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.

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.

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.

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.

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.

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.

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.

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.

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.

Hb S-ß-thalassemia: molecular, hematological and clinical comparisons.

Clinical and hematological features are presented for 261 patients with identified ß-thalassemia (ß-thal) mutations. Mutations causing Hb S [ß6(A3)Glu→Val]-ß(0)-thal were IVS-II-849 (A>G) in 44%, frameshift codon (FSC) 6 (-A) in 14%, Hb Monroe [ß30(B12)Arg→Thr] in 14%, and IVS-II-1 (G>A) in 10%. Mutations causing Hb S-ß(+)-thal with 14-25% Hb A (type III) were -29 (A>G) mutation in 60%, -88 (C>T) in 22% and the polyadenylation signal site (polyA) (T>C) mutation in 14%, and in Hb S-ß(+)-thal with 1-7% Hb A (type I), all had the IVS-I-5 (G>C) mutation. Hematologically, only minor differences occurred between the four Hb S-ß(0)-thal mutations, but among the three mutations causing Hb S-ß(+)-thal type III, levels of Hb A(2), Hb F, hemoglobin (Hb), MCV and MCH were highest in the -88 and lowest in the polyA mutations. Clinically, Hb S-ß(0)-thal and Hb S-ß(+)-thal type I were generally severe, and Hb S-ß(+)-thal type III disease with the -88 mutation was milder than that caused by the polyA mutation.

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.

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.

One hundred years of sickle cell disease.

The first formal report of sickle cell disease occurred 100 years ago. This review traces the early historical reports, the evolution of understanding of the genetics, the molecular and chemical basis of sickle haemoglobin, and the advances made over the last 30-40 years in improving the management. Newborn screening and close follow-up, especially early in life, has significantly improved survival but these advances require resources and sophisticated infrastructure. In sub-Saharan Africa over 250 000 births annually suggest that these advances are unlikely to be implemented within the foreseeable future. Prevention of the disease where possible, could reduce the numbers of new patients allowing better facilities for the care of others. As the disease results from the inheritance of abnormal haemoglobin genes from both parents, it is eminently preventable. The unanswered question, whether genotype detection and counselling will influence reproductive decisions, is currently being addressed by a project in central Jamaica.

Retained placenta in homozygous sickle cell disease.

OBJECTIVE: To document an increased prevalence of retained placenta in mothers with homozygous sickle cell disease. METHODS: A retrospective review (January 1, 1992, to December 31, 2005) at the University Hospital of the West Indies revealed 174 singleton deliveries in women with sickle cell disease who were matched by delivery date and age 1:1 with 174 mothers with normal hemoglobin phenotype. Cesarean delivery in 62 mothers (36%) with sickle cell and in 41 women with normal hemoglobin (24%) left 112 sickle cell and 133 normal hemoglobin pregnancies with spontaneous deliveries. Retained placenta was defined by an interval of at least 30 minutes. Duration and details of the third stage of delivery were obtained by review of records. Duration of delivery stages was assessed by Kaplan-Meier survival charts and tested using the log rank test. Known risk factors were sought by logistic regression or exact logistic regression when the number of outcomes was small. RESULTS: First-stage duration was similar in maternal genotypes (sickle cell 470 minutes [median] compared with normal hemoglobin 335 minutes [median]), but in sickle cell disease, the second stage was slightly delayed (sickle cell 16 minutes compared with normal hemoglobin 15 minutes) and the third stage (sickle cell 7 minutes compared with normal hemoglobin 6 minutes). Retained placenta occurred in 20 mothers (17.9%) with sickle cell (interval 30-340 minutes) compared with four among the women in the control group (3.0%, 30-107 minutes). Apart from a weak association with combined oxytocin and misoprostol, there were no significant associations with known risk factors or with hematologic indices within sickle cell disease. CONCLUSION: Retained placenta is common among mothers with sickle cell disease, and the lack of association with known risk factors suggests that maternal sickle cell disease may be a risk factor. LEVEL OF EVIDENCE: II.