Acute splenic sequestration in HbSS: observations from the Jamaican birth cohort.

OBJECTIVE: To document the prevalence, clinical features, haematology and outcome of acute splenic sequestration (ASS) in homozygous sickle cell disease (HbSS). STUDY DESIGN: A cohort study from birth. SETTING: The Medical Research Council Laboratories at the University of the West Indies, Kingston, Jamaica. PATIENTS: 311 cases of HbSS detected during the screening of 100 000 deliveries at the main government maternity hospital between 1973 and 1981. INTERVENTIONS: Long-term follow-up and free patient care focusing on ASS. MAIN OUTCOME MEASURE: Acute splenic sequestration. RESULTS: There were 183 episodes of ASS in 105 patients representing 35% of the cohort. The median age for first event was 1.07 years. During ASS, median values for haemoglobin fell by 32 g/dL, reticulocytes increased by 8% and total nucleated cells increased by 10.5%. ASS recurred in 47 (45%) patients. Conservative therapy in 133 episodes of 85 patients was associated with five deaths and splenectomy in 20 patients with 50 episodes had no deaths. Symptoms were generally non-specific but acute chest syndrome occurred in 17, and blood cultures revealed coagulase negative staphylococci in 5. The ASS case fatality rate was 3.6% and may be higher if autopsy evidence of ASS is included. There was no seasonal pattern but higher levels of fetal haemoglobin predicted patients less prone to ASS and its later occurrence. CONCLUSIONS: ASS remains an important cause of morbidity and mortality in HbSS in developing societies. ASS appears to be a non-specific response to many possible risk factors including coagulase negative staphylococci.

Spleen size in homozygous sickle cell disease: trends in a birth cohort using ultrasound.

OBJECTIVES: To provide ultrasound baselines for spleen length in homozygous sickle cell disease (HbSS) and in normal controls with a HbAA genotype. METHODS: The Jamaican cohort study identified 311 babies with HbSS and 246 matched HbAA controls during the screening of 100,000 consecutive deliveries in Kingston, Jamaica from 1973 to 1981. Ultrasonography commenced in 1988 when the youngest patients were aged 6 years at which time deaths, emigrations and default had reduced the numbers to 206 HbSS and 89 controls. It continued annually until 2000. RESULTS: The spleen was visualized in all HbAA controls but in only 1103/2138 (52%) scans in HbSS. Where available, mean splenic lengths were significantly lower in HbSS (77-103 mm in males, 70-83 mm in females) compared to normal controls (89-101 mm in males, 86-95 mm in females). Assessed by statistical modelling after adjusting for body height, the splenic ratio (splenic length/body height) declined over the age range 12-20 years in HbSS, consistent with progressive splenic fibrosis. Genetic factors known to inhibit sickling, α thalassemia and fetal hemoglobin level (HbF) significantly reduced the decline in splenic ratio. Clinical splenomegaly was an insensitive measure of splenic enlargement as only 50% of patients aged 18 years and above with spleens measuring ≥150 mm on ultrasonography had palpable spleens. CONCLUSIONS: An age-related decline in splenic length occurred in HbSS and occurred more slowly with genetic factors known to inhibit sickling. The standards provided may be of value in assessing minor degrees of subclinical acute splenic sequestration. ADVANCES IN KNOWLEDGE: These are the first standards available for splenic length in HbSS. They may be useful in detecting red cell sequestration, not apparent from clinical splenomegaly and also provide a model for identifying factors inhibiting vaso-occlusion.

Newborn screening for abnormal haemoglobins in Jamaica: Practical issues in an island programme.

OBJECTIVE: To report the diagnostic challenges of newborn screening for abnormal haemoglobins. SETTING: Cord blood samples from 13 hospitals in southwest Jamaica taken in 2008-2019. METHODS: Blood spots, collected from the umbilical cord, were analysed by high pressure liquid chromatography (HPLC) to reveal phenotypes for HbSS and HbCC, but genotype confirmation may require parental studies or gene sequencing. Such cases that were successfully traced were analysed in this follow-up study. RESULTS: HPLC screening of 121,306 samples detected HbAS in 11,846 (9.8%), HbAC in 4508 (3.7%) and other electrophoretic abnormalities in 1090 babies. Among 101 previously unconfirmed cases, 34/90 (38%) with HPLC evidence of a HbSS phenotype had other genotypes, and 7/11 (64%) with a HbCC phenotype had other genotypes. Syndromes from the interaction of ß thalassaemia occurred in 112 babies (85 with HbS, 27 with HbC) and of genes for hereditary persistence of fetal haemoglobin (HPFH) in 18 (12 with HbS, 6 with HbC). Variants other than HbS and HbC occurred in 270 babies, 16 in combination with either HbS or HbC, and 254 as traits. Most variants are benign even when inherited with HbS, although HbO Arab, HbD Punjab, or Hb Lepore Washington, which occurred in 6 cases, may cause sickle cell disease. CONCLUSIONS: Genes for ß thalassaemia and HPFH are common in western Jamaica and when associated with HbS may present diagnostic challenges in newborns, as HbF and HbA2 have not reached diagnostic levels. Family and DNA studies may be necessary for genotype confirmation.

Phenotypic variation in sickle cell disease: the role of beta globin haplotype, alpha thalassemia, and fetal hemoglobin in HbSS.

INTRODUCTION: The hematological and clinical features vary markedly between the different genotypes of sickle cell disease. Even within the single genotype of homozygous sickle cell disease (HbSS), there is marked variability that is presumed to result from interacting genetic and environmental factors. AREAS COVERED: The classification of the different genotypes of sickle cell disease with approximate prevalence at birth in different communities and some of the major clinical and hematological differences. This assessment includes three potential genetic factors influencing hematology and clinical outcome in HbSS, the beta globin haplotype, alpha thalassemia, and persistence of fetal hemoglobin (HbF). EXPERT OPINION: The author is a clinician with experience of sickle cell disease primarily in Jamaica but also in Greece, Uganda, Saudi Arabia, and India. It is therefore necessarily an account of clinical data and does not address current debates on molecular mechanisms. Most data derive from Jamaica where efforts have been made to reduce any symptomatic bias by long-term follow-up of patients all over the Island and further reduced by a cohort study based on newborn screening, which has been in operation for over 48 years.

Odisha Revisited: A Personal Account.

In 1986, a paper in the Lancet was the first to collate hematology, molecular findings, and clinical features of homozygous sickle cell (SS) disease in India. The paper came from the group organized by Professor Bimal Kar in Burla Medical College, Sambalpur University, in western Odisha. Although widely quoted, few readers will be aware of the history of this work that is now attached in an informal summary.

Sickle Cell Disease: Thoughts for India From the Jamaican Cohort Study.

The sickle cell gene in India represents a separate occurrence of the HbS mutation (the Asian haplotype), which has occurred against a genetic background characterised by high levels of fetal haemoglobin and widely varying frequencies of alpha thalassaemia. These features, which tend to inhibit sickling, change the expression of the disease, which, in India, may be further modified by poor nutrition, malaria and other infections, and limited public health resources. Sickle cell disease in Jamaica is predominantly of African origin (the Benin haplotype) and faces some similar challenges. This review assesses similarities and differences between disease expression in the two countries and seeks to explore lessons from Jamaica, which may be relevant to Indian health care. In particular, it addresses common causes of hospital admission as detailed from Indian clinical experience: anemia, bone pain crisis, and infections.

Retained Splenic Function in an Indian Population with Homozygous Sickle Cell Disease May Have Important Clinical Significance.

BACKGROUND AND OBJECTIVES: To determine whether the persistence of splenomegaly characteristic of the Asian haplotype of homozygous sickle cell (SS) disease is associated with continued splenic function, a comparison of patients from Odisha, India, and Jamaica. MATERIALS AND METHODS: Indian patients were examined in a cross-sectional study and compared with the Jamaican Cohort Study from birth. Splenomegaly was assessed in both populations with standard methods. Splenic function was assessed in both by counts of pitted red blood cells determined by differential interference contrast microscopy in the same laboratory. RESULTS: In Jamaica, the spleen became palpable in 55% of patients during the 1st year of life and the prevalence declined thereafter, whereas in Indian patients, the prevalence rose steeply after the age of 4 years. Raised pitted red cell counts, consistent with loss of splenic function, were common after 2 years in Jamaicans but did not increase in Indians until after the age of 5 years. INTERPRETATION AND CONCLUSIONS: The maximal risk of invasive pneumococcal infection in SS disease falls sharply after the age of 3 years, and persistence of splenic function in Odisha patients beyond this age may explain the apparent absence of pneumococcal septicemia in Indian patients and questions the role of pneumococcal prophylaxis.

Homozygous sickle cell disease in Central India & Jamaica: A comparison of newborn cohorts.

Background & objectives: Homozygous sickle cell (SS) disease in Central India runs a more severe clinical course than reports from other areas of India. The current study was undertaken to compare the disease in Central India (Nagpur) with that in Jamaica, both populations defined by newborn screening. Methods: The Nagpur cohort included infants born to sickling-positive mothers from May 2008 to 2012, examined by high-pressure liquid chromatography and DNA analysis. The Jamaican cohort screened 100,000 consecutive non-operative deliveries between June 1973 and December 1981, analyzed by haemoglobin (Hb) electrophoresis and confirmed by family studies and compatible HbA2levels. Results: In Nagpur, 103 SS patients were detected, but only 78 (76%) were followed up. In Jamaica, 311 cases were followed from birth and compliance with follow up remained 100 per cent up to 45 years. In the Nagpur cohort all had the Asian haplotype, and 82 per cent of Jamaicans had at least one Benin chromosome; none had the Asian haplotype. Compared to Jamaica, Nagpur patients had higher foetal Hb, less alpha-thalassaemia, later development of splenomegaly and less dactylitis. There were also high admission rates for febrile illness and marked anaemia. Invasive pneumococcal disease occurred in 10 per cent of Jamaicans but was not seen in Nagpur. Interpretation & conclusions: There were many differences between the disease in Nagpur, Central India and the African form observed in Jamaica. The causes of severe anaemia in Nagpur require further study, and reticulocyte counts may be recommended as a routine parameter in the management of SS disease. The role of pneumococcal prophylaxis needs to be determined in Nagpur patients. Future studies in India must avoid high default rates.

The additional genetic diagnosis of homozygous sickle cell disease in a patient with Waardenburg-Shah syndrome: a case report.

BACKGROUND: It is important that multiple genetic diagnoses are not missed. This case report describes the clinical features and management of a patient with co-inheritance of Waardenburg syndrome type 4 or Waardenburg-Shah syndrome, an extremely rare disease, and homozygous sickle cell disease not uncommon in the Caribbean. This case is unusual as it may be the first documented case of the co-inheritance of both these diseases. Given the commonality of sickle cell and related hemoglobinopathies, such combined disorders are likely to be under-reported. Importantly, reporting this case will add to the medical literature as it will raise awareness of the phenotypic manifestations of this disorder. CASE PRESENTATION: A 54-year-old Afro-Caribbean woman had a delayed diagnosis of homozygous sickle cell disease at 7 years of age by hemoglobin electrophoresis. The complications of sickle cell disease she experienced included bone pain, a chronic right leg ulcer, avascular necrosis of her left hip, and symptomatic cholelithiasis. This diagnosis was preceded by an earlier diagnosis of Waardenburg syndrome. The basis for the diagnosis of Waardenburg-Shah syndrome was the presence of pigmentary disturbances of her eyes (hypoplastic blue irides), congenital sensorineural hearing loss, and Hirschsprung's disease. She was mute and complained of chronic constipation which required disimpaction on several occasions. She attended a school for the deaf and communicated via writing. A Duhamel procedure bypassing her rectum was performed at age 9. She died following an admission for acute chest syndrome complications. CONCLUSION: Sickle cell disease can be diagnosed by newborn screening but, as in this case, may have a delayed presentation. The delay in diagnosis of homozygous sickle cell disease illustrates that other genetic disorders should be considered in patients who already have a diagnosis of one Mendelian disorder but show atypical features.

Causes of death and early life determinants of survival in homozygous sickle cell disease: The Jamaican cohort study from birth.

Globally, the majority of persons born with sickle cell disease do not have access to hydroxyurea or more expensive interventions. The objectives were to estimate the survival in homozygous sickle cell disease, unbiased by symptomatic selection and to ascertain the causes of death in a pre-hydroxyurea population. The utility of early life biomarkers and genetically determined phenotypes to predict survival was assessed. A cohort study based on neonatal diagnosis was undertaken at the Sickle Cell Unit, a specialist clinic delivering care to persons with sickle cell disease in Jamaica. Screening of 100,000 deliveries detected 315 babies with homozygous sickle cell disease of whom 311 have been followed from birth for periods up to 43 years. Pneumococcal prophylaxis and teaching mothers splenic palpation were important, inexpensive interventions. Anticipatory guidance, routine care and out-patient acute care were provided. Each participant was classified as alive, dead, or defaulted (usually emigration). Causes of death were ascertained from clinical records and/or post-mortem reports. Survival was assessed using the Kaplan-Meier function. Sex-adjusted Cox semi-parametric proportional hazards and Weibull modelling were used to assess the effects on survival of biomarkers. Survival to 40 years was 55.5% (95% CI 48.7% to 61.7%). Acute Chest Syndrome (n = 31) and septicemia (n = 14) were significant causes of death at all ages. Acute splenic sequestration (n = 12) was the most common cause of early deaths. Survival was significantly shorter in those with lower hemoglobin at 1 year, high total nucleated count at 1 year, and a history of dactylitis ever. In these hydroxyurea naïve patients, survival into midlife was common. Causes of death were often age specific and some may be preventable. Early life biomarkers predictive of decreased survival in SS disease identify a patient group likely to benefit from close clinical supervision and potentially high risk therapies.

ß-Thalassemia Mutations in Jamaica: Geographic Variation in Small Communities.

Over the last 43 years, surveys of over 200,000 subjects in Jamaica have identified ß-thalassemia (ß-thal) mutations. In most, these genes were detected at birth in patients with sickle cell-ß-thal and so the prevalence and distribution would not be influenced by subsequent clinical course. There were two newborn populations, 100,000 deliveries in the corporate area between 1973-1981 and 84,940 in south and western Jamaica between 2008-2016. A third population, which derived from the Manchester Project in central Jamaica, screened 16,612 secondary school children, aged predominantly 15-19 years, and identified 150 students with the ß-thal trait and 11 with sickle cell [Hb S (HBB: c.20A>T)]- or Hb C (HBB: c.19G>A)-ß-thal. The latter patients may have been subject to symptomatic selection, but this should not have affected those with ß-thal trait. Of the 24 different molecular mutations, ß0-thal genes accounted for 10.0-27.0% of these groups and most common was IVS-II-849 (A>G) (HBB: c.316-2A>G). Of the ß+ mutations, seven subjects had severe genes with low levels of ß chain synthesis but the majority were benign mutations in the promoter region. The -29 (A>G) (HBB: c.-79A>G) mutation dominated in the newborn study in Kingston, similar to experiences in Guadeloupe and African Americans but the -88 (C>T) (HBB: c.-138C>T) mutation was more common among school students in central Jamaica. Caribbean populations are genetically heterogeneous but variations within different parts of Jamaica is of potential importance for prenatal diagnosis and genetic counseling. This information may also be useful among the large Jamaican diaspora.

Variability of homozygous sickle cell disease: The role of alpha and beta globin chain variation and other factors.

The single base molecular substitution characterizing sickle cell haemoglobin, ß6glu→val, might be expected to result in predictable haematological and clinical features. However, the disease manifests remarkable diversity believed to reflect the interaction with other genetic and environmental factors. Some of the genetic modifiers include the beta globin haplotypes, alpha thalassaemia, factors influencing the persistence of fetal haemoglobin and the effects of the environment are addressed in this review. It is concluded that much of the genetic data present conflicting results. Environmental factors such as climate and infections, and psychological, educational and social support mechanisms also influence expression of the disease. These interactions illustrate how the expression of a 'single gene' disorder may be influenced by a variety of other genetic and environmental factors.

A Plea for the Newborn Diagnosis of Hb S-Hereditary Persistence of Fetal Hemoglobin.

The gene for hereditary persistence of fetal hemoglobin (HPFH) in the Caribbean is much more common than previously estimated. To avoid labeling persons with the benign syndrome Hb S (HBB: c.20A>T)/HPFH as a disease and wasting scarce resources, parental studies are recommended when newborn screening reveals a pattern consistent with an SS phenotype.

The Bone Pain Crisis of Sickle Cell Disease and Malaria: Observations from Gujarat, India.

BACKGROUND: Sickle cell disease is a common problem across central India, but its clinical features may differ from that in African populations. There is a need to define the features of sickle cell disease in India, and the current study addresses some features of the bone pain crisis. OBJECTIVES: The objective of the study was to describe the epidemiology of the bone pain crisis of sickle cell disease in Gujarat and explore the relationship with infection by Plasmodium vivax. MATERIALS AND METHODS: This was a prospective review of all admissions in patients with sickle cell disease to a private pediatric institution in Bardoli, Gujarat, in the year 2015. Hemoglobin electrophoresis of all patients was consistent with homozygous sickle cell disease, but family studies indicated that at least seven cases had the severe sickle cell-beta + thalassemia presumed to be the common IVS1-5G>C mutation. Clinical, hematological, and parasitological features were recorded. RESULTS: There were 914 admissions among 654 patients who had between one and seven admissions. The bone pain crisis accounted for 763 (83%) of admissions and increased between July and October coinciding with the monsoon period. Blood smears were examined for malarial parasites in 811 admissions and were positive for P. vivax in 73% patients. There was no evidence that P. vivax infections varied with the cause of admission or increased during the monsoon period. CONCLUSIONS: There was a high prevalence of P. vivax infection in hospital admissions of sickle cell patients, but the data did not support an etiological role in the bone pain crisis. A trial of malarial prophylaxis might determine its effect on the clinical features and outcome of sickle cell disease.

Evolving locally appropriate models of care for indian sickle cell disease.

The sickle cell gene in India represents a separate occurrence of the HbS mutations from those in Africa. Sickle cell disease in India occurs against different genetic and environmental backgrounds from those seen in African patients and there is evidence of clinical differences between the populations. Knowledge of the clinical features of African disease was drawn from the Jamaican Cohort Study, based on prospective follow up of all cases of sickle cell disease detected by the screening of 100,000 consecutive newborns in Kingston, Jamaica, and supplemented by observations from the Cooperative Study of Sickle Cell Disease in the US. Defining the principal causes of early morbidity in African sickle cell disease led to successful interventions including pneumococcal prophylaxis, parental education in the early diagnosis of acute splenic sequestration, and the early detection by trans-cranial Doppler of cerebral vessel stenosis predictive of stroke but their success depended on early diagnosis, ideally at birth. Although reducing mortality among patients with African forms of SS disease, the question remains whether these interventions are appropriate or justified in Indian patients. This dilemma is approached by comparing the available data in African and Indian forms of SS disease seeking to highlight the similarities and differences and to identify the deficiencies in knowledge of Indian disease. These deficiencies could be most readily addressed by cohort studies based on newborn screening and since much of the morbidity of African disease occurs in the first five years of life, these need not be a daunting prospect for Indian health care personnel. Newborn screening programmes for sickle cell disease are already underway in India and appropriate protocols and therapeutic trials could quickly answer many of these questions. Without this knowledge, Indian physicians may continue to use possibly unnecessary and expensive models of care.

Pregnancy in sickle cell-haemoglobin C (SC) disease. A retrospective study of birth size and maternal weight gain.

OBJECTIVE: To assess pregnancy and fetal outcomes in Jamaican subjects with sickle cell-haemoglobin C (SC) disease. STUDY DESIGN: A retrospective chart review over 21 years (1992-2012) of all pregnancies in SC disease and a comparison group matched by gender and date of delivery in mothers with a normal haemoglobin (AA) phenotype at the University Hospital of the West Indies, Jamaica. There were 118 pregnancies in 81 patients with SC disease and 110 pregnancies in 110 in the normal comparison group. Corrections were made for repeat pregnancies from the same mother. Outcome measures included maternal weight at 20, 25, 30, 35 and 38 weeks gestation, maternal pregnancy complications, birth weight, head circumference and crown heel length and were used to analyse possible predictors of birth weight. RESULTS: First antenatal visits occurred later in women with SC disease, who also had lower haemoglobin level and lower systolic blood pressure. The prevalence of pregnancy-induced hypertension, pre-eclampsia, ante-partum or postpartum haemorrhage did not differ between genotypes. Maternal weight gain was significantly lower in SC disease and there was a significantly lower birth weight, head circumference, and gestational age. CONCLUSIONS: Pregnancy in SC disease is generally benign but mothers had lower weight gain and lower birth weight babies, the difference persisting after correction for gestational age.

Sickle Cell Disease in Central India: A Potentially Severe Syndrome.

OBJECTIVES: To explore clinical, hematological and molecular features of homozygous sickle cell (SS) disease in central India. METHODS: Focusing on the pediatric age group attending a clinic at the Akola Government Medical College, Akola, Maharashtra State, India, a cross-sectional assessment of 91 patients with sickle cell disease was performed during one week in March 2015. RESULTS: Of the 91 patients, there were 49 with SS disease, 36 with sickle cell-beta thalassemia, and 6 with sickle cell-HbD Punjab. Alpha globin gene deletions occurred in only 8/49 (16 %) SS disease but fetal hemoglobin (HbF) levels were markedly elevated with mean and median of 24.4 %; all except 3 SS disease patients had the Xmn1(+/+) polymorphism consistent with the Asian haplotype. Among the 36 patients with sickle cell-beta thalassemia, 25 (69 %) had the severe beta(+) mutation, IVS1-5 G > C, and seven other molecular mutations, all beta(o) occurred in the other 11 patients. Many patients had a relatively severe clinical course. Comparison of SS disease and sickle cell-beta thalassemia showed no differences in the prevalence of dactylitis, bone pain crisis, acute chest syndrome, hemoglobin level, reticulocyte counts or hydroxyurea usage but patients with sickle cell-beta thalassemia had significantly more blood transfusions, and greater frequencies of splenomegaly and hepatomegaly. CONCLUSIONS: Many patients in central India have relatively severe manifestations. This may result from lower frequencies of alpha thalassemia and more frequent severe sickle cell-beta(+) thalassemia. There is a need for assessment of the indications and policies for blood transfusion and for hydroxyurea.

Predictors of renal function progression in adults with homozygous sickle cell disease.

Longitudinal studies of renal function may improve understanding of the pathophysiological mechanisms underlying sickle cell disease (SCD) nephropathy and may identify possible biological and clinical markers of renal function determined over time. Data from the Jamaica Sickle Cell Cohort Study (JSCCS) were extracted and the glomerular filtration rate (GFR) was estimated using the Chronic Kidney Disease Epidemiological and the SCD specific JSCCS-GFR equations from all adulthood serum creatinine measurements in homozygous SS patients. The other dataset consisted of measured GFR at two times about 13 years apart. Linear mixed model (LMM) regression analyses were conducted to determine predictors of GFR and serum creatinine over time. 191 individuals with SS disease had 867 GFR estimates available. Serum creatinine significantly increased from baseline whereas estimated GFR showed a significant decline. Serum creatinine showed positive association with increasing age, male gender, body mass index and sodium levels. Haemoglobin was a significant negative predictor of estimated GFR in age- and gender-adjusted models. A total of 24 females and 17 males had repeat measurements of their GFR. The mean annual decline in GFR was -3·2 ± 2·83 ml/min/1·73 m(2) . Haemoglobin was a significant positive predictor whereas serum creatinine, systolic blood pressure and urinary albumin: creatinine ratio were negative predictors of GFR.