During 426 patient-years of follow-up for patients with standard criteria, 3.3 acute chest syndromes, 1.3 cerebrovascular events, and 1.1 osteonecrosis per 100 patient-years were observed.

In 72 patients evaluated by transcranial Doppler studies (TCD), 34 patients were at risk of primary stroke and only 1 had a cerebrovascular event after a follow-up of 96 patient-years.

HU was interrupted definitely for 12 patients: 7 underwent allogeneic bone marrow transplantation, 1 failed to respond after 2 years of treatment, 1 with HbSC because of a total Hb level higher than 13 g/dL, 2 refused to pursue the treatment after 1 and 2 years, and 1 patient developed malignancy.

Hydroxyurea was also transiently stopped in 3 cases, 2 for pregnancy and 1 for systemic lupus syndrome, diagnosed one year after the beginning of treatment.

Despite a sustained increase in HbF level and an increase in hydroxyurea doses to 30 mg/kg per day, a girl aged 13 months at inclusion with previous history of splenic sequestration, was hospitalized 20 times during these 2 years of HU therapy and continued to present multiple vaso-occlusive crises and dactylitis during the first year of HU.

She died during the second year of therapy from acute severe anemia during an episode of splenic sequestration.

Acute promyelocytic leukemia was diagnosed in a 21-year-old female after 8 years of HU therapy.

Hospitalizations, VOCS, and ACS were more frequently observed after 3 years of treatment than during the first 3 years.

Recurrent stroke was observed once in an 8-year-old girl, 6 years after the initial event.

There were 8 patients followed for a median of 6 years (range, 3-9 years), with 44 cumulative patient-years of follow-up, at risk of secondary stroke.

Recurrent stroke occurred in one patient after 6 years of follow-up despite evidence of good compliance with therapy as assessed by hematologic response to HU.

As a whole, 34 patients were considered at risk of primary stroke on the basis of abnormal TCD, and 7 of the 21 explored by MRI/MRA had moderate/severe arterial stenosis.

Only 1 of these 34 patients presented a cerebrovascular event (seizures) after an evaluation of 96 patient-years.

One patient who died was described previously.

Toxicities of HU were reported with 2 transient episodes of thrombocytopenia (2 infants) that required temporary discontinuation of therapy.

There were 5 episodes observed of severe anemia (Hb, < 6 g/dL) that required transfusion (4 infants).

Aplastic crisis associated with a parvovirus infection was documented in one patient.

During the trial period, 75 ACS events occurred and were 2 times more frequent in the placebo arm (51 events) than in the HU arm (25 events).

In transfused patients, the prevalence of recurrent stroke has been reported at 13% to 22% (with one recurrence for each 24-41 patient-years) and the prevalence of TIA is 19%.

In particular, the Belgian experience with chronic transfusion is very disappointing because of a high rate of severe alloimmunization, mainly explained by the absence of blood donors of African origin.

Repeated vaso-occlusive crises are sometimes present from infancy and early childhood.

Furthermore, dactylitis, anemia, and high WBC counts in infancy predict a severe outcome, and this could trigger an early start of HU in these patients.

Of interest, 4 of the children included in the registry at younger than 2 years developed episodes of severe acute anemia.

One patient died of a fatal episode of splenic sequestration before completing 2 years of treatment.

During the dose titration, blood counts consistent with a finding of marrow depression were observed at least once in 35 percent of the patients who received placebo.

Treatment was temporarily stopped in almost all patients in the hydroxyurea group because of marrow depression; blood counts usually recovered within two weeks.

Treatment was interrupted in four patients in the placebo group because of increased bilirubinemia (bilirubin, > 10 mg per deciliter [103 umol per liter]).

Hair loss, rash, fever, and gastrointestinal disturbance were as common in patients receiving placebo as in those taking hydroxyurea.

In six patients (one in the hydroxyurea group) parvovirus b19 infection developed during treatment.

The aplastic crises caused by the virus were not prolonged, and all the patients recovered uneventfully.

We did not address the reversibility of chronic organ damage; it is unknown whether the inhibition of sickling could affect such preexisting lesions.

Hematopoietic depression did occur during therapy, as anticipated, but it was short lived.

Adverse reactions were equally common in both treatment groups.

There is concern that long-term hydroxyurea therapy may be carcinogenic or leukemogenic, because some other antineoplastic agents have such effects.

Adhesion molecules on the surface of erythrocytes, leukocytes and platelets are involved in vascular occlusion in sickle cell anemia.

On the other hand, hydroxyurea treatment reduced the percentage of reticulocytes (8.44% vs 4.46%) and of erythrocytes positive for CD36, CD71, CD49d and annexin V (Figures 1 and 2).

Hydroxyurea treatment reduced the percentage of annexin V+ erythrocytes in all patients, but one (Figure 1A).

Hydroxyurea treatment significantly reduced total leukocyte counts from pretreatment values.

The percentage of annexin V-labeled platelets was reduced during hydroxyurea treatment (Table 2) in all but two patients (Figure 1B).

The increase in MCV was positively correlated with the increase in F cells in the circulation and in hemoglobin concentration and negatively correlated with the percentage of reticulocytes and of cells expressing the adhesive molecules CD36, CD49d and annexin V (Figure 4).

This observation suggests that the increase in MCV may have a direct effect on the adhesive phenotype of sickle cells and that monitoring the increase of MCV may be used as indirect evidence of the decrease of the adhesive phenotype of erythrocytes in patients with sickle cell anemia treated with hydroxyurea.

In the present study we observed that the greatest PS exposure occurred on the largest erythrocytes, as demonstrated by flow cytometry (larger FSC) (Figure 3).

This population also showed a concentration of erythrocytes expressing CD71, CD36 and CD49d and of reticulocytes (data not shown).

Reticulocytes are the cells with the greatest adhesiveness to vascular endothelium in sickle cell anemia.

This increased adhesiveness has been attributed to the adhesion molecules CD36 and CD49d and, more recently, to PS exposure on the cell membrane.

PS exposure on the surface of sickle cells, in addition to affecting erythrocyte adhesion to the vascular endothelium, exacerbates anemia by enhancing phagocyte recognition and removal of these cells17 and favors the development of a thrombophilic state.

There is a direct correlation between PS exposure on sickle erythrocytes and the generation of thrombin.

Six patients with persistently abnormal TCD results developed stroke.

Persistent TCD elevation signals ongoing stroke risk.

Two patients who had quit transfusion subsequently died of sepsis.

From the SC group, 2 patients developed stroke soon after closure of the trial and started transfusion (1 at 2 weeks and another at 10 weeks after the trial).

In addition to the 12 stroke events in the STOP trial, 6 patients developed stroke during the posttrial follow-up (5 from the SC group and 1 from the TX group).

From the SC group, aside from the 2 patients who had stroke in the immediate posttrial period prior to choosing treatment, 1 patient who refused transfusion and 2 who started transfusion during the posttrial follow-up developed stroke.

The only patient from the TX group who developed stroke had discontinued transfusion after the trial.

All stroke events were ischemic infarctions.

All 6 patients who developed stroke during the posttrial follow-up had a last interpretable TCD that was abnormal prior to stroke regardless of transfusion status.

The data confirm that stroke risk increases with TCD velocity.

Elevated cerebral blood-flow velocities in SCD are related to severe anemia, vessel stenosis, and cerebral vasodilatation caused by tissue hypoxia.

Discontinuation of transfusion after at least 30 months in patients who have converted to normal velocities was associated with high risk of reversion to abnormal and chance of stroke.

Those with persistently abnormal TCD results despite transfusion often have severe vasculopathy and are at much higher risk for stroke.

Our report demonstrated in 2 patients that persistently abnormal TCD results while on transfusion is ominous and may predict the uncommon stroke that occurs on transfusion therapy.

Treatment was also withdrawn in 5 of 6 children who had developed hypersplenism, in 3 because of a pathological transcranial Doppler, and in 2 after a stroke.

One 18-year old patient, who had received hydroxyurea for 11 months and had only a slight reduction in the frequency of painful episodes, died suddenly from asystole while he was hospitalized for a painful crisis.

No autopsy was performed and death was attributed to a probable underlying SCD-related myocardiopathy.

In one child, already reported, a diagnosis of acute lymphoblastic leukemia with evidence of Philadelphia chromosome was made 1.5 months after starting hydroxyurea.

Of the five patients switched to hydroxyurea after normalization of their TCD under transfusion, two developed velocities above 200 cm/sec and were again prescribed regular exchange blood transfusions.

Treatment was also stopped in another patient because of the first occurrence of pathological TCD velocities.

Hydroxyurea was initiated in six patients because of history of stroke, which was the sole indication in two of them.

There were two stroke recurrences in our cohort.

One occurred after 3 months of treatment in a child in whom stroke was the only indication for hydroxyurea.

The second one occurred in a child whose past history of stroke was not the reason advocated by his physician for hydroxyurea treatment, this reason being the existence of painful crises.

This child had a stroke after 8 years of treatment.

Hypersplenism was observed in six Hb SS patients.

Before hydroxyurea treatment, three of them had splenomegaly and two a previous history of splenic sequestration.

The diagnosis was based on an increase in spleen size and concomitant thrombocytopenia; two cases, aged 6 and 7, had recurrent splenic sequestration crises.

Five patients were splenectomized, three of them have restarted hydroxyurea with good tolerance.

Hydroxyurea was stopped in seven of these patients (one because of headache, one because of hypersplenism, one because TCD velocity became abnormal, and four because of treatment failure).

Hypersplenism, which was diagnosed in six patients, is a classical complication of SCD, but recurrent splenic sequestration episodes are unusual in children aged 6 and 7 years, Hb SC children excepted, and suggest hydroxyurea-induced hypersplenism.

All these observations converge to suggest that hydroxyurea can prevent or delay functional asplenia, increasing the risk and lengthening the at-risk period for acute splenic sequestration episodes.

We, therefore, recommend careful evaluation of spleen size and blood tests at each evaluation in children with previous splenomegaly or a past history of splenic sequestration before starting hydroxyurea.

One malignancy occurred in our cohort, but analysis of this case led us to conclude that, most probably, the leukemia pre-existed the hydroxyurea administration, since the leukemia was diagnosed 1.5 months after starting hydroxyurea therapy.

This short interval strongly suggested that the bone pains which had prompted hydroxyurea treatment were in fact the first manifestation of the leukemia.

However, a special warning must be made concerning the potential occurrence of splenic twenty-five SCD children hypersplenism.

When the acute chest syndrome was diagnosed, patients had hypoxia, decreasing hemoglobin values, and progressive multilobar pneumonia.

Patients who were 20 or more years of age had a more severe course than those who were younger.

Neurologic events occurred in 11 percent of patients, among whom 46 percent had respiratory failure.

Among the specific causes were pulmonary fat embolism and 27 different infectious pathogens.

Eighteen patients died, and the most common causes of death were pulmonary emboli and infectious bronchopneumonia.

Infection was a contributing factor in 56 percent of the deaths.

Among patients with sickle cell disease, the acute chest syndrome is commonly precipitated by fat embolism and infection, especially community-acquired pneumonia.

Among older patients and those with neurologic symptoms, the syndrome often progresses to respiratory failure.

When we analyzed only patients who had hypoxia before transfusion (defined as an oxygen saturation of less than 91 percent), the values increased from 86 percent to 93 percent (P<0.001).

Respiratory failure was documented in 13 percent of patients.

Neurologic events occurred in 11 percent of patients.

The most common were altered mental status (in 56 percent), seizures (11 percent), and neuromuscular abnormalities (8 percent).

Anoxic brain injury occurred in three patients, central nervous system hemorrhage in three, and infarction in three.

Respiratory failure developed in 46 percent of patients with neurologic complications; 92 percent of these patients underwent transfusion, and 23 percent died.

Half the complications consisted of a transient decline in oxygen saturation.

Laryngospasm occurred in 10 patients, and pneumothorax developed in 2 patients, both of whom had had the acute respiratory distress syndrome before the bronchoscopy.

Eight patients underwent intubation because of bronchoscopic complications.

As compared with the patients who underwent bronchoscopy without incident, the patients who had complications were more likely to present with dyspnea (61 percent vs. 36 percent, P=0.04) and higher peak respiratory rates (mean, 47 vs. 41 per minute; P=0.03).

Eighteen patients died.

The primary causes of death were respiratory failure from pulmonary emboli (bone marrow, fat, or thrombotic) in six patients and bronchopneumonia in six.

The causes of death in the remaining patients were pulmonary hemorrhage, cor pulmonale, hypovolemic shock from splenic sequestration, overwhelming sepsis, intracranial hemorrhage, and seizure.

Overall, infection was a contributing factor in 10 deaths.

The organisms identified included Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae, legionella, cytomegalovirus, Staphylococcus aureus, and chlamydia.

A specific cause (either pulmonary fat embolism or an infectious agent) was identified in 256 (38 percent) episodes.

As in previous studies, we found that involvement of the lower lobes predominated, radiographic abnormalities progressed, and oxygenation and hemoglobin levels declined.

Neurologic complications developed in 22 percent of the adults in our study.

In nearly half these patients, respiratory failure subsequently developed.

The cause of the acute chest syndrome was established in 38 percent of episodes, and pulmonary infarction was the presumed cause in another 16 percent.

In contrast to prior studies, in which specific causes were seldom identified, infection and emboli were common causes in our study.

Chlamydia was the most common isolate and was associated with an increased rate of vaso-occlusive events, although the rate of infection with this organism was similar to that in the general population.

Mycoplasma and viral pneumonia, including that caused by parvovirus, occurred in all age groups, but predominated among young children.