Medicine
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This repository contains the published and unpublished research of the Faculty of Medicine by the staff members of the faculty
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Item Hemoglobin E-beta-thalassemia: Progress report from the international study group(Blackwell Publishing, 2005) Premawardhena, A.; de Silver, S.; Arambepola, M.; Olivieri, N.F.; Vichinsky, E.P.; Merson, L.; Muraco, G.; Allen, A.; Fisher, C.; Peto, T.; Weatherall, D.J.A long-term observational study of Hb E-beta-thalassemia in Sri Lanka is beginning to define some of the genetic and environmental factors that are responsible for its remarkable phenotypic variability. In this population there is a very small difference between the steady-state hemoglobin levels between the mild and severe phenotypes, and it has been possible to stop transfusion in many of those who have been on long-term treatment of this kind. These preliminary observations, made over the last 7 years, provide directions for future research into this increasingly important disease.Item Paraspinal extramcduallry erythropoiesis- a rare cause of spinal cord compression: two case reports(Sri Lanka Medical Association, 2004) Arambepola, M.; Premawardhena, A.P.; de Silva, S.; Olivieri, N.; Weatherall, D.J.INTRODUCTION: Extrameduallry erythropoiesis (EME) is characterized by the appearance of haemopoietic tissue outside the bone marrow. When EME occurs, albeit rarely, outside the liver and spleen problems may occur. We describe two patients with haemoglobin E- [β thalassaemia who had spinal cord compression, due to EME masses which was reversed with treatment with hydroxyurea and hypertransfusion. PATIENT A: Was a 27year old with HbE -(β thalassaemia. His mean pre transfusion haemoglobin level was 5.5 g/dl. He presented with a six-month history of progressive numbness of his legs. On examination he was found to be paraparetic. The magnetic resonance scan (MRI) showed external compression of the spinal cord between the 4th and 8th thoracic vertebrae. Patient was put on a hypertransfusion regimen and hydroxyurea and made a complete recovery within 4 weeks. Patient B: Was a 9 year old boy with a diagnosis of Haemoglobin E [β thalassaemia who presented with paraplegia which had developed over 3 months. His spinal MRI showed two masses one in the upper thoracic vertebrae and the other at the 1st lumbar level. He was commenced on hydroxyurea and hypertransfusiion to maintain pre-transfusion haemoglobin at >9.5g/dl) and his neurological recover was remarkable. Six months later he had no neurological deficit. DISCUSSION: The above cases highlight the potentially dangerous complications of EME when it involves the spinal cord. They also highlight that even lesions which are sufficiently large to cause complete paraplegia are potentially reversible. Hypertransfusion, hydroxyurea, surgery and previously been used with varying success. The problem remains in deciding the optimal method of management.Item Survival and complications in patients with haemoglobin E thalassaemia in Sri Lanka: a prospective, longitudinal cohort study.(Elsevier Ltd, 2022) Premawardhena, A.P.; Ediriweera, D.S.; Sabouhanian, A.; Allen, A.; Rees, D.; de Silva, S.; Perera, W.; Katugaha, N.; Arambepola, M.; Yamashita, R.C.; Mettananda, S.; Jiffry, N.; Mehta, V.; Cader, R.; Bandara, D.; St Pierre, T.; Muraca, G.; Fisher, C.; Kirubarajan, A.; Khan, S.; Allen, S.; Lamabadusuriya, S.P.; Weatherall, D.J.; Olivieri, N.F.Background: Worldwide, haemoglobin E β-thalassaemia is the most common genotype of severe β-thalassaemia. The paucity of long-term data for this form of thalassaemia makes evidence-based management challenging. We did a long-term observational study to define factors associated with survival and complications in patients with haemoglobin E thalassaemia. Methods: In this prospective, longitudinal cohort study, we included all patients with haemoglobin E thalassaemia who attended the National Thalassaemia Centre in Kurunegala, Sri Lanka, between Jan 1, 1997, and Dec 31, 2001. Patients were assessed up to three times a year. Approaches to blood transfusions, splenectomy, and chelation therapy shifted during this period. Survival rates between groups were evaluated using Kaplan-Meier survival function estimate curves and Cox proportional hazards models were used to identify risk factors for mortality. Findings: 109 patients (54 [50%] male; 55 [50%] female) were recruited and followed up for a median of 18 years (IQR 14-20). Median age at recruitment was 13 years (range 8-21). 32 (29%) patients died during follow-up. Median survival in all patients was 49 years (95% CI 45-not reached). Median survival was worse among male patients (hazard ratio [HR] 2·51, 95% CI 1·16-5·43), patients with a history of serious infections (adjusted HR 8·49, 2·90-24·84), and those with higher estimated body iron burdens as estimated by serum ferritin concentration (adjusted HR 1·03, 1·01-1·06 per 100 units). Splenectomy, while not associated with statistically significant increases in the risks of death or serious infections, ultimately did not eliminate a requirement for scheduled transfusions in 42 (58%) of 73 patients. Haemoglobin concentration less than or equal to 4·5 g/dL (vs concentration >4·5 g/dL), serum ferritin concentration more than 1300 μg/L (vs concentration ≤1300 μg/L), and liver iron concentration more than 5 mg/g dry weight of liver (vs concentration ≤5 mg/g) were associated with poorer survival. Interpretation: Patients with haemoglobin E thalassaemia often had complications and shortened survival compared with that reported in high-resource countries for thalassaemia major and for thalassaemia intermedia not involving an allele for haemoglobin E. Approaches to management in this disorder remain uncertain and prospective studies should evaluate if altered transfusion regimens, with improved control of body iron, can improve survival.Item Non-adherence to chelation therapy and associated psychosocial factors among transfusion-dependent thalassaemia patients in Kandy, Sri Lanka(Sri Lanka College of Paediatricians, 2021) Baminiwatta, A.; Gunathilake, R.; Arambepola, S.; Arambepola, M.BACKGROUND: Poor adherence to iron chelation may underlie the detrimental levels of iron overload previously reported among transfusion-dependent thalassaemia (TDT) patients in Sri Lanka. Given the many challenges faced by these patients and families, psychosocial factors may have a significant impact on medication adherence. OBJECTIVE: To assess chelation adherence among TDT patients and explore associated psychosocial factors. METHOD: TDT patients, aged over 4 years, admitted for blood transfusion to a tertiary care hospital, as well as their mothers, were recruited. Medication adherence was assessed using a questionnaire adapted from Brief Adherence Rating Scale. Serum ferritin (SF) values were recorded as objective measures of non-adherence. Mental health status of patients and their mothers was assessed using Strengths and Difficulties Questionnaire (SDQ) and General Health Questionnaire-30 (GHQ) respectively. Associated psychosocial factors were analysed using multiple linear regression. RESULTS: Fifty-two patients aged 4 to 28 years participated. Thirty-four (65%) were female. The average adherence rate was 90%. One fifth of patients had an adherence percentage less than 80%. The mean ferritin level was 3260 ng/ml, whereas 46.2% of patients had SF levels exceeding 2500ng/ml. SF levels correlated positively with non-adherence (r=0.34, 95%CI: 0.071-0.606, p=0.014). Based on multivariate analysis, increasing age and lower SDQ score of patient, lower educational level and greater GHQ-30 score of mother were independent predictors of higher SF levels, but not of adherence rates. CONCLUSIONS: In the paediatric unit of National Hospital, Kandy, 46% of patients had SF levels >2500 ng/ml. There was a significant correlation between SF levels and medication non-adherence (r=0.34, p=0.014). On multivariate analysis, increasing age and lower SDQ score of the patient, lower educational level and greater GHQ-30 score of the mother were independent predictors of higher SF levels, but not of adherence rates.Item 20 year follow up and survival analysis in a cohort of patients with Haemoglobin E beta Thalassaemia.(Sri Lanka Medical Association., 2019) Olivieri, N.F.; Premawardhena, A.P.; Amir-Arsalan, S.; Ediriweera, D.; Mettananda, S.; Bandara, W.D.; Arambepola, M.; de Silva, S.; Refai, M.A.C.M.; Allen, A.INTRODUCTION & OBJECTIVES: Haemoglobin E beta thalassaemia (EBT) is the commonest beta thalassaemia syndrome in the world and is extremely phenotypically variable. Unlike for transfusion dependent thalassaemia (TDT) there are no clear guidelines for the management of this disease. We have followed up a cohort of 109 patients with EBT for 20 years. Objective of the study was to study the 20-year survival and factors that affect survival. METHODS: Study was conducted at Kurunegala Thalassaemia centre. Transfusions were stopped in 1997 in all 109 patients. Since then they were assessed every three months by the clinical team for the next 20 years. Relevant haematological, biochemical, radiological assessments were done periodically. RESULTS: 32 (30%) of patients were dead at 20 years. Kaplan Meir survival curve identified the median survival to be 51 years. Splenectomy had been done in 73/109 (67%) patients. Splenectomy allowed 66% to be off transfusions even 9.7± 1.3 years post- surgery. However, 33% had to return to transfusions. The commonest cause of death in the cohort was infections (34.3%). Most (72%) infective deaths happened in those who were splenectomised. Transfusions needed to be restarted in 60%, of whom 33% went back to (>8 per year) regular transfusions at a mean 8.4 ±0.8 years after stopping transfusions. CONCLUSION: In this first ever long term follow up study of EBT, significantly shortened survival is observed. Though splenectomy allows prolonged transfusion free phases in many it increases risk of infective deaths. Overall the disease is far less benign than previously thought with a high prevalence of morbidity and mortality.Item A Cost-of-illness analysis of β-Thalassaemia major in children in Sri Lanka - experience from a tertiary level teaching hospital.(BioMed Central., 2020) Reed-Embleton, H.; Arambepola, S.; Dixon, S.; Maldonado, B. N.; Premawardhena, A.; Arambepola, M.; Khan, J. A. M.; Allen, S.BACKGROUND: Sri Lanka has a high prevalence of β-thalassaemia major. Clinical management is complex and long-term and includes regular blood transfusion and iron chelation therapy. The economic burden of β-thalassaemia for the Sri Lankan healthcare system and households is currently unknown. METHODS: A prevalence-based, cost-of-illness study was conducted on the Thalassaemia Unit, Department of Paediatrics, Kandy Teaching Hospital, Sri Lanka. Data were collected from clinical records, consultations with the head of the blood bank and a consultant paediatrician directly involved with the care of patients, alongside structured interviews with families to gather data on the personal costs incurred such as those for travel. RESULTS: Thirty-four children aged 2-17 years with transfusion dependent thalassaemia major and their parent/guardian were included in the study. The total average cost per patient year to the hospital was $US 2601 of which $US 2092 were direct costs and $US 509 were overhead costs. Mean household expenditure was $US 206 per year with food and transport per transfusion ($US 7.57 and $US 4.26 respectively) being the highest cost items. Nine (26.5%) families experienced catastrophic levels of healthcare expenditure (> 10% of income) in the care of their affected child. The poorest households were the most likely to experience such levels of expenditure. CONCLUSIONS: β-thalassaemia major poses a significant economic burden on health services and the families of affected children in Sri Lanka. Greater support is needed for the high proportion of families that suffer catastrophic out-of-pocket costs. KEYWORDS: Children; Cost-of-illness; Sri Lanka; Thalassaemia.Item A nationwide survey of hospital-based thalassemia patients and standards of care and a preliminary assessment of the national prevention program in Sri Lanka(Public Library of Science, 2019) Premawardhena, A.P.; Mudiyanse, R.; de Silva, S.T.; Jiffry, N.; Nelumdeniya, U.; de Silva, U.; Lamabadusuriya, S.P.; Pushpakumara, K.; Dissanayaka, R.; Jansz, M.; Rifaya, I.; Navarathne, U.; Thirukumaran, V.; Arambepola, M.; Bandara, W.D.; Vaidyanatha, U.; Mendis, D.; Weerasekara, K.; de Silva, N**.; Kumara, D.K.S.; Amarasena, S.D.; Hemantha, K. K.; Refai, M.A.C.M.; Silva, I.; Hameed, N.; Rajiyah, F.; Mettananda, S.; Allen, A.; Weatherall, D. J.; Oliveri, N. F.OBJECTIVES:Our aim was to describe the numbers and distribution of patients with different types of thalassemia and to assess the standards of care in all thalassemia treatment centers throughout Sri Lanka and the success of the ongoing prevention programme.METHODS:This cross-sectional island-wide survey was conducted by two trained medical graduates, who visited each thalassemia center to collect data from every patient, using a standardized form. Data was collected through review of patient registers and clinical records.RESULTS: We collected data on 1774 patients from 23 centers. 1219 patients (68.7%) had homozygous β-thalassemia, 360 patients (20.3%) had hemoglobin E β-thalassemia, and 50 patients (2%) had sickle β-thalassemia. There were unacceptably high serum ferritin levels in almost all centers. The annual number of births of patients with β-thalassaemia varied between 45-55, with little evidence of reduction over 19 years. CONCLUSIONS:Central coordination of the treatment and ultimately prevention of thalassemia is urgently needed in Sri Lanka. Development of expert centers with designated staff with sufficient resources will improve the quality of care and is preferred to managing patients in multiple small units.Item Response of jaundice to phenobarbitone in thalassaemic patients co-inheriting Gilbert syndrome(Sri Lanka Medical Association, 2004) Premawardhena, A.P.; Arambepola, M.; Fisher, C.A.; Oliveiri, N.F.; Weatherall, D.J.INTRODUCTION: Genetic mutations causing Gilbert's syndrome are found in up to 20% of Sri Lankans. The co-existence of Gilbert's syndrome together with haemolytic anaemias can lead to significantly higher level of serum bilirubin and also an increased risk of gall stone formation. In such patients persistent jaundice can be a distressing symptom. We used the hepatic enzyme inducer, phenobarbitone in a pilot study to treat symptomatic hyperbilirubinaemia in patients with haemoglobin E- p thalassaemia and Gilbert' syndrome. MATERIAL AND METHODS: Seven haemoglobin E (3 thalassaemia patients attending the Thalassaemia Unit of the Teaching Hospital Kurunegala in whom jaundice was a significant symptom and Gilberts syndrome mutations had been previously detected were started on phenobarbitone (15mg tds). No patients with predominant direct hyperbilirubinaemia were included in this study. Bilirubin levels were noted prior to the commencement of the study and were repeated 3 months later. RESULTS: Of the 110 patients with haemoglobin E [3 thalassaemia 26 were positive for the Gilberts syndrome mutation. Seven patients were concerned about the excessive yellow discoloration of their sclerae and skin. Their ages ranged from 15 to 24 years. The mean pre-treatment serum total and indirect bilirubin were 137.8 and 113.8 /xmol/1 and the post treatment mean 68.35 and 52.6 jimol/1 respectively (a mean reduction of 49%). The biochemical result was associated with a remarkable clearance of jaundice. The quality of life of these patients significantly improved as a result. There were no drop outs from the study and no side effects were noted in any of the participants. DISCUSSION: Phenobarbitone used at 15 mg tds seems an effective and safe method for treating the aesthetically unacceptable symptom of jaundice in patients with Gilberts syndrome. The lack of complete normalisation of the bilirubin levels may suggest the effect of the underlying haemolysis, the inadequacy of the dosage of phenobarbitone or the co-existence of mutations causing non-inducible hyperbilirubinaemia.Item The variable phenotypes of haemoglobin D in Sri Lankan patients(Sri Lanka Medical Association, 2006) Premawardhena, A.; Arambepola, M.; Weatherall, D.INTRODUCTION: There are only few reports of the occurrence of the variant haemoglobin, haemoglobin D Punjab (β 121 Glu-Gln) in Sri Lanka and its clinical spectrum has not been well documented. MATERIALS AND METHODS: During the clinical study of patients attending the thalassaemia clinic at Teaching Hospital Kurunegala we identified several individuals with haemoglobin D, some of whom had co-inherited it with other haemoglobin disorders. They were diagnosed using High Performance Liquid Chromatography (Bio Rad, USA) and later confirmed by polymerase chain reaction. CLINICAL STUDIES: Family 1: (Hb D-p thalassaemia) Describes a family with two individuals with haemoglobin D- β thalassaemia. Both were mildly anaemic but had severe hypochromasia and microcytosis. They were otherwise well. Family 2: (Hb D- Hb S disease) The propositus was an eight year old girl who presented with several episodes of sickling crises. Parents were carriers for Hb S and Hb D. Family 3: (Hb D- Hb E disease) The propositus was an individual with Hb E- Hb D disease. She was clinically well and the only abnormality was severe hypochromasia and microcytosis. DISCUSSION: Hb D when co-inherited with Hb E or thalassaemia does not appear to cause clinically significant disease. The co-inheritance of Hb D with Hb S, however, results in severe disease leading to sickling crises. Even though Hb D commonly does not cause severe disease, knowledge of its occurrence is important as the hypochromasia and microcytosis associated with it may lead to unnecessary iron therapy.Item Reappraisal of symptoms and signs of uncomplicated β thalassemia trait(Sri Lanka Medical Association, 2005) Premawardhena, A.; Malewana, T.; Weerasinghe, M.; Arambepola, M.INTRODUCTION: Although considered a mild disorder, J3 thalassemia trait has been reportedly associated with symptoms of anaemia, while in other series hepatosplenomegaly has been reported as associated with this diagnosis. No controlled study has examined the symptoms and signs of individuals with {5 thalassemia trait and compared these with age- and sex-matched normal individuals. Materials and METHODS: We administered a questionnaire to 397 parents of children with J3 thalassemia major attending the National Thalassemia Centre in Kurunagala, Sri Lanka, and to 87 normal volunteers. All individuals underwent physical examination by the same investigator, as well as testing by automated cell counter, and HPLC. RESULTS: The mean age of the parents (33 years) and controls (29.5 years) was not significantly different. In parents with thalassemia trait, 20% of males and 42% of females complained of reduced exercise tolerance compared to 12.5% of males and 38% of females in the controls. The questionnaire revealed that 41% of parents, and 36% of controls, complained of recurrent headache; 18% of parents, and 15% of controls, complained of lethargy. Mean quality-of-life score, recorded formally by a linear analog scale, from 0 to 10 was 7.1 in parents and 7.2 in controls. CONCLUSIONS: These findings suggest that, by contrast to many reports in the older literature, in uncomplicated p thalassemia trait there appears to be no symptoms or signs greater than those observed in a normal control population.