Recurrent infections in homozygous sickle cell disease.

The characteristics of 214 episodes of invasive bacterial infection among 176 patients with homozygous sickle cell (SS) disease were examined. Streptococcus pneumoniae occurred in 81 episodes, Salmonella spp in 70, Haemophilus influenzae type b in 30, Escherichia coli in 24, and Klebsiella spp in nine. The cumulative incidence showed that S pneumoniae and H influenzae occurred predominantly before 5 years of age and were uncommon thereafter, Salmonella spp increased almost linearly with age, and Klebsiella spp and E coli predominated in patients over 10 years of age. Escherichia coli had a different epidemiology-it was found in older children, almost entirely girls. Excluding this organism from an analysis of recurrent bacterial infections, the standardised incidence rates for second and third infections were 4.8 and 15.8 times greater, respectively, than the SS population average. This implies that the susceptibility to infection is characteristic of a subgroup of patients with SS disease and that sick patients with previous bacteraemia should be investigated early and aggressively for further infection.     

Genetic modifiers of homozygous sickle cell disease

Homozygous sickle cell (HbSS) disease is paradigmatic for the complex influence of genetic modifiers of a monogenic disease. The genetically determined variability of HbF concentration has a strong impact on the clinical phenotype. The pharmacologically induced increase of HbF leads to a reduced morbidity which demonstrates that the knowledge of genetic modifiers enables the development of new therapeutic strategies. The presence of alpha-thalassemia also ameliorates the disease phenotype albeit not to the same extent as HbF does. Both factors, HbF and alpha-thalassemia are insufficient to explain the clinical variability of HbSS disease. The introduction of genome analysis has now provided the tools to identify relevant gene loci that will likely be helpful in estimating the probability of severe complications such as the occurrence of stroke. Following the validation in prospective studies, the subtle analysis of genetic modifiers will therefore influence the management of patients with sickle cell disease.     

Delayed adolescent growth in homozygous sickle cell disease

Analysis of the growth abnormalities in sickle cell disease has been limited by the lack of longitudinal observations in individuals, and by an inability to quantitate the observed patterns. To investigate the timing and pattern of the adolescent growth spurt, longitudinal observations of height from the Jamaican cohort study were fitted to a mathematical model of growth (Preece-Baines model 1). The study included 44 children with homozygous sickle cell (SS) disease, 44 age and sex matched subjects with sickle cell haemoglobin C (SC) disease, and 44 age and sex matched controls with normal (AA) haemoglobin. Compared with AA controls, the onset of the adolescent growth spurt was delayed in SS disease by 1.4 years (95% confidence interval 0.8 to 2.0) with no significant sex difference. The age at peak height velocity was delayed by 1.6 years (0.9 to 2.3) in SS compared with AA subjects but the adolescent growth of SS children was otherwise normal and there was no difference in the attained height by age 17.9 years. The growth spurt was not delayed in SC disease. The age at menarche in girls with SS disease (mean (SD) 15.4 (1.3) years) was significantly later than girls with SC disease (13.7 (1.7) years) and those with AA haemoglobin (13.1 (1.3) years) but these genotype differences were no longer significant after controlling for the delay in the adolescent growth spurt. The normally coordinated but slightly delayed pattern of growth and normal adult heights suggests a good prognosis for adolescent growth delay in SS disease. Most children with SS disease can therefore be reassured on the outcome of retarded adolescent growth.     

Clinical presentation of homozygous sickle cell disease

The pattern of initial clinical symptoms and signs developing in a representative sample of 305 children with homozygous sickle cell (SS) disease diagnosed at birth was analyzed. Specific symptoms were present by age 6 months in 6% of the group, and had developed by the first to eighth birthdays in 32%, 61%, 78%, 86%, 90%, 92%, 94%, and 96%, respectively. Inclusion of nonspecific symptoms in the analysis led to earlier recognition by a mean of 3 months in the first year and by a mean of approximately 1 year between the ages of 2 and 4 years. Dactylitis was the most common initial symptom, noted in 40% of the group overall and in 50% in the first 2 years. Painful crisis was the first symptom in more than one fourth of the patients and was the most frequent symptom after the age of 2 years. Acute splenic sequestration led to presentation in one-fifth of the group overall and in one third of patients younger than 2 years. The most common nonspecific symptom was pneumonia. There was a significant trend of earlier presentation in children with low fetal hemoglobin levels. The age at presentation did not appear to be affected by alpha-thalassemia status.     

Factors affecting prepubertal growth in homozygous sickle cell disease

OBJECTIVE: To investigate the role of haematological indices, socioeconomic status, and morbidity in prepubertal growth in homozygous sickle cell (SS) disease. METHOD: Height, weight, and haematology were serially recorded in a cohort study of 315 children with SS disease from birth to 9 years at the sickle cell clinic of the University Hospital of the West Indies, Kingston, Jamaica. RESULTS: Height increment between 3 and 9 years correlated positively with total haemoglobin at age 7 years in boys but not girls. Attained height and weight at age 7 years correlated positively with haemoglobin and fetal haemoglobin in boys but not girls. Only the correlation between haemoglobin and weight showed a significant gender difference. Partial correlation analysis suggested that the effect of haemoglobin was accounted for by the effect of fetal haemolglobin and further analysis indicated that height correlated with F reticulocyte count (a measure of fetal haemoglobin production) in both sexes but not with the ratio of F cells to F reticulocytes (a measure of F cell enrichment). Growth was not significantly related to mean red cell volume, proportional reticulocyte count, alpha thalassaemia, socioeconomic status, or morbidity. CONCLUSION: A high concentration of fetal haemoglobin in boys with SS disease is associated with greater linear growth. It is postulated that in boys, low concentrations of fetal haemoglobin increase haemolysis and hence metabolic requirements for erythropoiesis, putting them at greater risk of poor growth. Differences in the relationship of haematology and growth between boys and girls with SS disease dictate that future analyses of growth take gender into account.     

Delayed adolescent growth in homozygous sickle cell disease.

Analysis of the growth abnormalities in sickle cell disease has been limited by the lack of longitudinal observations in individuals, and by an inability to quantitate the observed patterns. To investigate the timing and pattern of the adolescent growth spurt, longitudinal observations of height from the Jamaican cohort study were fitted to a mathematical model of growth (Preece-Baines model 1). The study included 44 children with homozygous sickle cell (SS) disease, 44 age and sex matched subjects with sickle cell haemoglobin C (SC) disease, and 44 age and sex matched controls with normal (AA) haemoglobin. Compared with AA controls, the onset of the adolescent growth spurt was delayed in SS disease by 1.4 years (95% confidence interval 0.8 to 2.0) with no significant sex difference. The age at peak height velocity was delayed by 1.6 years (0.9 to 2.3) in SS compared with AA subjects but the adolescent growth of SS children was otherwise normal and there was no difference in the attained height by age 17.9 years. The growth spurt was not delayed in SC disease. The age at menarche in girls with SS disease (mean (SD) 15.4 (1.3) years) was significantly later than girls with SC disease (13.7 (1.7) years) and those with AA haemoglobin (13.1 (1.3) years) but these genotype differences were no longer significant after controlling for the delay in the adolescent growth spurt. The normally coordinated but slightly delayed pattern of growth and normal adult heights suggests a good prognosis for adolescent growth delay in SS disease. Most children with SS disease can therefore be reassured on the outcome of retarded adolescent growth.     

Determinants of nocturnal enuresis in homozygous sickle cell disease.

The determinants of nocturnal enuresis in homozygous sickle cell (SS) disease have been investigated in 16 enuretic and 16 age and sex matched non-enuretic children. Overnight fluid deprivation tests (8pm-8am) demonstrated no significant difference in maximum urine osmolality or urine volumes, although the latter tended to be higher in the enuretic children. Maximum functional bladder capacity, estimated by maximum voided volume during oral fluid loading, was lower and the ratio of overnight urine volume to maximum functional bladder capacity higher in the enuretic than the non-enuretic group. Enuretic children were more likely than non-enuretics to be considered deep sleepers by their family. High urine volumes may contribute to nocturnal enuresis in SS disease, although the similar values in enuretic and non-enuretic children implies that additional factors determine the presence of enuresis. Low maximum functional bladder capacity, and a high ratio of overnight urine volume to maximum functional bladder capacity, appear to be important determinants.     

Parvovirus associated aplastic crisis in homozygous sickle cell disease.

Aplastic crises in homozygous sickle cell disease in Jamaica predominantly affect children and occur in epidemics. Of 67 cases in a cohort study of 314 children with homozygous sickle cell disease, 62 were attributable to human parvovirus infection. Affected children were aged 0.5-12.5 years, and the incidence rose to 28% by 10 years. No recurrences were seen. Symptoms and signs on presentation were attributable to the viraemia and acute anaemia. Asymptomatic thrombocytopenia was common. Blood transfusion was given in 54 cases (87%). Thirty eight children (61%) were admitted to hospital, 16 of whom were extremely ill on presentation and one of whom died soon after admission. Twenty four (39%) were managed as outpatients, 16 of whom were transfused. Parvovirus associated aplastic crisis is a self limited condition with excellent prognosis if diagnosed promptly and managed appropriately.     

Cerebrovascular complications and parvovirus infection in homozygous sickle cell disease

Human parvovirus B19 infection causes most clinically defined aplastic crises in homozygous sickle cell (SS) disease. With transfusion support, the outcome is generally benign; however, cerebrovascular complications in close temporal association with B19-induced aplastic crises have been described. We carried out a retrospective review, between 1978 and 1999, of 346 aplastic crises in patients with SS disease attending the Sickle Cell Clinic of the University Hospital of the West Indies, Kingston, Jamaica. Six cerebrovascular episodes, 5 with hemiplegia, occurred within 2 days of aplastic crises; and 4, all with features of encephalitis, occurred within 2 to 5 weeks. Hemiplegia in 2 children resolved completely, one is improving, and one persists 20 years later; one patient died from recurrent strokes. Of the 4 children whose events occurred later, all had seizure disorders and 2 had transient cortical blindness. The crude risk of cerebrovascular episodes in the 5-week interval after B19 infection was calculated as 58 times greater than expected, which is suggestive of a causal association.     

Factors affecting prepubertal growth in homozygous sickle cell disease.

OBJECTIVE: To investigate the role of haematological indices, socioeconomic status, and morbidity in prepubertal growth in homozygous sickle cell (SS) disease. METHOD: Height, weight, and haematology were serially recorded in a cohort study of 315 children with SS disease from birth to 9 years at the sickle cell clinic of the University Hospital of the West Indies, Kingston, Jamaica. RESULTS: Height increment between 3 and 9 years correlated positively with total haemoglobin at age 7 years in boys but not girls. Attained height and weight at age 7 years correlated positively with haemoglobin and fetal haemoglobin in boys but not girls. Only the correlation between haemoglobin and weight showed a significant gender difference. Partial correlation analysis suggested that the effect of haemoglobin was accounted for by the effect of fetal haemolglobin and further analysis indicated that height correlated with F reticulocyte count (a measure of fetal haemoglobin production) in both sexes but not with the ratio of F cells to F reticulocytes (a measure of F cell enrichment). Growth was not significantly related to mean red cell volume, proportional reticulocyte count, alpha thalassaemia, socioeconomic status, or morbidity. CONCLUSION: A high concentration of fetal haemoglobin in boys with SS disease is associated with greater linear growth. It is postulated that in boys, low concentrations of fetal haemoglobin increase haemolysis and hence metabolic requirements for erythropoiesis, putting them at greater risk of poor growth. Differences in the relationship of haematology and growth between boys and girls with SS disease dictate that future analyses of growth take gender into account.     

Body shape in young children with homozygous sickle cell disease

Body shape, defined by detailed anthropometric measurement, was compared in 64 children with homozygous sickle cell (SS) disease, and in 123 children with a normal hemoglobin (AA) genotype, aged 4 to 6 years. Children with homozygous sickle cell disease showed an average reduction in weight, height, sitting height, limb length, interacromial and intercristal diameters, and skinfold thickness. They showed increased anteroposterior chest diameters with an increased anteroposterior-lateral chest diameter ratio. This report establishes that the effect of homozygous sickle cell disease on growth patterns in childhood is apparent before the age of 6 years. The relationship to changes in body shape, seen during adolescence and in affected adults, and their possible determinants, are discussed.     

Factors associated with lowered intelligence in homozygous sickle cell disease.

The intelligence quotient (IQ) of 60 patients with homozygous sickle cell (SS) disease and 60 age and sex matched controls with a normal haemoglobin (AA) genotype aged 15-18 years, followed up in a cohort study from birth, was assessed by the Wechsler intelligence scales for children or for adults. IQ appeared to be normally distributed in both genotypes but mean values in SS disease were 5.6 points (95% confidence interval (CI) 1.0 to 10.2) lower than in AA controls (p = 0.016). The difference occurred in both verbal (5.5 points, p = 0.017) and performance (5.0 points, p = 0.044) subscales of the IQ score and the IQ defect in SS disease was associated with a significantly lower attention factor score (p = 0.005) but not with other factor scores. The genotype difference in IQ was not accounted for by differences in parental occupational level, school absenteeism, or school drop out, or reported activity level. In SS disease, IQ was not related to mean steady state haemoglobin, fetal haemoglobin, or mean cell haemoglobin concentration, or clinical severity as judged by the frequency of painful crises, hospital admission, or sick visits. IQ, at age 15-18 years, correlated with the patients'' height at all ages from 1 to 10 years (partial correlations increasing from 0.14 (p = 0.15) at age 1 to 0.27 (p = 0.004) at age 10). Adjusting for height reduced the mean genotype difference in IQ to 5.5 (95% CI 0.6 to 10.3) points at age 1 and to 2.6 points (95% CI to -2.3, 7.5) at age 10. Prepubertal height therefore accounted for much of the genotype difference in IQ. It is speculated that early factors, possible nutritional, contribute to both impaired growth and mental development in sickle cell disease.     

Height and weight reference curves for homozygous sickle cell disease

OBJECTIVE—To derive height and weight growth reference curves for children with homozygous sickle cell disease.
STUDY DESIGN—Subjects (n = 315) were participants in a population based, longitudinal cohort study of sickle cell disease in Kingston, Jamaica. Regular measurements of height and weight were made from enrollment into the study at birth up to 22 years of age.
RESULTS—Sex specific growth reference curves for height for age and weight for age covering the age range 0-18 years are presented.
CONCLUSION—These growth reference curves are suitable for identifying coincidental growth problems in children with homozygous sickle cell disease.

     

Gall stones in Jamaican children with homozygous sickle cell disease.

Gall stones were detected by ultrasonography in 30 of 226 (13%) children with homozygous sickle cell disease aged 5-13 years participating in a cohort study from birth. Children with gall stones had significantly lower total haemoglobin and fetal haemoglobin and higher bilirubin concentrations, but further analysis showed that the apparent effects of haemoglobin and fetal haemoglobin concentration were secondary to their relationship with bilirubin concentrations. Abdominal pain crises were significantly associated with gall stones but both factors appeared to reflect an increased clinical severity and were probably not causally related. No patients had symptoms specific of gall stones and an association with abdominal pain crisis should not, of itself, be considered an indication for surgery.     

Significance of fever in Jamaican patients with homozygous sickle cell disease

OBJECTIVE—To investigate the cause and outcome of high fever in Jamaican children with homozygous sickle cell disease.DESIGN—Retrospective review of febrile episodes in a three year period (1 September 1993 to 31 August 1996).SETTING—Sickle cell clinic, an outpatient clinic in Kingston run by the Medical Research Council Laboratories (Jamaica).PATIENTS—Patients with homozygous sickle cell disease under 17 years of age presenting with an axillary temperature ? 39.0°C (102.4°F).MAIN OUTCOME MEASURES—Diagnosis, death.RESULTS—There were 165 events in 144 patients (66 (45.8%) boys) with a median age of 6.1 years. Bacteraemia was found in 10 (6.1%) events (three Streptococcus pneumoniae, two Haemophilus influenzae type b, two Salmonella sp, one Escherichia coli, one Enterobacter sp, and one Acinetobacter sp), and urinary tract infections in four (2.4%). All cultures of cerebrospinal fluid were sterile. Acute chest syndrome occurred in 36 (21.8%) events. A painful crisis was associated with 45 (27.3%) events and was the only pathology identified in 20 events (12.1%). Hospital admission was necessary in 66 cases including all those with bacteraemia and 31 with acute chest syndrome. There were two deaths: a 5 year old boy with septic shock associated with H influenzae septicaemia, and a 3 year old boy with the acute chest syndrome.CONCLUSIONS—Painful crisis and acute chest syndrome were the most common complications associated with high fever, but other important associated features included bacteraemia and urinary tract infection. Enteric Gram negative organisms accounted for 50% of positive blood cultures.     

Invasive pneumococcal disease in homozygous sickle cell disease: Jamaican experience 1973-1997

OBJECTIVES: To examine the clinical features and epidemiology of invasive pneumococcal disease in homozygous sickle cell (SS) disease and the efficacy of pneumococcal prophylaxis. STUDY DESIGN: A retrospective study of 80 episodes in 68 patients in the Jamaican Sickle Cell Clinic in a 25-year period (1973-1997). RESULTS: Clinical features included a history of fever (94%), vomiting (70%), an ill appearance (80%), fever (89%), abnormal chest signs (43%), and meningismus (39%). There were 14 deaths-13 among 68 initial episodes (6 of which were deaths on arrival) and one death during a recurrence. Thirteen episodes occurred in patients who should have been receiving antibiotic prophylaxis. Ten were due to failure to adhere to protocols, and 3 occurred during prophylaxis; one patient was receiving oral erythromycin, and two had received injections of benzathine penicillin 4 and 24 days before the episode. All but one of the pneumococcal isolates were susceptible to penicillin. The 32 patients who received pneumococcal vaccine had more mild clinical courses as indicated by a greater chance of being treated as outpatients or surviving after admission (Mann-Whitney U test, P =.03). CONCLUSIONS: Penicillin remains the mainstay of prophylaxis, although breakthroughs occur and will become more common with the increasing frequency of penicillin-resistant organisms. Pneumococcal immunization appears to ameliorate the course of invasive disease.     

Significance of fever in Jamaican patients with homozygous sickle cell disease.

OBJECTIVE: To investigate the cause and outcome of high fever in Jamaican children with homozygous sickle cell disease. DESIGN: Retrospective review of febrile episodes in a three year period (1 September 1993 to 31 August 1996). SETTING: Sickle cell clinic, an outpatient clinic in Kingston run by the Medical Research Council Laboratories (Jamaica). PATIENTS: Patients with homozygous sickle cell disease under 17 years of age presenting with an axillary temperature >/= 39.0 degrees C (102.4 degrees F). MAIN OUTCOME MEASURES: Diagnosis, death. RESULTS: There were 165 events in 144 patients (66 (45.8%) boys) with a median age of 6.1 years. Bacteraemia was found in 10 (6.1%) events (three Streptococcus pneumoniae, two Haemophilus influenzae type b, two Salmonella sp, one Escherichia coli, one Enterobacter sp, and one Acinetobacter sp), and urinary tract infections in four (2.4%). All cultures of cerebrospinal fluid were sterile. Acute chest syndrome occurred in 36 (21.8%) events. A painful crisis was associated with 45 (27.3%) events and was the only pathology identified in 20 events (12.1%). Hospital admission was necessary in 66 cases including all those with bacteraemia and 31 with acute chest syndrome. There were two deaths: a 5 year old boy with septic shock associated with H influenzae septicaemia, and a 3 year old boy with the acute chest syndrome. CONCLUSIONS: Painful crisis and acute chest syndrome were the most common complications associated with high fever, but other important associated features included bacteraemia and urinary tract infection. Enteric Gram negative organisms accounted for 50% of positive blood cultures.     

Stroke in a cohort of patients with homozygous sickle cell disease.

Strokes occurred in 17 of 310 children with homozygous sickle cell disease who were followed from birth, representing an incidence of 7.8% by the age of 14 years. Two children had subarachnoid hemorrhage, one having resolution of symptoms after aneurysm surgery and another dying of a presumed second hemorrhage 14 days later. The remaining 15 strokes were presumed to be cerebral infarction, although autopsy, angiographic, or computed tomographic evidence was available in only 8 children. There were 6 deaths, 2 in the acute event and 4 after recurrence, which occurred in 6 (46%) of 13 patients who survived the initial episode. There were 10 recurrent episodes at a median interval of 9 months after the initial event. Steady-state hematologic data revealed significantly higher leukocyte counts than in control subjects without strokes at age 1 year and in the last study preceding the stroke. The initial stroke coincided with an acutely lowered hemoglobin value in 5 patients (3 aplastic crises, 1 acute splenic sequestration, 1 probable pulmonary sequestration) and with painful crises in another 7 patients. We conclude that a high leukocyte count and an acute decrease of hemoglobin are risk factors for stroke in patients with homozygous sickle cell disease.