Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
From www.bloodjournal.org by guest on June 15, 2017. For personal use only. Clinical Events in the First Decade in a Cohort of Infants With Sickle Cell Disease By Frances M. Gill, Lynn A. Sleeper, Steven J. Weiner, Audrey K. Brown, Rita Bellevue, Ranjeet Grover, Charles H. Pegelow, and Elliott Vichinsky for The Cooperative Study of Sickle Cell Disease Within the Cooperative Study ofSickleCellDisease,694 infants with confirmed sickle cell disease were enrolled at less than 6 months of age. Information about the nature and frequency of complications was collected prospectively over a IO-year period. Painful crises and acute chest syndrome were the most common sickle cell-related events in homozygous sickle cell anemia (SS), hemoglobin SC disease (SC), and Sa thalassemia patients [overall incidence in SS patients of 32.4 and 24.5 cases per 100 person-years, respectively). Bacteremia occurred most frequently in SS children under 4 years of age andin SC patients less than 2 years of age. The mortality rate was low in this cohort compared with that found in previous reports. Twenty children, all with Hb SS. died 11.1 deathsper 100 person-yearsamong SS patients). Infection, most commonly with Streptococcus pneumoffiaeand Hemophilus influenzae,caused 11 deaths. Two children died of splenic sequestration, 1 of cerebrovascular accident, and 6of unclear causes. Two patients underwent cholecystectomies, and 17 underwent splenectomies after one or more splenic sequestration crises. The experienceof this cohort should reflect closely the true clinical course ofthose childrenwith Hb SS and Hb SC disease who are observed in sickle cell centersin the United States. 0 1995 by The American Society of Hematology. T and 53% (365) were male. The majority of infants (77% during the first 3 years) were identified in the newborn hemoglobinopathy screening programs conducted atthe centers. Other infants were referred to the centers after being diagnosed as having sickle cell disease. The mean entry age was3.0 t 1.4 months(mean i 1 standard deviation), and the mean period of follow-up was 4.2 2 2.6 years. Twenty-five percent ofthe sample was observed for more than 6 years. Over theIO-year period, 20 patients (2.9%) diedand 161 (23.2%) were lost to follow-up (20.1% of SS patients, 27.2% of SC patients, 37.5% of Sp', and 2 1.4% ofSp" patients). The mean length of study participation for the infants lost to the study was 3.0 f 2. l years, compared with 4.7 2 2.6 years for those who were retained in the study and who did not die. Of those lost to follow-up, 27% participated in the study for 4 or more years. Table 1 provides details of the composition and follow-up of the cohort. There were less than 100 person-years of observation for SS patients morethan 6 years of age and SC patients more than 5 years of age. Data on the experience of children at older ages will accrue as this cohort ages. HE COOPERATIVE STUDY of Sickle Cell Disease (CSSCD) is a multicenter, longitudinal study that began patient enrollment in 1978. Within this study a subset of children was enrolled before 6 months of age at the time of a routine visit to a participating center. Information from this infant cohort is of particular value because data on all significant events have been prospectively collected. The experience of children over a 10-year period is reported here. A report of preliminary data on some events was presented at the National Institutes of Health (NIH)-sponsored Consensus Workshop for Hemoglobinopathy Screening in the Newborn.' MATERIALS AND METHODS Patients The designthe of CSSCD has been described Nineteen clinical centers entered 703 infants less than 6 months of age into the study between October 1978 and October 1988. The hemoglobin diagnosis was not confirmed in 9 infants; 694 infants with confirmed hemoglobin genotype are included in this analysis. Sixtytwo percent of the infants had homozygous sickle cell anemia (SS), 32% hemoglobin SC disease (SC), 5% Sp' thalassemia (Sp'), and 2% SO" thalassemia (Sp'). Forty-seven percent (329) were female From The Division of General Pediatrics, Department of Pediatrics, The University of Pennsylvania School of Medicine, Philadelphia, PA;theNewEngland Research Institutes, Watertown, MA; the Department of Pediatrics, State University of New York Health Science Center at Brooklyn, NY; Interfaith Medical Center, Comprehensive Sickle Cell Program, Brooklyn, NY; St Luke Hospital Sickle Cell Program, New York, NY; the Division of Pediatric Hematology, University of Miami, Miami, FL; and Oakland Children's Hospital, Oakland, CA. Submitted December 30, 1994; accepted February 23, 1995. Supported by the Division of Blood Diseases and Resources of the National Heart, Lung, and Blood Institute. Address reprint requests to Frances M. Gill, MD, The Children's Hospital of Philadelphia, 34th and Civic Center Blvd, Philadelphia, P A 19104. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact. 0 1995 by The American Society of Hematology. 0006-4971/95/8602-0003$3.00/0 776 Laboratory Diagnosis The Centers for Disease Control (CDC) determined the hemoglobin genotype by cellulose acetate and citrate agar electrophoreses and by quantitation ofthe fetal hemoglobin and hemoglobin A, have a CDClevels. There were 42 infants (6.1%) whodidnot confirmed diagnosis; the hemoglobin diagnosis of the participating center's laboratory was used instead. Complete blood counts were performed at the local center. a-Globin gene mapping to determine the presence of 01 thalassemia was performed on samples from 3 10 of the 427SS infants (73%) by Dr Stephen H. Embury at the University of California at San Francisco.?,' Data Collection Standardized forms wereused to record data collected during visits to the centers for scheduled visits and for acute events. Visits were scheduled for health maintenance in these young children at 2, 4, 6 , 9, 12, 15. 18, 21, and24 months andyearly thereafter. Patients included in this study received all their care, including that for acute events. at the participating centers. An acute event form was completed each time a patient came to the clinic or emergency room or was hospitalized for an event related to sickle cell disease. No attempt was made to set standard protocols for treatment of patients enrolled in the study. Specifically, there were no set recommendations for use of red blood cell transfusions, use of daily penicillin for prevention of infection, or age at administration of pneumococcal vaccine. However, in 1986 use of penicillin V administered in two daily doses for prophylaxis became standard therapy in all study centers. Polyvalent pneumococcal vaccine was administered Blood, VOI 86, NO 2 (July 15), 1995:pp 776-783 From www.bloodjournal.org by guest on June 15, 2017. For personal use only. 777 THE FIRST DECADE IN SICKLE CELL DISEASE Table 1. ComDosition of the Infant Cohort Hemoglobin Genotype Patients ~~~ 1.781.4 ss sc 62 Sg+ thalassemia S@' thalassemia Total 96 Person-Years of Observation* ~ 427 221 32 14 694 32 5 2 100 951.2 117.6 58.2 2,908.3 * Excludes 76.3 person-years of follow-up time accrued after the institution of chronic transfusion programs. For SS and Sg'thalassemia patients, complete follow-up time was 1,851.7 person-years and 64.2 person-years, respectively. excluded because of chronic transfusion programs. Group comparisons of incidence rates were conducted using exact binomial and the normal approximation to binomial hypothesis testing methods. Ninety-five percent confidence intervals (CI) were constructed using the normal approximation to the binomial distribution. Kaplan-Meier event-free survival curves were estimated and compared using the logrank test6 Time to event was measured by age rather than time on study, because follow-up began close to the time of birth. Descriptive statistics are presented as percentages and means 2 1 standard deviation. All hypothesis tests and confidence intervals are two-sided. A P value of .05 or less was considered a significant result. RESULTS to the study children, but each center determined the age of immunization. This age varied from 6 months at initial vaccination with revaccination at 2 years to initial vaccination at 2 years of age. Hemophilus influenzae type B vaccine became available in 1985 and was recommended for use at 18 months in sickle cell patients. The improved, conjugated vaccines used in infants were not available until 1990, after the period covered in this report. Dejinition of Events Sickle cell-related events were defined in a manual of operation used in each center. Only events that brought the child to the center for medical care were recorded. Standard treatment protocols or transfusion criteria were not set for the events. The event definitions were as follows. A painful event was defined as pain in the extremities, back, abdomen, chest, or head for which no other explanation (eg, osteomyelitis or appendicitis) could be found. Meningitis was defined as abnormal cerebrospinal fluid (CSF) findings and culture of CSF. Acute anemic episode was defined as either an acute splenic sequestration defined as a decrease of the hemoglobin or hematocrit level of at least 20% from baseline accompanied by an increase in palpated spleen size of at least 2 cm from baseline or as another acute anemic event defined by an acute reduction of the hemoglobin or hematocrit level of at least 30%from baseline and not caused by non-sickle cell problems (eg, blood loss, cancer, etc). Itwasnot possible to clearly separate other anemic events into aplastic episodes or hyperhemolytic episodes, so these were grouped as other anemic events for analysis. Clinical centers classified only six events as being hyperhemolytic. Acute chest syndrome was defined as the new appearance of an infiltrate on chest radiograph or, in presence of pulmonary symptoms and negative chest radiograph, abnormalities on an isotopic scan of the lungs. A skeletavjoint event was defined as acute pain involving one or more bones that lasted at least 7 days; osteomyelitis with identification of an etiological agent by culture; or nontraumatic swelling of one or more joints with pain or effusion. A patient entering with pain in his extremities would be recorded as a painful event, but if the pain lasted in the bone(s) for 7 days, a skeletalfjoint event form would be completed. Hand-foot syndrome was defined as pain and tenderness, with or without swelling, in the hands and/or feet of a child less than 10 years old. These events were reported on a hand-foot form rather thanon a skeletayjoint event form. A cerebrovascular accident (CVA) was defined as an acute neurologic syndrome secondary to the occlusion of an artery or to hemorrhage with resultant neurologic symptoms and signs. Statistical Analysis Incidence rates are presented as the number of cases per 100 person-years. To obtain incidence estimates that reflect the natural history of sickle cell disease, rates (for all events except transfusion) were based on events and follow-up time that preceded the institution of a chronic transfusion program; 2.6% of all follow-up time was Incidence of Events The incidence rates by age of the most common problems in Hb SS and SC patients are given in Table 2. All events with a positive blood culture result are included in the bacteremia category, even if there was an associated event such as meningitis. There were too few patients with S@thalassemia to define accurate incidence rates. There was no difference by gender in the incidence of acute anemic events, bacteremia, hand-foot syndrome, CVA, right-upper quadrant syndrome, receipt of transfusion, or death. Hb SS male children had a significantly higher incidence of acute chest syndrome (29.l v 20.1, P = .Owl)than did female children. Hb SS female patients had a significantly higher incidence of painful crises than did male patients (35.7 v 28.9, P = .0122). The reasons for these differences are unknown. All results given below are for combined genders. All deaths occurred in Hb SS patients with an overall incidence of 1.1 per 100 person-years (95% CI, 0.6 to 1.6). Time to First Event The data were used to determine the time until the first episode of selected complications. The time was significantly shorter in Hb SS compared with that in SC patients ( P S .01) for painful crisis, acute chest syndrome, all acute anemic events, splenic sequestration, hand-foot syndrome, bacteremia, transfusion, and CVA. Figure 1 shows the estimated percentage of patients experiencing a first event by a specified age for six common events. The risk of painful crisis and acute chest syndrome begins in the first year of life and increases steadily (Fig l). Half of all SS and SC patients experience a painful crisis by 4.9 years and 7.1 years of age, respectively. The acute chest syndrome is experienced byhalfof all SS patients by 5.8 years of age. Hand-foot syndrome is uncommon in SC patients, whereas one quarter of SS patients seek medical care for this event by 2.5 years of age. Acute anemic events are also uncommon in SC patients, but 10% of SS patients have had a splenic sequestration event by 3 years of age. Event Recurrence The risk of event recurrence was examined for the following events: acute anemia, painful crisis, acute chest, handfoot syndrome, and bacteremia. There were significant differences by hemoglobin genotype for recurrence of the acute From www.bloodjournal.org by guest on June 15, 2017. For personal use only. GILL ET AL 778 Table 2. Incidence per 100 Person-Years by Age Anemia Age <6 mo 2.0 6-12mo 18.2 1 Yr26.8 10.6 2 Yr26.3 10.4 3 Yr34.2 1.5 4 yr25.5 6.2 5.3 Genotype Painful Event Bacteremia Acute Chest Splenic Other Hand-Foot CVA ss sc 2.9 0.0 9.5 3.8 24.0 8.5 38.3 15.3 42.4 1.528.5 49.6 23.3 40.82.0 33.6 39.2 29.1 41.6 40.3 37.9 23.0 l .9 6.8 3.5 16.4 1 .o 0.0 5.5 0.0 2.9 0.0 5.0 0.0 14.6 0.0 31.3 1 .o 0.0 0.0 3.2 0.0 1.2 ss sc 7.7 ss6.5 sc 5.8 ss 8.7 1.2 sc ss4.7 sc ss 2.0 sc 5 yr ss sc 628.9 1.8 7 Yr20.8 ss 4.1 1.8sc ss 1.5 sc 8-10yr ss sc 0.0 9.9 0.0 1.5 0.0 13.1 0.0 0.0 1.4 1.30.0 9.7 22.5 5.2 2.9 1 .o 0.0 0.0 0.0 chest syndrome ( P < .01) and bacteremia ( P < .001). One quarter of S S patients experiencing the acute chest syndrome had a recurrent event within 6 to 9 months, whereas one quarter of SC children had a recurrent event within 3 years. Bacteremia recurred in 20 percent of S S children within 18 months, but recurrence was rare among the SC patients. Painful crisis recurred within 6 months in 32% of S S patients and 19% of SC patients. Hand-foot syndrome recurred within 6 months in 25% of S S and in 12% of SC children. Effect of cv Thalassemia a-Globin gene typing of 310 S S children showed that 10 (3.2%)had 2, 90 (29.0%) had 3, 207 (66.8%) had 4,and 3 (1.0%) had 5 cv genes. Analysis of the incidence of clinical events was performed for the 100 patients with cv thalassemia (2 or 3 genes) and for the 210 who had 4 or 5 cv genes (Table 3 ) . Children with cv thalassemia had a significantly higher incidence of painful events and a significantly lower incidence of acute chest syndrome and of acute anemic events other than splenic sequestrations. Specific Events Bacteremia. Bacteremia, defined as an acute event with positive blood culture results, occurred as an isolated event or in association with other complications such as acute chest syndrome, meningitis, osteomyelitis, and urinary tract infection. The responsible organism and associated events are detailed in Table 4. In Hb S S patients, the mortality rate was 14.5%in the 62 bacteremic infections with Streprococcus pneumoniae and 20.0% in the 10 bacteremic infections with H injluenzae. There were no deaths from bacteremia in the Hb SC patients or in SP thalassemia patients. Four bacteremic events occurred in 2 of the 32 Sp+ thalassemia patients. One patient had two infections 2 weeks apart with P-hemolytic streptococcus. The other patient had an 5.8 0.0 15.2 3.3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 8.3 0.0 3.0 0.0 1.9 0.0 2.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.5 0.7 2.1 1.5 0.0 0.0 acute chest syndrome caused by S pneumoniae and 2 years later sepsis with p hemolytic streptococcus. No episodes of bacteremia occurred in the 14 SPo thalassemia patients. Seventeen patients had bacteremia more than once. Twelve S S , 1 SC, and 2 SP+ patients had two episodes, and 2 S S patients had three. None of these patients died. Meningitis. There were 15 episodes of meningitis in Hb S S patients. Ten cases were caused by S pneumoniae. In addition to the 8 patients with positive blood culture results detailed above, 1 patient had a positive cerebrospinal fluid culture result but a negative blood culture result. In another patient who had received ampicillin before the diagnosis of meningitis, the CSF findings were compatible with bacterial meningitis, and the urine CIE was positive for Spneumoniae. One case was caused by H injluenzae, and 4 were presumed to be viral because no organism was isolated. Of the 8 cases of meningitis in Hb SC patients, 1 was caused by H injluenzae and 7 were presumed to be viral events. The reason for the higher incidence of viral meningitis in the SC patients is unknown. No cases of meningitis occurred in the S@ thalassemia patients. The incidence of bacteremia with S pneumoniae and H injluenzae and resulting mortality rate in Hb S S patients by calendar year is shown in Fig 2. Variation in the incidence is seen from year to year, as has been previously described.' Acute anemic events. In the S S cohort, 76 children had 127 acute anemic episodes. Forty-three patients had 61 acute splenic sequestration events, and 16 of these patients underwent splenectomy. Patients requiring splenectomy had a median age of 1.6 years (range, 0.3 to 4.1 years) at the time of the first sequestration event and a median age of 2.6 years (range, 0.8 to 5.3 years) at the time of splenectomy. The median interval from first sequestration to splenectomy was 8.2 months (range, 0.6 to 44.8 months). Among the S S patients undergoing splenectomy, there was one episode of From www.bloodjournal.org by guest on June 15, 2017. For personal use only. THE FIRST DECADE IN SICKLECELL 779 DISEASE a 1o.81 I:: 0.6 E 0.4 - r 02 E 0.4 c , A y W - 1.0 1 L ss 2 3 4 5 6 7 08 19 21 30 sc ss - l - 0.0 1 4 5 B SB+ 10.2 0.0 1 0 SBo 6 7 8 9 Age at Rrst WMUl cltsll,(9) 1 0 AgnatflrstAcuteChsatsyndmne(yn) 1.o C 1 D t :I : P P E 0.7 c E 0.7 LL y 'SBO ss - 2 0.6 - 0.6 . 0 1.0 *sc J c :::: E I 0 # 0.7 cp . 1 . 2 . . . . . . 1 . . . . . . . 2 3 4 5 6 7 8 9 Age at !% Acute l Anemic E r n Norrspbnic(ym) . 9 . . 1 0 1F : F 0.9 0.8 1 I - 0 . 3 4 5 6 7 8 AQS at Flm BMnsmieEvent (yn) . . . 1 0 0 . 1 . 2 . 3 Age at . 4 . 5 m . 6 . 7 8 . . . 9 1 0 (m) Fig 1. Age at first clinical eventin patients with sickle cell disease, from birthto 10 years of age. (A) Painful event.(B) Acute chest syndrome. (C) Hand-foot syndrome (dactylitis).(D)Bacteremia. (E) Acute anemic events not including splenic sequestration. (F) Splenic sequestration. bacteremia ( S viridans) in the months before splenectomy and none in patients after splenectomy. Acute anemic episodes were rare in SC children; 7 children had 10 events, 8 of which were caused by splenic Table 3. Comparison of Event Rates (Cases per100 Person-Years) in Hb SS Patients With and Without a Thalassemia SS (n = 2101 ~~ .2179 Painful event 43.27 27.63 Acute chest 20.08 26.96 Bacteremia6.00 4.49 Splenic sequestration .g291 3.73 3.63 Other anemic events 2.07 4.30 CVA 1.15 SS + a Thalassemia (n = 100) ~~~ P Value ~ <.0001 a120 0.00 a324 B186 sequestration. None of these patients required splenectomy. One S$ thalassemia patient had splenectomy at the age of 7.2 years after three sequestration episodes, the first occuring at 5.6 years of age. Mortality. Twenty children, all with Hb SS, died during the study period, for an overall incidence of 1.1 per 100 person-years. The mortality rate was highest between 6 months and 3 years of age (Fig 3). Eleven children died from infection (9 S pneumoniue and 2 H injuenzue), 1 from an infarctive CVA, 2 from acute splenic sequestration, and 6 from unclear causes. Of these 6 who died from unclear causes, no information is available for 1 patient. Autopsies were performed on 2 of the others. A 6-month-old found dead in bedwas classified as a sudden-infant-death syndrome, although no cultures were perf0rmed.A 2-year-old who collapsed while playing was found to have pulmonary congestion and some splenic enlargement. Autopsies were From www.bloodjournal.org by guest on June 15, 2017. For personal use only. GILL ET AL 780 Table 4. Bacteremic Events in SS and SC Patients Total Organism BoneiJoint Meningitis No. of Chest Cases Acute Bacteremla Isolated S pneumoniae H influenzae ss sc ss sc sc ss sc S viridans ss sc ss sc Other 14 ( 1 ) 8* (2) 3 0 1 3 2 2 0 2 1 4 1 0 0 1 0 0 0 1 0 0 1 0 0 0 0 2 1 l* 0 0 0 I§ 0 1 0 0 0 0 0 0 1 0 1 3 1 5 2 3 2 2 0 SCt Salmonella sp 9 6 (2) 2 5 ss E coli 39 (6) 12 10 4 5 1 ss S aureus 62 1 0 1 0 1 1 The numbers in parentheses are the number of deaths. * T w o of eight patients had concurrent pulmonary infiltrate (acute chest syndrome). t One SC patient had E coli bacteremia with a urinary tract infection. t Enterobacter. § H parainfluenza. notperformedon theremaining 3 children, and cause of death could not be determined clinically. A l-year-old child visitingHaiti became unconsciouswhileplaying andwas dead on arrival at the local hospital. A 2-year-old child had vomiting and diarrhea for 2 days, then had a seizure, was comatose on arrival at the hospital, and was declared to be Achest brain dead after 4 daysonlifesupportsystems. radiograph showed right pleural effusion and density.A 2.5year-old had fever for 1 day followed by lethargy and coma and died in the emergency department. Red blood cell transjiusions. Red blood cell transfusions were frequentlyadministered to Hb SS patients: 35% had received a transfusion by the age of 5 years compared with only8% of Hb SC patients. Among the Hb SS patients, 356 (48.7%) of the transfusions were administered for acute (51 3 % ) wereadministeredas pal-t ofa eventsand407 chronic transfusion program. No standard criteria for transfusionwere set by thestudy. In Hb SS patients the most common acute indications for transfusion were acute anemia (34.6%), acute chestsyndrome(27.5%), infection (9.8c?r), . ...... .. .. .. .. 3.14 . .. .. 1.00 1979 1980 1981 1982 1983 1984 YEAR 1985 1986 1987 1988 . Fig 2. Rates of Spneumoniae and H influenzae bacteremia and mortality caused by bacteremia in patients with sickle cell anemia who are 6 months to4 vears of age. 11. Incidence of bacteremia;(a) incidence of mo,.tality caused by bacteremia. From www.bloodjournal.org by guest on June 15, 2017. For personal use only. THE FIRST DECADE IN SICKLE CELL DISEASE 781 1 .0 ....................................................... .>_.. L. ... ................................ ......................... \___ -> 0.9 $ 0.8 ~ 6 12 c 0 P E 8 0.7 e n 0.6 0.5 Fig 3. Mortality in children with sickle call anemia. Ninetyfive percentconfidencebands are shown. l 0.5 0.0 3.5 I 3.0 I 2.5 1.02.0 and surgery (9.8%). Treatment of CVA was the indication for only 5.6% of acutely administered transfusions but accounted for 60.2% of those administered on a long-term basis. The second most frequent indication for chronic transfusion therapy was for prevention of recurrent anemic episodes. DISCUSSION The longitudinal study of the children in this infant cohort yields important information about the type and severity of events encountered by infants and young children with sickle cell disease. The advantages of this cohort study are the large number of children enrolled, the entry of all study subjects before 6 months of age, the inclusion of patients from a number of centers, and the prospective collection of data on virtually all significant events. As previously described,8"' the children with SS and SO' thalassemia in our study have had a more severe disease course than have those with SC and Sp' thalassemia. The most frequent events for all four genotypes are the painful crisis and the acute chest syndrome. In contrast, the handfoot syndrome and acute anemic episodes occur frequently only in SS and Sgo thalassemia children. Painful crises and the hand-foot syndrome rates in the study are certainly lower than the true incidence because only episodes for which the parents sought medical care were recorded. Those clinical events which result from cumulative organ damage were infrequent in this young cohort. Although cerebrovascular accidents occurred as early as 2 years of life, this complication was rare in the cohort: 13 events in SS patients and none in SC or S o thalassemia patients. The highest incidence (2.0 per 1 0 0 person-years) occurred in the 6 to 7 years of age SS group. An overall incidence of approximately 8% has been reported in other studies."," In a study of patients in Los Angeles conducted over a 25-year period, the overall incidence of stroke was 8.8% in 785 SS patients and 3.0% in 231 SC patients. However, the median l l I I 1.5 I I 4.05.0 I I 4.5 Age at Death (yrs) age at first CVA was 13.1 years in SS patients (range, 0.6 to 47.1 years) and 47.2 years in SC patients (range, 8.9 to 64.4 years)." In the Jamaican cohort study, 7.8%of patients had experienced a CVA by 14 years of age (median age, 6 years and 3 months; range, 15 months to 14 years)." The incidence of CVA in our newborn cohort is expected to increase as the cohort ages. The extension study of this cohort now in progress will provide needed data about uncommon events and about those caused by cumulative organ damage. Significant complications occurred in the first 6 months of life: bacteremia and splenic sequestration in SS patients and acute chest syndrome in SS and SC patients. Bacteremia was most frequent during the first 3 years of life in Hb SS children. The mortality rate was high from bacteremia in the SS patients in this age group (15.6% mortality in S pneumoniae infections and 22.2% in H injluenzae infections). In Hb SC patients, bacteremia occurred most frequently during the first 2 years of life, as was previously reported for the young SC patients in the entire CSSCD." The frequency of Spneumoniae and H injluenzae type B bacteremia in our SC cohort is higher than that reported for normal children seen in "walk-in" clinics in this ~ountry.'"'~ In a Jamaican cohort observed from birth, SC patients had serious infections at twice the rate of concurrently observed children with hemoglobin AA.L6 In contrast to the high mortality rate in the SS patients, none of the infections in SC or Sp+ thalassemia patients in this cohort were fatal. The infections in SC children appear to have been less fulminant andor more amenable to treatment than those in SS patients, perhaps because of the longer preservation of splenic function in SC patients.l7 However, fatal infections do occur in SC patients. Mortality in this infant cohort (1.1 deaths per 100 personyears for SS patients and 0 for other genotypes) is lower than that previously reported.8,'0,18-20 In a large patient group observed longitudinally in Los Angeles for the 25 years From www.bloodjournal.org by guest on June 15, 2017. For personal use only. 782 preceding 1990, the death rate in the first 5 years of life was about 3 per 100 person-years for SS patients and about 0.4 for SC children. The rate decreased dramatically in the 5to 9-year-old patients to about 0.8 per 100 person-years for SS patients and to 0 for SC patients.” In the cohort of Jamaican newborns, 13% of the SS and 5% of the SC children died by 2 years of age. In this Jamaican cohort, the deaths that occurred in SS children less than 6 months of age and all deaths in SC children were from diseases common to normal children and not related to the sickling disorder. In contrast, 10% of the Jamaican SS patients died between 6 and 12 months of age from infection or acute splenic sequestration. Children in the Jamaican cohort with fatal splenic sequestration died outside the hospital or within a short time of admission.2’ In the cohort study presented here, only two deaths were caused by splenic sequestration. Education of parents about this complication and the need for early medical treatment combined with the frequent use of red blood cell transfusions may explain the lower mortality rate from splenic sequestrations in our cohort. The low mortality rate in our cohort is due to multiple factors, including improvements in medical care, early identification and enrollment of affected infants in sickle cell treatment centers, parent education about serious complications and about the importance of seeking immediate medical care, and immediate antibiotic treatment for febrile illnesses. A randomized, placebo-controlled study showed the efficacy of twice-daily oral penicillin in decreasing mortality from S pneumoniae infections in SS patients.” Penicillin prophylaxis became standard in participating centers after the study results were published in1986. Although there were fewer infections with Spneumoniae and no deaths from infection in our cohort after 1986, the difference was not statistically significant compared with the earlier period. The protective effects of penicillin may have been obscured for several reasons. Two centers had used penicillin prophylaxis routinely and some selectively since 1978, the beginning of the cohort study. The number of person-years of observation for young children (those less than 2 years of age) was also lower in the last few years of the study and may have been too low to observe protective effects of penicillin prophylaxis. In a large patient population observed in Los Angeles, 233 SS children less than 6 years of age had been observed for 781 person-years by 1980.23Although none of the children received pneumococcal vaccine or penicillin prophylaxis, the mortality rate from Spneumoniae sepsis decreased from 75% before July 1972 to 0% after that date, and the mortality rate from S pneumoniae meningitis decreased from 65% to 18% in a comparable period. The overall mortality rate of 14.5% from all S pneumoniae infections in our newborn cohort is similar to that of the Los Angeles post-l972 experience. The use of penicillin prophylaxis and the age of polyvalent pneumococcal vaccination was variable in our cohort. The immunization of infants with conjugated H influenzae B vaccines was introduced after the period of observation reported here. These vaccines have dramatically decreased the incidence of invasive H influenzae B infections in normal GILL ET AL children and should help decrease morbidity and mortality in patients with sickle cell disease. The extension study now in progress should provide better information about the protective effects of prophylactic penicillin therapy andthe conjugated HIB vaccine. A conjugated polyvalent pneumococcal vaccine is now under development. The effects of a thalassemia on sickle red blood cells are well k n ~ w n .The ~ ~ clinical . ~ ~ effects of this interaction have been more difficult to ascertain. It has been reported that coexisting a thalassemia increases the incidence of certain complications of sickle cell disease, such as aseptic necrosis and proliferative retinopathy. In the analysis of painful crises from the CSSCD, increased hematocrit and lower fetal hemoglobin levels were associated with anincreased frequency of painful events, but no independent effect of coexisting CY thalassemia was found.26In a longitudinal study of patients, those with S S - a thalassemia had significantly different risk of events for only two categories of complications. The relative risk for soft tissue events (eg, renal, central nervous system, and leg ulcers) was significantly lower, the relative risk being .33 with 95% confidence interval of .17 to .61. Urinary tract infections also were significantly less common, with a relative risk of .61 and a 95% confidence interval of .37 to .97. No difference existed in the risk for other events, such as painful crisis or acute chest syndrome.“’ In this newborn cohort, the SS patients with a thalassemia had a higher incidence of painful crises than did those without a thalassemia but had lower incidences of acute chest syndrome, acute anemic events that were not splenic sequestration crises, and transfusion. All CVAs occurred in Hb SS patients without a thalassemia, but the number of events was small. More experience with larger numbers of young children will be needed to determine the possible effects of a thalassemia on clinical events in Hb SS patients. Life expectancy, especially in the early years of life, has improved significantly for children with sickle cell disease as medical care has improved and as deaths from infection have decreased. Newborn screening, parent education, early institution of penicillin prophylaxis therapy, and careful medical attention are essential for prevention of early mortality. Further improvement in the quality and length of life will depend on the prevention of chronic organ damage. New drug therapies and the judicious use of bone marrow transplantation may offer such improvement in the lives of patients with sickle cell disease. APPENDIX The following were senior investigators in the CSSCD: Clinical centers: L. McMahon, Boston City Hospital (Boston, MA); 0. Platt, Children’s Hospital (Boston, MA); F. Gill, K. Ohene-Frempong, Children’s Hospital (Philadelphia, PA); G. Bray, J. Kelleher, S. Leikin, Children’s National Medical Center (Washington, DC); E. Vichinsky, B. Lubin, Children’s Hospital (Oakland, CA); A. Bank, S. Piomelli, Columbia Presbyterian Hospital (New York, NY); W. Rosse, J. Falletta, T. Kinney, Duke University (Durham, NC); J. Smith, Y. Khakoo, Harlem Hospital (New York, NY); R. Scott, 0. Castro, C. Reindorf, Howard University (Washington, DC); H. Dosik, S. Diamond, R. Bellevue, Interfaith Medical Center (Brooklyn, NY); W. Wang, J. Wili- From www.bloodjournal.org by guest on June 15, 2017. For personal use only. THE FIRST DECADE IN SICKLECELL 703 DISEASE mas,LeBonheurChildren’sHospital(Memphis, TN);A. Brown, S. Miller, R. Reider, P. Gillette, State University of New York Downstate Medical Center (Brooklyn, NY); W. Lande, S. Embury, W. Mentzer, San Francisco General Hospital (SanFrancisco,CA); D. Wethers, R. Grover, St. Luke’s-Roosevelt MedicalCenter (New York, NY); M. C. Koshy, N. Talishy, University of Illinois (Chicago, E); Pegelow, J.D. Temple, P. Klug, University of Miami (Miami, m);H. Zarkowsky, Washington University (St Louis, MO); IL);H. C. Dampier,WylerChildren’sHospital(Chicago, Pearson, A. Ritchey,YaleUniversity (New Haven,CT); Statistical Coordinating Centers: P. Levy, D. Gallagher, A. Koranda, Z. Floumoy-Gill, E. Jones, University of Illinois School of Public Health (Chicago, IL; 1979-89); S. McKinlay, 0. Platt, D. Gallagher, D. Brambilla,and L. Sleeper, New EnglandResearchInstitutes(Watertown,MA;19891995); M. Espeland,Bowman-Gray School of Medicine (Winston-Salem, NC); Program Administration: M. Gaston, C. Reid, and J. Verter,NationalHeart,Lung,and Blood Institute (Bethesda, MD). REFERENCES 1. Gill FM, Brown A, Gallagher D, Diamond S, Goins E, Grover R, Lubin B, Moore G, Gaston MH: Newborn experience in the Cooperative Study of Sickle Cell Disease. Pediatr Suppl 83:827, 1989 2. Gaston M, Rosse WF: The Cooperative Study of Sickle Cell Disease: A review of study design and objectives. Am J Pediatr Hematol Oncol 4:196, 1982 3. Farber MD, Koshy M, Kinney TR:Cooperative Study of Sickle Cell Disease: Demographic and socioeconomic characteristics of patients and families with sickle cell disease. J Chronic Dis 38:495, 1985 4. Dozy AM, Kan YW, Embury SH, Mentzer WC, Wang WC, Lubin B, Davis JR, Koenig HM: Alpha-globin gene organisation in blacks precludes the severe form of alpha-thalassemia. Nature 280:605, 1979 5. Embury SH, Miller JA, Dozy AM, Kan W, Chan V, Todd D: Two different molecular organisations account for the single alpha globin gene in alpha-thalassemia-2 genotype. J Clin Invest 66:1319, 1980 6. Hanis EK, Albert A: Survivorship Analysis for Clinical Studies. New York, NY, Marcel Dekker, 1991 7. Wong WY, Powars DR, Chan L, Hiti A, Johnson C, Overturf G: Polysaccharide encapsulated bacterial infection in sickle cell anemia: A thirty year epidemiologic experience. Am J Hematol39: 176, 1992 8. Powars DR: The natural history of sickle cell disease-The first ten years. Semin Hematol 12:267, 1974 9. Serjeant GR, Ashcroft MJ, Serjeant BE: The clinical features of haemoglobin SC disease in Jamaica. Br J Haematol24:491, 1973 10. Powars D, Chan LS, Schroeder WA: The variable expression of sickle cell disease is genetically determined. Semin Hematol 27:360, 1990 11. Balkaran B, Choi G, Moms JS, Thomas PW, Serjeant BE, Serjeant GR: Stroke in a cohort of patients with homozygous sickle cell disease. J Pediatr 120:360, 1992 12. Zarkowsky H, Gallagher D, Gill FM, Wang WC, Falletta JM, Lande Levy PS, Verter JI, Wethers D, the Cooperative Study of Sickle Cell Disease: Bacteremia in sickle hemoglobinopathies. J Pediatr 109579, 1986 13. McGowan JE, Bratter L, Klein JO, Finland M: Bacteremia in febrile children seen in a “walk-in” pediatric clinic. N Engl J Med 288:1809, 1973 14. Teele DW, Pelton SI, Grant M A , Herskowitz J, Rosen DJ, Allen CE, Wimmer RS, Klein JO: Bacteremia in febrile children under 2 years of age: Results of cultures of blood of 600 consecutive febrile children seen in a “walk-in” clinic. J Pediatr 82:227, 1975 15. Jaffee DN, Fleisher, GR: Temperature and total white blood cell counts as indicators of bacteremia. Pediatrics 87:670, 1991 16. Topley JM, Cupidore L, Vaidya S, Hayes RJ, Serjeant GR: Pneumococcal and other infections in children with sickle cell-hemoglobin C (SC) disease. J Pediatr 101:176, 1982 17. Pearson HA, Gallagher D, Chilcote R:The developmental pattern of splenic dysfunction in the sickle cell diseases. Pediatrics 76:392, 1985 18. Stevens MCG, Hayes RJ, Vaidya S, Serjeant GR: Fetal hemoglobin and clinical severity of homozygous sickle cell disease in early childhood. J Pediatr 98:37, 1981 19. Rogers DW, Vaidya S, Serjeant GR: Early splenomegaly in homozygous sickle-cell disease: An indicator of susceptibility to infection. Lancet 2:963, 1978 20. Overturf GD, Powars D, Baroff LJ: Bacterial meningitis and septicemia in sickle cell disease. Am J Dis Child 131:784, 1977 21. Topley M, Rogers DW, Stevens MCG, Serjeant GR: Acute splenic sequestration and hypersplenism in the first five years in homozygous sickle cell disease. Arch Dis Child 56:765, 1981 22. Gaston MH, Verter JI, Woods G, Pegelow C, Kelleher J, Presbury G, Zarkowsky H, Vichinsky E, Iver R, Lobe1 J, Diamond S, Holbrook CT, Gill FM, Ritchey K, and Falletta JM for the Prophylactic Penicillin Group: Prophylaxis with oral penicillin in children with sickle cell anemia. N Engl J Med 314:1593, 1986 23. Powars D, Overtuft G, Weiss J, Lee S, Chan L: Pneumococcal septicemia in children with sickle cell anemia. Changing trend of survival. JAMA 2451839, 1981 24. Steinberg MH: The interactions of a-thalassemia with hemoglobinopathies. Hematol Oncol Clin North Am 5:453, 1991 25. Steinberg MH, Rosenstock W, Coleman MB, Adams JG, Platica 0, Cedero M, Rieder R, Wilson JT, Milner P, West S, and the CSSCD: Effects of thalassemia and microcytosis on the hematologic and vasoocclusive severity of sickle cell anemia. Blood 63:1353, 1984 26. Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, Kinney TR: Pain in sickle cell disease: Rates and risk factors. N Engl J Med 325:11, 1991 WM. From www.bloodjournal.org by guest on June 15, 2017. For personal use only. 1995 86: 776-783 Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell Disease [see comments] FM Gill, LA Sleeper, SJ Weiner, AK Brown, R Bellevue, R Grover, CH Pegelow and E Vichinsky Updated information and services can be found at: http://www.bloodjournal.org/content/86/2/776.full.html Articles on similar topics can be found in the following Blood collections Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.