Annual stroke incidence in Nigerian children with sickle cell disease and elevated TCD velocities treated with hydroxyurea.

BACKGROUND: Elevated transcranial Doppler (TCD) velocities accurately predict stroke risk in children with sickle cell disease (SCD). Chronic blood transfusion, the gold standard for primary stroke prevention, is faced with numerous challenges in Africa. Hydroxyurea (HU) has been shown to reduce elevated TCD velocities in children with SCD. AIM: To determine the effectiveness of HU in reducing the risk of primary stroke in a cohort of Nigerian children with SCD and elevated velocities treated with HU. METHODS: Children with SCD and TCD velocities ≥170 cm/sec treated with HU were prospectively followed with 3-monthly TCD and neurological evaluations for ≥12 months to determine the incidence of primary stroke. RESULTS: One hundred and four children, 53 males, and 51 females were enrolled into the study. Their ages ranged from 2 to 16 years with a mean of 6 years. At first TCD examination, velocities ranged from 173 to 260 cm/sec with conditional and abnormal risk velocities in 60 (57.7%) and 44 (42.3%) children, respectively. Follow up ranged from 1 to 8 years with a mean of 3.6 years. Mean TCD velocities showed a significant decline from 198.2 (standard deviation [SD] = 15.6) cm/sec to 169.3 (SD = 21.4) cm/sec (P < 0.001). One stroke event occurred in the cohort, giving a stroke incidence of 0.27/100 person years. CONCLUSION: HU significantly reduces TCD velocities in Nigerian children with SCD and elevated TCD velocities, with a corresponding reduction in the incidence of primary stroke. HU may represent a potential alternative for primary stroke prevention in low and middle income countries where the burden of SCD resides.

Stroke recurrence in Nigerian children with sickle cell disease treated with hydroxyurea.

AIMS AND OBJECTIVES: To compare the outcome after a first clinical stroke, following treatment with and without hydroxyurea (HU). SUBJECTS AND METHODS: A retrospective review of a cohort of Nigerian children with SCD, who had suffered a first stroke, was carried out. Outcomes in the group of children who received and did not receive HU were compared. RESULTS: Thirty two children presented with stroke and one died of haemorrhagic stroke at presentation. All the children had haemoglobin SS phenotype, and ischaemic stroke was the predominant form seen. Mean age at first clinical stroke was 7 years, 7 months (SD=2 years, 4 months). Thirteen children received HU while 18 declined HU therapy. Maximum dose of HU ranged from 20-25 mg/kg/ day. The secondary stroke incidence of 7/100 person years in the HU group was significantly lower than the 28/100 person years in the non-HU group (P=0.001, OR 3.808, 95% CI 1.556, 9.317). Children who did not receive HU were more likely to drop out of school and to have moderate-severe motor disabilities requiring caregiver assistance for daily living. CONCLUSION: In settings where facilities for chronic blood transfusion are not accessible or feasible, HU therapy should be considered for secondary stroke prevention in children with SCD.

Chronic blood transfusion for primary and secondary stroke prevention in Nigerian children with sickle cell disease: a 5-year appraisal.

BACKGROUND: Chronic blood transfusion (CBT) diminishes the risk of primary and secondary stroke in sickle cell disease (SCD). We appraised CBT and assessed its feasibility as an option for stroke prevention in a setting of limited resources. METHODS: All new cases of SCD seen in the Paediatric Hematology/Neurology units of the University College Hospital, Ibadan, Nigeria over a 5-year period were screened and followed up to identify those who had an indication for CBT for stroke prevention. Caregivers were counseled and offered CBT when indicated. Children of caregivers who accepted chronic transfusion were carefully followed up and outcomes documented. RESULTS: Five (10%) of the caregivers of the 50 children who had an indication for CBT for stroke prevention consented to the treatment. They all had homozygous sickle cell anemia and had suffered a stroke. None of the children with abnormal TCD velocities consented to CBT. Two children experienced transfusion reactions, fatal in one. The mean annual cost of chronic transfusion (without chelation) was $3,276 (SD = 1,168). Major reasons given for declining CBT were high costs of blood transfusion, unavailability of blood, the need to regularly seek for blood donors, and the indefinite duration of blood transfusions. CONCLUSION: High economic costs, unavailability of blood, need to regularly seek for blood donors, cultural beliefs, and high frequency of transfusion reactions are major challenges to a successful CBT program in Nigeria. There is a need for government subsidy on blood transfusions and improved efforts towards provision of safe and affordable blood.

Correlates of steady-state haematocrit and hepatosplenomegaly in children with sickle cell disease in Western Nigeria.

BACKGROUND: Sickle cell disease is a common genetic disorder in Nigeria. OBJECTIVES: To determine the steady state haematocrit, liver size and spleen size in children with sickle cell disease and the factors that influence them. METHODS: This was a retrospective study of children with sickle cell disorders who attended the anaemia clinic of the Children's Outpatient Department, University College Hospital, Ibadan between the years 2000-2009. Relevant data extracted from their case notes included socio-demographic variables, haemoglobin phenotype, steady state haematocrit and liver and splenic sizes. Means were compared with t-test and correlation tested with Pearson correlation. Statistical significance was set at p < 0.05. RESULTS: A total of 415 (Male: female ratio 1.1:1) children were studied and 385 (92.8%) and 30 (7.2%) of the children were of haemoglobin (Hb) SS and Hb SC phenotypes respectively. Their ages ranged from 0.5-17 years with a mean (SD) of 7.3 (4.4) years. Mean (SD) steady state haematocrit for children with HbSC was 28.3 (4.5) % and significantly higher than 24.1 (3.7) % in HbSS. Mean steady state haematocrit was also higher in children from higher than lower socio-economic classes. There was a negative correlation of haematocrit with age, with hepatomegaly and splenomegaly. Steady state hepatomegaly occurred more frequently in HbSS than in HbSC. CONCLUSION: Haemoglobin phenotype, age and socio-economic status have some modifying influences on the steady-state features of sickle cell disease in Nigerian children. In addition, increasing liver and spleen sizes seem to be related to a decreasing haematocrit.

Causes of death in childhood cancer at the Department of Paediatrics, University College Hospital, Ibadan.

There is a dearth of information on the mortality of children with cancer in Nigeria but the few available reports suggest a poor outcome. The objectives of this study were to determine the underlying and immediate causes of death from childhood cancer. The mortality summary cards of all cases of childhood cancer seen at the Department of Paediatrics, University College Hospital, Ibadan between January 1998 and December 2004 were reviewed. Eighty-eight cases of childhood cancer were seen, out of whom 52 (59.1%) died, but only the 48 deaths with complete data were analyzed. These deaths comprised of 37 males and 11 females giving a male:female ratio of 3.4:1. Their ages ranged from 1 to 13 years with a mean of 7.3 +/- 3.4 years. The majority (71.4%) of all patients presented with diffuse or metastatic disease at diagnosis and this was associated with increased risk of dying. Of the 48 cases reviewed, 39 (81.3%) died without any remission of the primary tumour including 5 (10.4%) with disease progression despite treatment and 15 (31.3%) who died before treatment; only 4 cases (8.3%) died from tumour relapse. The immediate causes of death were infections (39.6%), bone marrow suppression (29.2%), treatment-related mortality (27.1%), organ failure (22.9%), bleeding (16.7%) and other metabolic causes (8.3%). Potentially reversible factors such as infections, bone marrow suppression and treatment-related events are the commonest causes of death from childhood cancer in Ibadan. Therefore, early presentation, prompt identification and effective management of these problems may reduce childhood cancer mortality in Nigeria.

Early deaths and other challenges to childhood cancer survival in Ibadan, Nigeria.

OBJECTIVES: To determine the frequency of early deaths and the associated risk factors in children suffering from cancer at the University College Hospital, Ibadan. DESIGN: A retrospective study involving review of case notes of children suffering from cancer. SETTING: Department of Paediatrics, University College Hospital, Ibadan, Nigeria. SUBJECTS: All cases of childhood cancer managed in the Department between January 1998 and December 2004. Inclusion criteria were histological or cytological confirmation of diagnosis, suggestive clinical features and availability of details about the course of the illness. MAIN OUTCOME MEASURES: Interval between diagnosis and death, rate of early death (death within 30 days of diagnosis) and risk factors for early death. RESULTS: Eighty eight cases of childhood cancer were seen out of whom 52 died during the period. Four cases with incomplete data were excluded from subsequent statistical analysis. There were 29 (34.5%) early deaths defined as death within 30 days of diagnosis. The odds of early death were increased in the presence of bilateral kidney involvement, masses in the liver, splenic masses, pulmonary metastasis and stage D of Burkitt lymphoma. Logistic regression analysis revealed that pulmonary metastasis was a significant independent predictor ofearly death. CONCLUSIONS: Early childhood cancer mortality rate is high. Early diagnosis and referral for appropriate care may reduce childhood cancer mortality in Nigeria.

Variation in the relationship between anti-MSP-1(19) antibody response and age in children infected with Plasmodium falciparum during the dry and rainy seasons.

Malaria remains a major parasitic disease in Africa, with 300-500 million new infections each year. There is therefore an urgent need for the development of new effective measures, including vaccines. Plasmodium falciparum merozoite surface protein-1(19) (MSP-1(19)) is a prime candidate for a blood-stage malaria vaccine. Blood samples were collected from children aged 10 days to 15 years in the months of January-March (N = 351) and October-November (N = 369) corresponding to the dry and rainy seasons, respectively. P. falciparum infection was determined by microscopy and enzyme linked immunosorbent assay (ELISA) was used to determine the total IgG and IgG subclasses. There was a significant increase in the mean anti-MSP-1(19) antibody titre in the dry season (p < 0.05), compared to the rainy season. A significantly positive correlation between the anti-MSP-1(19) antibody titre and parasite density (p < 0.01, r = 0.138) was observed. In the rainy season, unlike in the dry season, P. falciparum positive children had higher anti-MSP-1(19) antibody titres than P. falciparum negative children and this difference was significant (p < 0.05). When all individuals were grouped together, the anti-MSP-1(19) antibody titre increased with age in both seasons (r = 0.186 and 0.002), this increase was more apparent in the dry season. However, when the study population was divided into P. falciparum positive and negative groups, it was observed that in the rainy season, there was a negative correlation between anti-MSP-1(19) titre and age in P. falciparum positive individuals, while those who were P. falciparum negative had a positive correlation between anti-MSP-1(19) titre and age. Analysis of anti-MSP-1(19) IgG subclass showed that IgG1 and IgG3 mean titres were highest in both the dry and rainy seasons with an increase in the mean antibody titres for IgG1, IgG2 and IgG3 in the rainy season. In the dry season there was a positive correlation between IgG1, IgG2, and IgG3 titres with age, while IgG4 was negative, whereas in the rainy season there was a positive correlation between IgG2 and IgG4 (non-cytophilic antibodies) with age and a negative correlation for IgG1 and IgG3 (cytophilic antibodies) with age. Seasonal differences in the level of MSP-1(19) IgG subclass titres were observed for P. falciparum negative and positive individuals. Only samples, which were positive for IgG2 and IgG4, showed positive correlation between parasitemia and total IgG. The incidence of P. falciparum infection, which increases during the rainy season, might be an important determinant of anti-MSP-1(19) antibody levels in children living in Igbo-Ora and the results point to the fact that non-cytophilic antibodies to MSP-1(19) in children might be associated with an increase in total IgG and parasitemia.

Stroke in Nigerian children with sickle cell disease.

We reviewed our records over a 15-year period to determine whether or not the impression that stroke complicating sickle cell disease was less common than reported in North America. Records of children aged 16 years and below with a diagnosis of stroke seen at the University College Hospital, Ibadan, Nigeria between 1988 and 2002 were examined. Thirty-nine such patients were identified but only 31 had detailed records available for study. Twenty-seven of these had sickle cell disease, 26 with haemoglobin genotype SS and 1 with Hb S+C. Sickle cell disease was therefore responsible for 87% of stroke seen in children at our centre. With an average clinic population of about 500 patients with sickle cell disease, the hospital frequency of stroke among these patients is estimated at 5.4%. The mean age of occurrence of the first stroke was 6.8 years ranging from 17 months to 11 years. Of the 7 patients who had CT scans of the brain done, 5 had evidence of cerebral infarction while 2 had intracerebral haemorrhage. While only 2 deaths occurred among the cases reviewed, morbidity was significant with only 6 patients achieving complete recovery. Recurrent stroke occurred after an average of 25.6 months in 8 of 13 patients who were followed up (61.5%). The incidence of stroke among African children with sickle cell disease appears to be not as high as reported in patients from North America.

Certain red cell genetic factors and prevalence of chloroquine-induced pruritus.

The hypothesis that chloroquine-induced pruritus (CIP) may be determined by certain genetic factors was tested by investigating the epidemiology of CIP with respect to certain genetic red cell markers namely, haemoglobin genotype, glucose-6-phosphate dehydrogenase (G6PD) deficiency and the ABO blood groups. Three hundred consecutive patients treated for malaria with chloroquine at the University College Hospital, Ibadan, Nigeria were recruited into the study. They were observed over 3 days for presence of CIP. ABO blood groups, G6PD and Hb genotypes were determined appropriately for each patient. One hundred and twenty four (41.3%) of the patients responded positively to CIP. There was a reduced frequency of the sickle cell trait (HbAS) among itchers relative to non-itchers. This suggests that the trait may be protective against CIP. G6PD deficiency was also found to be relatively more common among itchers than non-itchers. This indicates that G6PD deficiency may increase susceptibility to CIP. There was however no difference in the distribution of itchers among the different ABO blood groups. It was concluded that CIP may be associated with certain genetic red cell markers particularly Hb and G6PD types which are known malaria markers but not ABO blood groups.

Glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase. A novel bifunctional enzyme in malaria parasites.

Plasmodium falciparum glucose 6-phosphate dehydrogenase (Pf Glc6PD), compared to other Glc6PDs has an additional 300 amino acids at the N-terminus. They are not related to Glc6PD but are similar to a family of proteins (devb) of unknown function, some of which are encoded next to Glc6PD in certain bacteria. The human devb homologue has recently been shown to have 6-phosphogluconolactonase (6PGL) activity. This suggests Pf Glc6PD may be a bifunctional enzyme, the evolution of which has involved the fusion of adjacent genes. Further functional analysis of Pf Glc6PD has been hampered because parts of the gene could not be cloned. We have isolated and sequenced the corresponding Plasmodium berghei gene and shown it encodes an enzyme (Pb Glc6PD) with the same structure as the P. falciparum enzyme. Pb Glc6PD is 950 amino acids long with significant sequence similarity in both the devb and Glc6PD domains with the P. falciparum enzyme. The P. berghei enzyme does not have an asparagine-rich segment between the N and C halves and it contains an insertion at the same point in the Glc6PD region as the P. falciparum enzyme but the insertion in the P. berghei is longer (110 versus 62 amino acids) and unrelated in sequence to the P. falciparum insertion. Though expression of this enzyme in bacteria produced largely insoluble protein, conditions were found where the full-length enzyme was produced in a soluble form which was purified via a histidine tag. We show that this enzyme has both Glc6PD and 6PGL activities. Thus the first two steps of the pentose phosphate pathway are catalysed by a single novel bifunctional enzyme in these parasites.

Associated morbidities in children with sickle-cell anaemia presenting with severe anaemia in a malarious area.

A prospective study of 104 consecutive cases of patients with sickle-cell anaemia (SCA) presenting with severe anaemia (packed cell volume < or = 15%) was carried out in the Children's Emergency Ward of the University College Hospital, Ibadan, in 1991. The patients were classified according to the type of anaemic crisis, by physical findings, serum bilirubin and reticulocyte counts. Other investigations included a blood film for malaria parasites, blood culture, radiological investigation and lumbar puncture when necessary. The most common problems associated with SCA patients in anaemic crisis were malaria and bacterial infections--68 (66%) and 18 (17.3%) of cases, respectively. Acute chest syndrome was significantly more frequent in patients with hyperhaemolytic and acute splenic sequestration crisis compared with aplastic crisis (P < 0.05). Conjugated hyperbilirubinaemia was also significantly more frequent among patients with hyperhaemolytic crisis compared with all other anaemic crises (chi2 = 13.18, P = 0.001). The overall case fatality was 86.5/1,000 SCAs, with no fatalities in those with aplastic crisis. There were complications in six of the nine mortalities. Co-existing bacterial infections and conjugated hyperbilirubinaemia were associated with increased morbidity and mortality in patients with anaemic crisis. Patients with SCA crisis should have early evaluation and prompt treatment for associated infections.

Evaluation of a rapid immunochromatographic card test for Plasmodium falciparum in Ibadan, Nigeria.

This short report describes the results of a rapid, simple and cost effective immunodiagnostic test for malaria in Ibadan, Nigeria. A total of 77% patients presenting at the children outpatient clinic, University College Hospital with malaria symptoms were screened for malaria parasites by microscopy using Giemsa stain and by the immunochromatographic card test. The immunodiagnostic test had a sensitivity of 93.1% and a specificity of 95.8%, making a good alternative for malaria diagnosis especially in rural areas without electricity, where microscopy is not possible, and a decision is to be made on when to start treatment.

The disposition of chloroquine and its main metabolite desethylchloroquine in volunteers with and without chloroquine-induced pruritus: evidence for decreased chloroquine metabolism in volunteers with pruritus.

The pharmacokinetics of chloroquine and its main metabolite desethylchloroquine have been carried out in volunteers with and without chloroquine-induced pruritus. It was shown that the volunteers with pruritus tended to metabolize chloroquine slower than the volunteers without pruritus because the metabolic ratio was lower in the volunteers with pruritus than that in the volunteers without pruritus. However, the overall pharmacokinetic patterns were comparable between the two groups and agreed with published data. The 24-hour urinary collections in the two groups of volunteers indicated that the volunteers with pruritus excreted more chloroquine (although not statistically significant) than the volunteers without pruritus. This also indicates that they metabolized less chloroquine. There were no side effects of note in any of the volunteers. The volunteers who gave positive histories of chloroquine-induced pruritus had mild episodes of itching after intake of the drug; the pruritus subsided within 48 hours in all instances.

Hyperventilation-precipitated cerebrovascular accident in a patient with sickle cell anaemia.

Hyperventilation exercise during electroencephalography precipitated a recurrence of right hemiplegia and aphasia in a patient with Hb SS disease. Although recovery of function started within hours of the event, full recovery has not occurred six months after. Hyperventilation provocative test during electroencephalography should be discouraged in patients with sickle cell anaemia.

Identification of a subpopulation of immune Nigerian adult volunteers by antibodies to the circumsporozoite protein of Plasmodium falciparum.

Collections of human sera from malaria-endemic areas would be valuable for identifying and characterizing antigens as malaria vaccine candidates if the contributing serum donors' ability to resist infection were fully characterized. We prepared such a serum collection from 26 apparently immune Nigerian adults who failed to develop patent parasitemia for at least 20 weeks following a documented increase in antibodies to the circumsporozoite protein (CSP) from Plasmodium falciparum. Volunteers were evaluated five times per week for malaria symptoms and bimonthly for parasites by examining thick blood smears. The incidence rate over 13 months for the cohort was 42% (47 malaria-confirmed volunteers) and the risk of infection was 1.3 infections/year. Responses to CSP did not correlate with protection. Because antibody responses to antigens other than CSP may be associated with protection, the sera from these immune individuals may be useful for identifying and characterizing other potential malaria vaccine candidates.

Protein energy malnutrition and cerebral malaria in Nigerian children.

Eight (14 per cent) out of 57 consecutive cerebral malaria patients (all < 5 years old) were malnourished, including one with marasmus and another recovering from kwashiorkor. This was significantly lower than among other paediatric patients in the same children's emergency ward (112/319, i.e. 35 per cent, P < 0.01). Poor outcomes (death or recovery with neurological deficits) were commoner in the malnourished group (4/8) than the well nourished group (7/49) (P = 0.037, Fisher's exact test). Malnourished children should receive malaria chemoprophylaxis during nutritional rehabilitation.

The clinical manifestations of cerebral malaria among Nigerian children with the sickle cell trait.

In order to describe the interaction between haemoglobin type and the clinical manifestations of cerebral malaria, we studied 60 children aged between 6 and 60 months at University College Hospital, Ibadan, Nigeria. Haemoglobin AS individuals with cerebral malaria did not exhibit major differences in clinical and laboratory characteristics when compared with their haemoglobin AA counterparts. There were no deaths among the Hb AS children compared with an 18% mortality in the Hb AA group. Blood transfusion rates were higher in the AS than in the AA children (86% vs 44%). The higher transfusion rates in the AS group is consistent with in-vitro observations of sickling of parasitized red cells containing Hb S which in vivo would be cleared by the reticuloendothelial system. It is concluded that the clinical manifestations of cerebral malaria are essentially similar in children with haemoglobins AS and AA but the former have higher transfusion needs and are less likely to die.