The ability to identify patients at high risk of complications from sickle cell disease would be helpful in selecting appropriate treatment. Miller and colleagues analyzed data from the Cooperative Study of Sickle Cell Disease to determine if there were features of the disease in infants and young children that could serve as predictors of disease severity later in life.

From October 1978 through October 1988, 414 infants (mean age: 3.0 ± 1.5 months) with sickle cell anemia or sickle cell–β⁰-thalassemia were enrolled in the Cooperative Study of Sickle Cell Disease. Of these 414 infants, 392 were included in the study; 380 had sickle cell anemia and 12 had sickle cell–β⁰-thalassemia. Follow-up ended in August 1998. The mean duration of follow-up was 10.0 ± 4.8 years. The database was closed in August 1999.

Clinical events included stroke, a “painful event” of the arms, legs, back, abdomen, chest or head that lasted more than two hours and required medical care, dactylitis (defined as pain and tenderness, with or without swelling, in the hands or feet, or both), acute splenic sequestration, the acute chest syndrome, the right upper quadrant syndrome, osteomyelitis and appendicitis. The four specific adverse events that served as proxies for severe sickle cell disease were (1) death related to sickle cell disease, (2) stroke, (3) an average of at least two painful events per year for three consecutive years during the entire follow-up period and (4) the occurrence of at least one episode of acute chest syndrome yearly during the entire follow-up period, with at least one episode per year for three consecutive years.

Of the 392 children in the study, 70 (17.9 percent) had one or more of the four adverse outcomes that qualified their disease as severe. There were an equal number of boys and girls in the group with severe disease. The most common adverse event that resulted in a classification of severe disease was stroke, which occurred in 25 (36 percent) of the 70 children. Stroke occurred at a mean age of 6.1 years.

Eighteen (26 percent) of the 70 children with severe disease died. Infection was the most common cause, accounting for 56 percent of the deaths. Splenic sequestration was the cause of death in 6 percent, and acute chest syndrome was the cause in 6 percent.

Ten children were classified as having severe disease because of acute chest syndrome. The mean age at which children were classified as having severe disease on the basis of acute chest syndrome was 3.5 years, and the mean number of episodes of chest syndrome during follow-up was 16.9 ± 9.2. In 17 children classified as having severe disease because of frequent pain, the mean number of painful events during follow-up was 41.7 ± 10.0.

The mean steady-state hemoglobin level in all of the children during the study was 9.0 ± 1.3 g per dL. This value correlated inversely and linearly with the severity of disease. Children with a hemoglobin level of less than 7 g per dL (700 g per L) were 2.64 times more likely to have severe disease than children with a hemoglobin level of 7 g per dL or more. The mean steady-state leukocyte count in the absence of infection during follow-up was 13,700 ± 450 per mm³ (13.7 × 10⁹ per L). Higher white blood cell counts correlated with severe disease.

Forty-one of the 70 children had dactylitis before their first birthday, and these patients were 2.67 times more likely to have severe disease. Multivariate analysis revealed that the highest risk of severe disease was in children with the combination of a hemoglobin level of less than 7 g per dL and early dactylitis, or one of these risk factors and a leukocyte count greater than 20,000 per mm³ (20 × 10⁹ per L).

The authors conclude that early dactylitis, a steady-state hemoglobin level of less than 7 g per dL and leukocytosis in the absence of infection are manifestations of sickle cell disease that may predict the possibility of severe disease later in life. They believe that the data provide a prognostic model to help estimate, but not specifically determine, a patient's risk of severe disease. The information from this study might be helpful in designing prospective trials for high-risk children who may benefit from interventional therapies such as stem-cell transplantation.