstrate the usefulness and feasibility of a combination of therapies in treating certain complications and may provide optimal timing for certain interventions.