The beta thalassaemia trait in Jamaica.

The objective of this study was to review the prevalence and features of the beta thalassaemia trait in Jamaican populations. Screening of 221,306 newborns over the last 46 years has given an indication of the distribution and prevalence of beta thalassaemia genes, and screening of 16,612 senior school students in Manchester parish, central Jamaica, has provided their haematological features. The prevalence of the beta thalassaemia trait predicted from double heterozygotes was 0.8% of 100,000 babies in Kingston, 0.9% of 121,306 newborns in southwest Jamaica, and 0.9% of school students in Manchester. Mild beta+ thalassaemia variants (-88 C>T, -29 A>G, -90 C>T, polyA T>C) accounted for 75% of Kingston newborns, 76% of newborns in southwest Jamaica, and 89% of Manchester students. Severe beta+ thalassaemia variants were uncommon. Betao thalassaemia variants occurred in 43 patients and resulted from 11 different variants of which the IVSII-849 A>G accounted for 25 (58%) subjects. Red cell indices in IVSII-781 C>G did not differ significantly from HbAA, and this is probably a harmless polymorphism rather than a form of beta+ thalassaemia; the removal of 6 cases in school screening had a minimal effect on the frequency of the beta thalassaemia trait. Red cell indices in the beta+ and betao thalassaemia traits followed established patterns, although both were associated with increased HbF levels. The benign nature of beta+ thalassaemia genes in Jamaica means that cases of sickle cell-beta+ thalassaemia are likely to be overlooked, and important clinical questions such as the role of pneumococcal prophylaxis remain to be answered.

The haematology of Jamaicans: red cell indices in HbAA, HbAS, HbAC, and HbA-HPFH genotypes.

Based in the parish of Manchester in central Jamaica, the Manchester Project offered free detection of haemoglobin genotype to senior classes in 15 secondary schools between 2008 and 2013. Restricting the database to 15,103 students aged 15.0-19.9 years provided an opportunity to examine the red cell characteristics of the different haemoglobin genotypes, including normal (HbAA) in 85.0%, the sickle cell trait (HbAS) in 9.7%, HbC trait (HbAC) in 3.5% and hereditary persistence of foetal haemoglobin (HbA-HPFH) in 0.4%. Compared to the normal HbAA phenotype, HbAS had significantly increased mean cell haemoglobin concentration (MCHC), red cell count (RBC), and red cell distribution width (RDW) and decreased mean cell volume (MCV) and mean cell haemoglobin (MCH), these differences being even more marked in HbAC. Compared to HbAA, the HbA-HPFH had significantly increased RDW, but there were no consistent differences in other red cell indices, and there were no significant differences in haematological indices between the two common deletion HPFH variants, HPFH-1 and HPFH-2. Although these changes are unlikely to be clinically significant, they contribute to an understanding of the haematological spectrum of the common haemoglobin genotypes in peoples of African origin.

Voluntary premarital screening to prevent sickle cell disease in Jamaica: does it work?

To determine whether identifying haemoglobin genotype, and providing education and counselling to senior school students will influence their choice of partner and reduce the frequency of births with sickle cell disease. The Manchester Project provided free voluntary blood tests to determine haemoglobin genotype to the fifth and sixth forms (grades 11-13), median age of 16.7 years, of all 15 secondary schools in the parish of Manchester in south central Jamaica. A total of 16,636 students complied, and counselling was offered to carriers of abnormal genes over 6 years (2008-2013). The genotypes of their offspring were determined by newborn screening of 66,892 deliveries in 12 regional hospitals over 8 years (2008-2015). The study focused on the genotypes of live deliveries to female students with the four most common haemoglobin genotypes: 7905 with an AA genotype, 898 with the sickle cell trait, 326 with the HbC trait and 78 with the beta thalassaemia trait. A total of 2442 live deliveries were identified by the end of 2015 in mothers screened at school. Eleven babies had clinically significant genotypes, and the prevalence of SS and SC disease did not differ from that predicted by random mating. First pregnancy was not delayed in AS or AC mothers. There was no evidence that knowledge of maternal haemoglobin genotype influenced choice of partner. On an interview, mothers of affected babies correctly recalled their genotype, but either did not discuss this with their partners or the latter refused to be tested. Subjects delaying child bearing for tertiary education would be largely excluded from the present study of first pregnancies and may make greater use of this information. Future options are a greater role for prenatal diagnosis.

Newborn screening for sickle cell disease in Jamaica: logistics and experience with umbilical cord samples.

The study aims to describe the logistics and results of a programme for newborn screening for sickle cell disease based on samples from the umbilical cord. Samples were dried on Guthrie cards and analysed by high pressure liquid chromatography. All suspected clinically significant abnormal genotypes were confirmed by age 4-6 weeks with family studies and then recruited to local sickle cell clinics. The programme has screened 66,833 samples with the sickle cell trait in 9.8 % and the HbC trait in 3.8 %. Sickle cell syndromes occurred in 407 babies (204 SS, 148 SC, 35 Sbeta+ thalassaemia, 6 Sbetao thalassaemia, 6 sickle cell-variants, 8 sickle cell-hereditary persistence of fetal haemoglobin) and HbC syndromes in 42 (22 CC, 14 Cbeta+ thalassaemia, 1 Cbetao thalassaemia, 5 HbC- hereditary persistence of fetal haemoglobin). Focusing on the year 2015, screening was performed in 15,408, compliance with sample collection was 98.1 %, and maternal contamination occurred in 335 (2.6 %) but in only 0.05 % did diagnostic confusion require patient recall and further tests. This model of newborn screening for sickle cell disease is accurate, robust and economic. It is hoped that it may be helpful for other societies with high prevalence of abnormal haemoglobins and limited resources, who are planning to embark on newborn screening for sickle cell disease.

Newborn Screening for Sickle Cell Disease: Jamaican Experience.

OBJECTIVES: To review the history of newborn screening for sickle cell disease with especial reference to Jamaica. METHODS: A summary was done of the history, the development of associated laboratory technology and the implementation of newborn screening for sickle cell disease in Jamaica. RESULTS: Screening was initiated at Victoria Jubilee Hospital, Kingston from 1973-1981, reactivated in 1995 and extended to the University Hospital of the West Indies in 1997 and to Spanish Town Hospital in 1998. From August 2008, there was a progressive recruitment of 12 hospitals in the south and west of Jamaica which has raised the frequency of islandwide newborn coverage from 25% in 1973 to 81%. The results of this extended programme in southwest Jamaica are presented. Dried blood spots collected from the umbilical cord proved stable, cheap and efficient; mean sample collection rates were 98%, maternal contamination occurred in < 1% and caused diagnostic confusion in < 0.1%. By March 31, 2015, a total of 54 566 births have been screened, detecting 161 with homozygous sickle cell (SS) disease, 125 with sickle cell-haemoglobin C (SC) disease and 36 with sickle cell-beta thalassaemia. Of the 327 babies with clinically significant sickle cell syndromes, all except five who died within seven days of birth were confirmed by four to six weeks and recruited to local sickle cell clinics. CONCLUSION: Early detection of sickle cell disease and recruitment to clinics is known to reduce its morbidity and mortality. The methods currently detailed provide an effective and economic model of newborn screening which may be of value elsewhere.

Homozygous sickle cell disease in Uganda and Jamaica a comparison of Bantu and Benin haplotypes.

OBJECTIVE: To compare the haematological and clinical features of homozygous sickle cell (SS) disease in Bantu and Benin haplotypes in a cross-sectional study of 115 Ugandan patients attending the Sickle Cell Clinic at Mulago Hospital, Kampala, Uganda, with 311 patients in the Jamaican Cohort Study METHODS: This involved comparison of clinical features and haematology with special reference to genetic determinants of severity including fetal haemoglobin levels, beta-globin haplotype and alpha thalassaemia status. RESULTS: The Bantu haplotype accounted for 94% of HbS chromosomes in Ugandan patients and the Benin haplotype for 76% of HbS chromosomes in Jamaica. Ugandan patients were marginally more likely to have alpha thalassaemia, had similar total haemoglobin and fetal haemoglobin levels but had higher reticulocyte counts and total bilirubin levels consistent with greater haemolysis. Ugandan patients had less leg ulceration and priapism, but the mode of clinical presentation, prevalence of dactylitis, features of bone pain and degree of delay in sexual development, assessed by menarche, were similar in the groups. In Ugandan patients, a history of anaemic episodes was common but these were poorly documented. CONCLUSION: The haematological and clinical features of the Bantu haplotype in Uganda were broadly similar to the Benin haplotype in Jamaica except for less leg ulceration and priapism and possibly greater haemolysis among Ugandan subjects. Anaemic episodes in Uganda were treated empirically by transfusion often without a clear diagnosis; better documentation including reticulocyte counts and observations on spleen size is necessary to evolve appropriate models of care.

The changing face of homozygous sickle cell disease: 102 patients over 60 years.

Earlier reports on homozygous sickle cell (SS) disease have been biased by severely affected cases. The Jamaican clinic which seeks to avoid such bias has 102 patients surviving beyond 60 years. The objective of this study was to examine the features of elderly cases and assess factors determining survival and the behaviour of this disease with advancing age. A retrospective review of all cases and prospective assessment in survivors was conducted at The Sickle Cell Clinic at the University of the West Indies, Kingston, Jamaica previously operated by the MRC Laboratories. All patients with SS disease born prior to December 31, 1943 who would, by January 2004, have passed their 60th birthday were traced and their current status ascertained. The molecular and clinical features were assessed and observations on the clinical behaviour of the disease and of haematology and biochemistry are presented. Of the 102 patients, 58 had died, four had emigrated and 40 were alive, resident in Jamaica and aged 60-87 years. Survival was associated with female gender and higher foetal haemoglobin but not with alpha-thalassaemia or beta-globin haplotype. A tendency to familial clustering among elderly survivors did not reach statistical significance. Painful crises ameliorated with age and there was a benign course in pregnancy. Mean haemoglobin levels fell with age and were generally associated with rising creatinine levels indicating the importance of renal failure. Elderly survivors present some features of intrinsic mildness but also manifest age-related amelioration of painful crises and falling haemoglobin levels from progressive renal damage.

Sickle haemoglobin and haemoglobin Stanleyville II: possible confusion with sickle cell-haemoglobin C disease.

OBJECTIVES: To bring to the attention of East African practitioners, the characteristics of Hb Stanleyville II, its interaction with HbS, and the resemblance of the double heterozygote to sickle cell-haemoglobin C (SC) disease. DATA SOURCES: A prospective study of 100 patients with Sickle Cell (SS) disease in the steady state attending the sickle cell Clinic at Mulago Hospital, Kampala, Uganda. STUDY SELECTION: Out of 100 patients with SS disease, two were also heterozygous for an alpha chain variant identified as Hb Stanleyville II. CONCLUSIONS: In association with HbS, Hb Stanleyville II produces a hybrid haemoglobin band which on alkaline haemoglobin electrophoresis, travels in the position of HbC. Such cases may cause confusion with sickle cell-haemoglobin C (SC) disease. The index cases in both families had associated alpha thalassaemia but from this small group, no conclusions may be drawn on the haematological or clinical significance of the interaction of Hb Stanleyville II with SS disease.

Haematological response to parvovirus B19 infection in homozygous sickle-cell disease.

Infection with human parvovirus B19 is known to cause aplastic crises in patients with homozygous sickle-cell disease. We studied the haematological consequences of parvovirus B19 infection in 280 such patients who had been followed up from birth in Jamaica. Evidence of seroconversion was routinely sought with a baculovirus-based, enzyme immunoassay in serum samples taken during aplastic crises and in all stored annual serum samples. 70% of patients had seroconverted by age 20 years; of 177 infections, haematological change was typical of aplastic crises in 118 (67%), minor in 16 (9%), and not discernible in 43 (24%). This assay increased the detection of unsuspected seroconversion-an observation important in planning a strategy for parvovirus B19 immunisation.

Foetal haemoglobin in homozygous sickle cell disease: a study of patients with low HBF levels.

High foetal haemoglobin (HbF) levels are believed to ameliorate the manifestations of homozygous sickle cell (SS) disease. The corollary implies that patients with low HbF levels should have more severe clinical courses. We investigated this in a retrospective study of 50 Jamaican patients with steady-state HbF levels below 1% compared with a control group (A) of 54 subjects with steady-state HbF levels between 2.5 and 3.4% (around the 25th centile for our population), and a second control group (B) of 60 patients with steady-state HbF levels between 4.6 and 5.2% (around the 50th centile). Comparisons across the groups indicated significantly fewer females in the study group (16, 50 and 57%, respectively). Examination for haematological trends across the groups showed positive linear trends for haemoglobin (Hb) (P=0.004), packed cell volume (PCV) (P=0.01), mean cell volume (MCV) (P= < 0.001), mean cell haemoglobin (MCH) (P= < 0.001) and a negative trend for haemoglobin A2 (P=0.03). Clinically, there were no differences in the incidence of painful crises, abdominal crises and the acute chest syndrome, but leg ulcers were significantly less frequent in the study group (P=0.04). Therefore low HbF levels do not appear to increase the clinical severity of SS disease and may be protective against leg ulceration.

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.

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.

Jamaican Sbeta+-thalassaemia: mutations and haematology.

The sickling disorders are a common cause of morbidity and mortality in Jamaica. Sickle cell beta+-thalassaemia is the fourth commonest form, occurring in one in every 3000 births. This is a heterogeneous condition, producing HbS, HbF and HbA2 with variable amounts of HbA, depending on the mutation and, within a defined population, only a few beta-thalassaemia mutations occur at high frequency. This study establishes the frequency of beta-thalassaemia mutations in Sbeta+-thalassaemia patients in Jamaica. In addition, comparison of the haematological phenotypes is possible by looking at the 'average steady-state haematology' of the different mutational groups. Blood samples from 132 unrelated Sbeta+-thalassaemia patients attending the MRC Sickle Cell Unit at the University of the West Indies were analysed by amplification refractory mutation system (ARMS) polymerase chain reaction (PCR) or sequencing to determine the nature and frequencies of the underlying beta-thalassaemia mutations. Ten mutations were identified, four of which accounted for 93% of patients studied. These were -29(A --> G) in 71 (54%), -88(C --> T) in 27 (20%), polyA(T --> C) in 17 (13%) and IVS1-5(G --> C) in nine (7%). The six remaining mutations found at low frequency were C24(T --> A) in two patients and one each of IVS2-848(C --> A), -90(C --> T), IVS1-5(G --> T), IVS1-5(G --> A) and IVS1-6 (T --> C). In one individual, no mutation was found. The three commonest mutations were all associated with haemoglobin levels of greater than 10 g/dl, whereas IVS1-5 (G --> C) had a more severe haematological phenotype. The predominance of -29(A --> G) and -88(C --> T) is in keeping with other studies on populations of African origin. IVS1-5(G --> C) is found chiefly in Indian populations, and all affected families acknowledged Indian ancestry, reflecting the prominent Indian community in Jamaica.

Microchromatographic quantitation of hemoglobin A levels in phenotypes of sickle cell-beta(+) thalassemia.

The inheritance of the sickle cell gene in combination with a gene for beta(+) thalassemia results in a spectrum of sickle cell-beta(+) thalassemia syndromes with varying levels of hemoglobin A (HbA). Some severe sickle cell-beta(+) thalassemia syndromes have small amounts of HbA, which may be difficult to quantitate in the presence of fetal hemoglobin. A microcolumn chromatographic method, using 0.5 M Tris-acetic acid developers with varying pH values from 9.0 to 6.0, appears to adequately quantitate small amounts of HbA. This method is relatively simple and cheaper than high-performance liquid chromatography, a major consideration in developing countries.

Plasma proteins in children with trichuris dysentery syndrome.

AIMS: To determine whether in Trichuris trichiura dysentery there is (1) evidence of a systemic inflammatory response, (2) evidence that the plasma protein disturbance has special characteristics compared with uninfected children in the endemic environment. METHODS: Three groups of children (age 1.6 to 11.4 years) were studied: 53 cases of trichuris dysentery syndrome (TDS), 16 cases of chronic non-secretory diarrhoea not infected with the parasite ("disease controls", DC), and 20 asymptomatic, parasite-free primary schoolchildren (normal controls, NC). C reactive protein, alpha 1 antitrypsin, caeruloplasmin, albumin, total globulin, fibrinogen, fibronectin, ferritin, and transferrin were measured on a single occasion for each. The study was thus a cross sectional descriptive survey for group comparison. Plasma viscosity was measured on admission for TDS and DC and repeated after six weeks and six months for TDS. RESULTS: Plasma C reactive protein, alpha 1 antitrypsin, total globulin, fibronectin, and viscosity were significantly higher in TDS than in NC. DC children also had acute phase protein elevations (C reactive protein, caeruloplasmin, viscosity). However, the increase in caeruloplasmin was specific to the DC group while an increase in fibronectin was specific to the TDS group. Serial measurement of viscosity in TDS showed a modest but significant fall during the six months following treatment. CONCLUSIONS: There is an acute phase response in intense trichuriasis and a specific elevation of plasma fibronectin. Plasma viscosity remains abnormally high six months after treatment, although lower than at diagnosis.

Glomerulonephritis after human parvovirus infection in homozygous sickle-cell disease.

Glomerulonephritis with proteinuria of sufficient degree to manifest the nephrotic syndrome followed aplastic crises induced by human parvovirus (B19) in seven patients with homozygous sickle-cell disease, within 7 days in five patients and 6-7 weeks in two. Segmental proliferative glomerulonephritis was found in all four patients who underwent acute renal biopsies and focal segmental glomerulosclerosis was found in the fifth patient who had a biopsy 4 months later. One patient recovered completely, one died in chronic renal failure after 3 months, and the others had impaired creatinine clearance, four with continuing proteinuria.

Ocular findings in Saudi Arabian patients with sickle cell disease.

AIM: This study was set up to determine whether or not retinal changes occur in sickle cell disease in Saudi Arabian subjects with either the Benin, which exists in the south western part of the kingdom, or Asian haplotypes in the east, and to compare the findings with those in sickle cell disease in Jamaica. METHODS: Retinal examination and fluorescein angiography were performed in 61 patients with SS disease (40 eastern, 20 south western, 1 central region) and 10 with sickle cell beta(0) thalassaemia. RESULTS: Peripheral retinal vascular changes were common, and a qualitatively abnormal vascular border believed to imply risk of proliferative sickle retinography (PSR) was significantly more common in south western SS patients and PSR was shown in one of these. There were no differences in visual acuity, the presence of peripheral retinal patches, or the circumferential or posterior extent of peripheral retinal vessel closure between SS disease and sickle cell beta(0) thalassaemia or between SS disease in the two regions. Compared with the Jamaican Cohort Study, > 180 degrees of the peripheral retinal vasculature was seen significantly less frequent, suggesting factors inhibiting vascular remodeling in Saudi patients in early life. CONCLUSION: Sickle cell disease in Saudi Arabia affects the retina and represents a potential threat to vision. Changes occur whatever the haplotype, and is similar to that observed in Jamaica.