Although information about the precise world distribution and frequency of the inherited hemoglobin disorders is still limited, there is no doubt that they are going to pose an increasing burden on global health resources in the future. Their high frequency is a reflection of natural selection combined with a high frequency of consanguineous marriages in many countries, together with an epidemiological transition; whereby, as public health measures improve in the poorer countries of the world, more babies with these disorders are surviving to present for treatment.

World distribution, population genetics, and health burden of the hemoglobinopathies

BACKGROUND Regular blood transfusion therapy still remains the cornerstone in the management of β-thalassemia. Although recommendations are clear for patients with β-thalassemia major, uniform transfusion guidelines are lacking for patients with hemoglobin E β-thalassemia. In this study, we aim to describe the adequacy, trends, and determinants of blood transfusion therapy in a large cohort of pediatric patients with β-thalassemia major and hemoglobin E β-thalassemia. METHODS/PROCEDURE This cross-sectional study was performed among all regularly transfused patents with β-thalassemia aged 2 to 18 years attending three large thalassemia centers in Sri Lanka. Data were collected using an interviewer-administered questionnaire, perusal of clinical records, and physical examination of patients by trained doctors. RESULTS A total of 328 patients (male 47%) were recruited; 83% had β-thalassemia major, whereas 16% had hemoglobin E β-thalassemia. Sixty-one percent of patients had low pretransfusion hemoglobin levels (  200 mL/kg/year) by a majority (56%). Median pretransfusion hemoglobin was significantly lower in patients with hemoglobin E β-thalassemia compared with β-thalassemia major (P < 0.001); however, there was no difference in requirement for high transfusion volumes over 200 mL/kg/year in both groups (P = 0.14). Hepatomegaly and splenomegaly were more common in hemoglobin E β-thalassemia and were associated with lower pretransfusion hemoglobin. Transfusion requirements were higher among patients with hepatitis C and in those who are underweight. CONCLUSIONS Over 60% of regularly transfused patients with β-thalassemia have low pretransfusion hemoglobin levels despite receiving large transfusion volumes. Patients with hemoglobin E β-thalassemia are undertransfused and specific recommendations should be developed to guide transfusions in these patients.

Blood transfusion therapy for β-thalassemia major and hemoglobin E β-thalassemia: Adequacy, trends, and determinants in Sri Lanka

BACKGROUND Thalassaemia, a hereditary haemoglobin disorder, is a major public health concern in some parts of the world. Although Bangladesh is in the world's thalassaemia belt, the information on this disease is scarce. Additionally, the awareness of this life threatening, but potentially preventable disease is surprisingly poor. However, mass awareness is pivotal for the development of an effective preventive strategy. In this context, the understanding of parental perspectives is essential to grasp the magnitude of the problem. Therefore, this study aimed to investigate the parental knowledge gaps and perceptions regarding thalassemia, the barriers confronted by the parents for caring for their thalassaemic children and their attitude to prenatal screening and prenatal diagnosis. METHODS This cross-sectional study was conducted between January 2018 and December 2018 at a dedicated thalassemia hospital located in Dhaka. A structured questionnaire was used for face-to-face interviews with parents of thalassaemic children. Descriptive statistics were used to analyse data. RESULTS Of 365 respondents, nearly all respondents (97%) had not heard about the term, 'thalassemia' before the disease was diagnosed in their children; all (100%) were unscreened for carrier status prior to marriage. Mean knowledge scores were significantly higher in respondents with higher income and education. Most respondents (~ 91%) had a guilty feeling for not undergoing premarital screening. Only around 36% of them had heard about prenatal diagnosis. Approximately 25% participants would consider prenatal diagnosis in a future pregnancy, while 70% of them were unsure and only ~ 5% would decline prenatal diagnosis. Only 9.3% mothers had prenatal diagnosis in a previous pregnancy. Nearly 80% of the parents faced difficulty for obtaining blood donors regularly and a similar proportion (~ 81%) of them did not receive support from any organized blood clubs. More than 40% of the parents reported they felt socially stigmatized. CONCLUSION This study suggests poor parental knowledge regarding thalassaemia including prenatal diagnosis and the challenges faced while caring for their children. These findings would be of paramount importance in planning and devising effective prevention and intervention strategies in Bangladesh as well as other countries with similar sociocultural setting.

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The parental perspective of thalassaemia in Bangladesh: lack of knowledge, regret, and barriers.

Hydroxyurea is an antimetabolite drug that induces fetal haemoglobin in sickle cell disease. However, its clinical usefulness in β-thalassaemia is unproven. We conducted a randomised, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of hydroxyurea in transfusion-dependent β-thalassaemia. Sixty patients were assigned 1:1 to oral hydroxyurea 10-20 mg/kg/day or placebo for 6 months by stratified block randomisation. Hydroxyurea treatment did not alter the blood transfusion volume overall. However, a significantly higher proportion of patients on hydroxyurea showed increases in fetal haemoglobin percentage (89% vs. 59%; p < 0.05) and reductions in erythropoietic stress as measured by soluble transferrin receptor concentration (79% vs. 40%; p < 0.05). Based on fetal haemoglobin induction (> 1.5%), 44% of patients were identified as hydroxyurea-responders. Hydroxyurea-responders, required significantly lower blood volume (77 ± SD27ml/kg) compared to hydroxyurea-non-responders (108 ± SD24ml/kg; p < 0.01) and placebo-receivers (102 ± 28ml/kg; p < 0.05). Response to hydroxyurea was significantly higher in patients with HbE β-thalassaemia genotype (50% vs. 0%; p < 0.01) and Xmn1 polymorphism of the γ-globin gene (67% vs. 27%; p < 0.05). We conclude that oral hydroxyurea increased fetal haemoglobin percentage and reduced erythropoietic stress of ineffective erythropoiesis in patients with transfusion-dependent β-thalassaemia. Hydroxyurea reduced the transfusion burden in approximately 40% of patients. Response to hydroxyurea was higher in patients with HbE β-thalassaemia genotype and Xmn1 polymorphism of the γ-globin gene. 

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A randomised double-blind placebo-controlled clinical trial of oral hydroxyurea for transfusion-dependent β-thalassaemia

Objectives To determine the prevalence of hepatitis B, hepatitis C, and human immunodeficiency virus (HIV) in chronically transfused β-thalassemia major (TM) patients, and to assess their quality of life (QoL). Methods This cross-sectional study was conducted in three different thalassemia centers located in Peshawar, Khyber Pakhtunkhwa from January to July 2019. These centers provide screened blood and essential medical care for thalassemia patients. These centers include the Fatimid Foundation, Hamza Foundation, and Rehman Medical Institute, Peshawar, Khyber Pakhtunkhwa. A total of 431 blood transfusion-dependent β-thalassemia patients registered at these centers were selected. QoL in β-TM patients was assessed by a newly developed instrument, the TranQoL questionnaire. For the data analysis procedure, Microsoft Excel and Statistical Package for the Social Sciences; version 22 (SPSS Inc., Chicago, IL) was used. Results A total of 431 patients were included in our study. The ages ranged from five years to 23 years with a mean age of 11.54 ± 3.6 years; 58.93% were male and the rest were female with a male to female ratio of 1.43:1. A total of 129 (29.93%) patients were infected by transfusion-transmitted infections (TTIs). Hepatitis C virus (HCV) was found prevalent in 23.66%, hepatitis B virus (HBV) was found in 4.87%, and HIV was found prevalent in 1.39% cases. The results showed a high proportion of HCV in males 27.95% as compared to females 17.51% (p value = 0.31). Patients were divided into high (good) QoL score of >50 and low (poor) score of <50. In patients with hepatitis C, the QoL was poor in 90 (88.23%) patients and was good in only 12 (11.76%) patients (p value=0.01); in the hepatitis B group, it was good in only eight (38.09%) and poor in 13 (61.90%) patients (p-value 0.04), and for patients with HIV, it was poor in all six patients (p=0.001). Conclusion Our study concludes that transfusion-transmitted disease is very high and that HCV is the leading TTI followed by HBV and HIV. QoL in patients with TTIs was poor. The use of advanced technology in blood screening, voluntary donations, donor selection, and asepsis during blood transfusion is imperative to curtail the transmission.

Prevalence of Transfusion Transmitted Infections and the Quality of Life in β-thalassemia Major Patients.

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.

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A nationwide survey of hospital-based thalassemia patients and standards of care and a preliminary assessment of the national prevention program in Sri Lanka.

Oral Presentation Abstract (OP 042), 130th Anniversary International Medical Congress, Sri Lanka Medical Association, 13th-16th July 2017 Colombo, Sri Lanka

An islandwide hospital based epidemiological survey of haemoglobinopathies and an assessment of standards of care in 23 centres

Objectives
To report the clinical and virologic epidemiology of a recent epidemic of hepatitis C in thalassaemia patients in Sri Lanka.
Background
Transfusion‐dependent thalassaemia patients remain at risk for hepatitis C virus (HCV). Here, we report a cluster of recent HCV infections in Sri Lankan thalassaemia patients and examine the phylogenetic relationship of viral sequences.
Methods
We conducted two prospective cross‐sectional surveys of 513 patients in four Sri Lankan thalassaemia centres in 2014/2015 and re‐surveyed one centre in 2016. We screened for anti‐HCV antibodies using the CTK Biotech enzyme‐linked immunosorbent assay (ELISA) kits and confirmed active infection by reverse transcription‐polymerase chain reaction (RT‐PCR) for HCV‐RNA. HCV genomes were sequenced by unbiased target enrichment.
Results
Anti‐HCV antibodies were found in 116/513 (22.6%) of patients initially tested. Active hepatitis C infection was found in 26 patients with no cases of active hepatitis B infection. Of 26 patients with HCV, two were infected with genotype 1(a), and the rest had 3(a). In a single centre (Ragama), 122 patients (120 new cases and two previously tested, but negative) were retested for anti‐HCV antibodies. 32/122 (26.2%) patients were seropositive. Twenty‐three (23/122; 18.8%) of these new cases were confirmed by HCV PCR (all genotype 3[a]).
Conclusion
There is a significant cluster of recent HCV cases in multiply transfused thalassaemia patients in several centres in Sri Lanka. Most of the viruses shared a close phylogenetic relationship. The results are consistent with recent continuing transfusion‐transmitted HCV infection. Routine surveillance for HCV of chronically transfused patients is required irrespective of screening of blood products.

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Udaya B. Nelumdeniya

Papers

A nationwide survey of hospital-based thalassemia patients and standards of care and a preliminary assessment of the national prevention program in Sri Lanka.

An islandwide hospital based epidemiological survey of haemoglobinopathies and an assessment of standards of care in 23 centres

Transfusion-transmitted hepatitis C: A cluster of cases in transfusion-dependent thalassaemia patients in Sri Lanka.