No abstract

Pulmonary hypertension, diagnosed by Doppler echocardiography, is common in adults with sickle cell disease. It appears to be a complication of chronic hemolysis, is resistant to hydroxyurea therapy, and confers a high risk of death. Therapeutic trials targeting this population of patients are indicated.

CUTE CHEST SYNDROME AND painful episodes are the most common precedents of death in adults with sickle cell anemia (SCA). 1 A randomized, doubleblinded, placebo-controlled trial, the

A randomized, controlled clinical trial established the efficacy and safety of short-term use of hydroxyurea in adult sickle cell anemia. To examine the risks and benefits of long-term hydroxyurea usage, patients in this trial were followed for 17.5 years during which they could start or stop hydroxyurea. The purpose of this follow-up was to search for adverse outcomes and estimate mortality. For each outcome and for mortality, exact 95% confidence intervals were calculated, or tests were conducted at a 5 0.05 level (P-value <0.05 for statistical significance). Although the death rate in the overall study cohort was high (43.1%; 4.4 per 100 person-years), mortality was reduced in individuals with long-term exposure to hydroxyurea. Survival curves demonstrated a significant reduction in deaths with long-term exposure. Twenty-four percent of deaths were due to pulmonary complications; 87.1% occurred in patients who never took hydroxyurea or took it for <5 years. Stroke, organ dysfunction, infection, and malignancy were similar in all groups. Our results, while no longer the product of a randomized study because of the ethical concerns of withholding an efficacious treatment, suggest that long-term use of hydroxyurea is safe and might decrease mortality. Am. J. Hematol. 85:403-408, 2010. V

In 1,814 patients with sickle cell disease who had been transfused, the overall rate of alloimmunization to erythrocyte antigens was 18.6%. The rate of alloimmunization in this group appears to be an explicit function of the number of transfusions received because it increases exponentially with increasing numbers of transfusions. Alloimmunization usually occurred with less than 15 transfusions, although the rate of alloimmunization continued to increase when more transfusions were given. The rate of alloimmunization was less in patients with hemoglobin SC disease and sickle-beta+ thalassemia because these patients had received fewer transfusions. Children less than 10 years old had a slightly lower rate of alloimmunization than patients in other age groups even after correction for the number of transfusions given. Women were more frequently alloimmunized than men; this was largely due to the fact that women received more transfusions than men, but in the age group 16 to 20 years the increase may have been due in part to alloimmunization owing to pregnancy. Forty-five percent of those alloimmunized made antibodies of only one specificity; 17% made four or more antibodies reacting with different antigens. Antibodies to the C and E antigens of the Rh group, the Kell antigen, and the Lewis antigens were most commonly made. These findings may be important in formulating a rational transfusion policy in sickle cell disease.

Few results on cardiac catheterization have been published for patients with sickle cell disease (SCD) with pulmonary hypertension (PHTN). Their survival once this complication develops is unknown. We analyzed hemodynamic data in 34 adult patients with SCD at right-sided cardiac catheterization and determined the relationship of PHTN to patient survival. In 20 patients with PHTN the average systolic, diastolic, and mean pulmonary artery pressures were 54.3, 25.2, and 36.0 mm Hg, respectively. For 14 patients with SCD without PHTN these values were 30.3, 11.7, and 17.8 mm Hg, respectively. The mean pulmonary capillary wedge pressure in patients with PHTN was higher than that in patients without PHTN (16.0 versus 10.6 mm Hg; P ‫؍‬ .0091) even though echocardiography showed normal left ventricular systolic function. Cardiac output was high (8.6 L/min) for both groups of patients. The median postcatheterization follow-up was 23 months for patients with PHTN and 45 months for those without PHTN. Eleven patients (55%) with PHTN died compared to 3 (21%) patients without PHTN ( 2 ‫؍‬ 3.83; P ‫؍‬ .0503). The mean pulmonary artery pressure had a significant inverse relationship with survival (Cox proportional hazards modeling). Each increase of 10 mm Hg in mean pulmonary artery pressure was associated with a 1.7-fold increase in the rate (hazards ratio) of death (95% CI ‫؍‬ 1.1-2.7; P ‫؍‬ .028). The median survival for patients with PHTN was 25.6 months, whereas for patients without PHTN the survival was still over 70% at the end of the 119-month observation period (P ‫؍‬ .044, Breslow-Gehan logrank test). Our findings suggest that PHTN in patients with SCD shortened their sur-

Acute chest syndrome (ACS) is an important cause of morbidity and mortality in sickle cell disease (SCD). Previous studies reported conflicting pictures of ACS making therapeutic interventions difficult. The Cooperative Study of Sickle Cell Disease prospectively followed 3,751 patients enrolled from birth to 66 years of age for ACS. Data on presenting signs and symptoms, laboratory findings, and hospital course were collected. There were 1,722 ACS episodes in 939 patients. Young children (age 2 to 4 years) presented with fever and cough, a negative physical exam, and rarely had pain. Adults were often afebrile and complained of shortness of breath, chills, and severe pain. Upper lobe disease was more common in children; multilobe and lower lobe disease affected adults more often. Severe hypoxia occurred in 18% of adults tested and could not be predicted by examination or laboratory findings. Bacteremia was documented in 3.5% of episodes, but was strongly influenced by age (14% of infants and 1.8% of patients <10 years). ACS was most common in winter with children having the most striking increase. Transfusion was used less frequently, but earlier in children. Young children were hospitalized for 5.4 days versus 9 days for adults. Fifty percent of adults had a pain event in the 2 weeks preceding ACS and children were more likely to have febrile events. The death rate was four times higher in adults than in children. Fatal cases generally developed rapid pulmonary failure and one third were associated with bacteremia. Age has a striking effect on the clinical picture of ACS. In children, ACS was milder and more likely due to infection, whereas in adults ACS was severe, associated with pain and had a higher mortality rate.

Diastolic dysfunction and pulmonary hypertension each contribute independently to prospective mortality in patients with SCD. Patients with both risk factors have an extremely poor prognosis. These data support the implementation of echocardiographic screening of adult patients with SCD to identify high-risk individuals for further evaluation.