EVAN S. FIELDSTON
HISTORY OF PRESENT ILLNESS
A 13-year-old African-American male presented to the emergency department with a 2-day history of worsening back pain. The pain was located in his upper and lower back, and although he was uncomfortable in any position, standing upright made his back pain significantly worse. His pain was not relieved with cyclobenzaprine, a muscle relaxant. The patient had no history of trauma and he denied weakness, sensory loss, and bowel or bladder dysfunction as well as recent fevers, upper respiratory symptoms, cough, nausea, vomiting, weight loss, and night sweats.
The boy’s medical history was remarkable for one previous episode of back pain 2 years earlier that required use of a wheelchair for 2 weeks. He received iron supplements for treatment of anemia that was discovered at that time. Additional details of that episode were not available. He had never been hospitalized and had no surgical problems. He was not sexually active and had no history of cigarette or drug use. Family history was significant for a sister with sickle cell trait.
T 37.7°C; RR 24/min; HR 110 bpm; BP 105/70 mmHg; Weight 35 kg (<10th percentile)
The patient was a well-developed, well-nourished male crying in pain. Head, eyes, ears, nose, and throat were normal. There was no lymphadenopathy. There was no thoracic wall tenderness. The heart and lung sounds were normal. His abdomen was soft and nontender without hepatomegaly or splenomegaly. He had no point tenderness of his back; however, he complained of “inside pain” over his sacrum. Rectal examination revealed normal sphincter tone and no palpable masses. His extremities were warm with good peripheral pulses and full range of motion of all four extremities. His neurologic examination revealed normal strength, sensation, and 2+ reflexes.
Complete blood count revealed 8400 white blood cells/mm3 (81% segmented neutrophils, 17% lymphocytes, 2% basophils, 1% eosinophils, and no bands), hemoglobin of 10.4 g/dL; mean corpuscular volume (MCV) 72 fL; mean corpuscular hemoglobin content (MCHC) 23.4 g/dL; red cell distribution width (RDW) 15.1; and platelets 241 000 platelets/mm3, and a reticulocyte count of 3%. Blood smear showed anisocytosis, poikilocytosis, and polychromasia. Electrolytes, blood urea nitrogen, creatinine, and glucose were normal. Erythocyte sedimentation rate was 20 mm/h. Urinalysis revealed small amounts of urobilinogen.
COURSE OF ILLNESS
The patient was treated with morphine and ketorolac without much relief. He became febrile to 38.7°C and blood and urine cultures were obtained. The pain became localized to his sacral/coccygeal region, but he had no numbness or tingling and his reflexes remained normal. While abdominal radiograph did not reveal bowel obstruction, it suggested a likely underlying condition (Figure 5-6) that was later confirmed by specific testing. An MRI of the lumbosacral spine was negative for an abscess or a locally infiltrative process.
FIGURE 5-6. Plain radiograph of spine showing vertebral deossification due to marrow hyperplasia and flattened, widened vertebral bodies with biconcave depressions of the end plates known as “H-shaped” or “fish mouth” vertebrae.
DISCUSSION CASE 5-5
Back pain is less common in children than in adults, but unlike adults, it usually is the result of a serious underlying pathology. In adolescents, traumatic or overuse injuries such as compression fractures, musculoskeletal strain, spondylolyis, spondylolithesis, and lumbar disc herniation should be considered. Most of these injuries often present during the adolescent growth spurt and are associated with repeated lifting and back extension, especially in sports. Infections of the vertebral column that cause back pain include osteomyelitis and diskitis especially in toddlers and young children. Less common but serious causes include spinal epidural, paraspinal or psoas abscess, transverse myelitis, and pyomyositis. Urinary tract infections and pneumonia can cause back pain but these are less likely in the absence of urinary or respiratory symptoms. Neoplastic diseases like leukemia and lymphoma should be considered especially with progressive, indolent pain. Malignancies are usually accompanied by constitutional symptoms including weight loss, fatigue, fever, and loss of appetite. Rare causes of back pain include spinal hematoma, spinal tuberculosis (Pott disease), and brucellosis, a zoonotic infection transmitted from animals to man that causes flu-like symptoms including back pain. Back pain secondary to acute bone infarction often occurs in adolescents with sickle cell disease (SCD). Patients usually have normal or mildly elevated temperature and ESR. However, in some cases this condition is indistinguishable from acute osteomyelitis. SCD should be included in the differential diagnosis of an African-American child with back pain, anemia, and a family history of sickle cell trait. In this case, the acute fall in the patient’s hemoglobin level, splenomegaly, vertebral abnormalities, and the persistence and severity of the patient’s symptoms prompted further evaluation leading to the diagnosis. While most patients are diagnosed by newborn screening tests, some patients may inadvertently not be screened or may be lost to follow-up.
Biconcave vertebral depressions, known as the “fish mouth” deformity, suggested the diagnosis of SCD (Figure 5-6), a group of conditions characterized by the presence of hemoglobin S in the absence of normal hemoglobin A or in a quantity greater than that of hemoglobin A. Hemoglobin electrophoresis confirmed the diagnosis of sickle-beta+ thalassemia (Sbeta+ thalassemia): HbA (18.4%), HbS (63%), HbF (8.1%), HbA2 (7.7%). Sbeta+ thalassemia, a less severe form of SCD, results from inheritance of the sickle hemoglobin (HbS) and beta+ thalassemia genes. In Sbeta+ thalassemia, some normal beta-chains are produced and therefore some HbA is present. A similar hemoglobin profile may be seen in HbSS disease following transfusion. However, in this case, the patient never received a red blood cell transfusion. Therefore, his diagnosis was a vasoocclusive event secondary to underlying Sbeta+ thalassemia. In retrospect, the anemia diagnosed during his previous episode of back pain was likely due to SCD rather than isolated iron deficiency anemia.
INCIDENCE AND ETIOLOGY
SCD is an autosomal recessive genetic disorder characterized by the presence of sickle hemoglobin (HbS) in red blood cells. Approximately 8% of the African-American population carries sickle cell trait (heterozygote) and approximately 0.2% of African-American newborns have SCD (homozygote). More than 70 000 Americans have SCD. The most common forms of SCD are homo-zygous sickle cell disease (HbSS), sickle-hemoglobin C disease (HbSC), and two types of sickle beta-thalassemia: sickle-beta+ thalassemia and sickle-beta0 thalassemia (Table 5-6). Individuals who inherit the genes for both HbA and HbS have sickle cell trait, a generally benign and asymptomatic carrier state.
TABLE 5-6. Genotypes of the four common types of sickle cell disease in the United States.
HbS results from an inherited abnormality of hemoglobin function caused by substitution of valine for glutamine at the sixth position of the beta-globin gene. Deoxygenated HbS polymerizes, distorting the shape of the red blood cell. Red blood cell distortion leads to hemolysis and vaso-occlusion, the two dominant features of SCD. Beta-thalassemia generally results from single point mutations that result in decreased (beta+ thalassemia) or absent (beta0) synthesis of beta globin. This commonly results in microcytic and hypochromic anemia.
The occurrence of sickle cell-B thalassemia is determined by the distribution and prevalence of two abnormal genes. The sickle gene occurs in high frequency among populations in Equatorial Africa, Mediterranean, Middle East, and India; populations that were exposed during evolution to selection pressure from falciparum malaria. The distribution of beta-thalassemia tends to be sporadic with high frequencies in the Mediterranean and in South East Asia. The combination of beta thalassemia with the sickle mutation results in the combined heterozygous condition known as Hb S-beta thalassemia. The clinical problems are quite variable depending on the amount of Hb A produced. Sickle-beta0 thalassemia produces no normal beta-chains and therefore no Hb A. S-beta0 thalassemia resembles HbSS electrophoretically, hematologically, and clinically. In contrast, the spectrum of severity in Hb S-beta+ thalassemia varies ranging from very little Hb A production to near normal amounts depending on the beta thalassemia mutation.
Universal screening for SCD has been widely available in most states in the United States since 1986, and therefore most children with SCD are diagnosed as newborns. A few infants, even in states with universal screening, may not be screened and the diagnosis may be missed in others because of extreme prematurity, blood transfusions prior to screening, or inadequate follow-up after discharge. In some patients with sickle-beta+ thalassemia, the levels of Hb A are sufficiently high to impair polymerization of Hb S and reduce intravascular sickling of the red blood cells. The early clinical course in these patients is mild with significant symptoms appearing later in life.
Acute and chronic complications of SCD involve multiple organ systems (Table 5-7). Acute painful events are the most common cause of emergency room visits and hospitalizations among patients with SCD. These events may be precipitated by weather extremes or temperature changes, dehydration, infection, stress, and menstruation; however, the majority of painful events have no identifiable trigger. Painful episodes vary from mild to debilitating. Pain is usually self-limited, lasting from a few hours to a few days though inadequate treatment may prolong the episode for weeks. Bones and joints are major sites of pain in vasoocclusive events. Acute bone pain is caused by marrow ischemia resulting in necrosis and periosteal inflammation. Pain is widespread and migratory during the acute painful crisis. Local tenderness, warmth, swelling, and impaired motion occur with a severe pain episode as the generalized pain improves. In the finger and toes it is known as dactylitis. It is seen as early as 6 months of age, but usually stops by age 10 years due to the replacement of red marrow with fatty tissue. As seen in this patient, vertebral infarction may lead to collapse of the end plates known as “fish mouth” vertebra. No single clinical feature can reliably distinguish osteomyelitis from bone infarction. In the femoral head, aseptic necrosis of the femoral head occurs in 30% by 30 years.
TABLE 5-7. Complications of sickle cell disease by organ system.
Other manifestations of vasoocclusive events include acute chest syndrome, which occurs more often in children than in adults, but has higher mortality in adults than in children (4% vs. 2%). Stroke occurs more frequently in HbSS, in 8%-10% of patients by age 20 years, and is also more common in childhood with a high rate of recurrence (70%-90%). Priapism occurs in approximately 40% of males, including children. Leg sores and ulcers appear in 10% of patients, usually after the age of 10 years. Hepatomegaly is found in half of patients and cholelithiasis in 30%-70%. Over time, splenic infarcts lead to functional asplenia, which affects 14% of patients by 6 months and 94% of patients by age 5 years. Renal failure occurs in 5%-18% of patients with median onset of 23 years of age. Half of patients with SCD survey past the fifth decade, with many not having overt organ failure, but rather death from an acute episode of pain, chest syndrome, or stroke. Patients with more symptomatic disease and lower fetal hemoglobin levels had lower survival.
Hemoglobin electrophoresis. This is the most common method in clinical laboratories used to determine hemoglobin phenotype.
Complete blood count with differential. At baseline, hemoglobin values in patients with S-beta+ thalassemia, reticulocyte, and white blood cell counts are close to normal with the major difference being a modestly low mean corpuscular volume (MCV) and mean corpuscular hemoglobin content (MCHC). This is in contrast to Hb SS disease where the steady-state WBC and reticulocyte counts are higher than in an unaffected person. The white blood count is often elevated with both bone infarcts and infection; however, a shift in the differential toward neutrophil predominance is more likely with osteomyelitis than with infarction.
Peripheral blood smear. Microcytosis, hypochromia, anisocytosis, and poikilocytosis characterize Hb S beta (+) thalassemia. Sickled cells are not always seen especially when high levels of non-S hemoglobin are present making the diagnosis less obvious in some cases.
Blood cultures. Blood cultures should be obtained before antibiotics are administered. Blood cultures are negative in bone infarction and frequently positive in osteomyelitis.
Sequential radionuclide bone marrow and bone scan. Diminished radionuclide uptake on the bone marrow scan is indicative of decreased blood flow in the bone marrow, and abnormal uptake on the bone scan at the site of pain are seen with bone infarction. In contrast, acute osteomyelitis results in normal activity on bone marrow scans and increased activity on bone scans.
Magnetic resonance imaging (MRI). MRI can replace bone scan in evaluation of bone pain in patients with sickle cell disease without exposure to ionizing radiation. MRI findings of cortical defects, adjacent fluid collections in soft tissue, and bone marrow enhancement suggest infection.
Plain radiography. Radiography is useful in monitoring the progression of established changes of infection, infarction, and osteomyelitis but not in diagnosing acute infections or infarctions. In older children and adolescents, plain radiographs may show deossification due to marrow hyperplasia and flattened, widened vertebral bodies with biconcave depressions of the end plates known as “H-shaped” or “fish mouth” vertebrae (Figure 5-6).
Severe bone pain should be considered a medical emergency that prompts timely and aggressive management until the pain decreases to a tolerable level. Major barriers to effective management of pain are inadequate assessment of pain and biases against opioid use. Most of the time, these biases are based on clinician uncertainty regarding opioid tolerance and physical dependence, and confusion with addiction.
As previously mentioned, bone infarction resembles osteomyelitis. Fever in cases of bone infarction is due to necrosis and inflammation associated with marrow ischemia. Blood cultures must be obtained if empiric antibiotics are initiated. Appropriate antibiotics should cover Salmonella and Staphylococcus aureus, the most common causes of osteomyelitis in children with sickle cell disease.
Patients with signs of moderate to severe dehydration should receive 10-20 mL/kg of intravenous normal saline followed by intravenous fluid at or slightly above (1-1.5 times) the daily fluid requirement. It is important to assess the severity of pain at presentation and at frequent intervals using age-appropriate pain-measuring scales. Pain should be re-evaluated every 15 minutes until pain starts to decrease, then every 30-60 minutes as needed. Severe acute pain requires intravenous (IV) medication, such as morphine sulfate, hydrocodone, or fentanyl with or without nonsteroidal antiinflammatory drugs, such as ketorolac and ibuprofen. Patient-controlled analgesia (PCA) devices restore patient control over their pain and may be used for patients in severe pain. PCA pumps provide analgesic medication continuously at a low baseline rate and allow patients to self-administer an additional dose of opiod whenever they feel a need for more pain relief. Continuous epidural analgesia has been used in patients with pain below the fourth thoracic dermatome who failed IV PCA opioids, and nonopioid analgesics; however, not much information is available about its use in SCD patients.
Patient and parental preferences for pain medication should be considered since individual variations in drug metabolism determine dose-response to analgesia. The use of parental meperidine should be avoided because of CNS toxicity related to its metabolite normeperidine. Patients receiving opioids for more than 1 or 2 weeks should be weaned slowly over several days to prevent withdrawal symptoms. Side effects of opioids including respiratory depression and sedation should be monitored closely. Antiemetics like compazine or metachlorpropamide effectively treat symptoms of opioid-related nausea. Stool softeners to prevent constipation should be taken daily if patients remain on opioids for more than a few days.
Chronic treatment of SCD should be under the supervision of a hematologist and includes appropriate immunizations, penicillin prophylaxis in children, folic acid supplementation, and hydroxyurea to increase fetal hemoglobin production. Some patients may receive blood transfusions to decrease the risk of stroke.
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