Leg Ulcers: A Report in Patients with Hemoglobin E Beta Thalassemia and Review of the Literature in Severe Beta Thalassemia.

BACKGROUND: Leg ulcers are a frequent complication in patients with the inherited hemoglobin disorders. In thalassemia, the literature is limited, and factors associated with the development of leg ulcers in hemoglobin E (HbE) beta thalassemia, the most common form of severe beta-thalassemia worldwide, have not previously been reported. METHODS: We reviewed all available medical records of patients with HbE beta thalassemia to document the onset of leg ulcers at the 2 largest treatment centers in Sri Lanka. We reviewed the literature to identify studies reporting outcomes of interventions for ulcers in severe thalassemia. RESULTS: Of a total of 255 actively registered patients with HbE thalassemia in the 2 centers, 196 patient charts were evaluable. A leg ulcer with a documented date of onset was recorded in 45 (22%) of 196 evaluable patients, aged (mean ± SEM) 22.2 ± 1.4 years. Most had been irregularly transfused; steady-state hemoglobin was 6.4 ± 0.2 g/dL. Treatment achieving healing in 17 patients included transfusions, antibiotics, oral zinc, wound toileting, and skin grafting. CONCLUSION: Leg ulcers may be more common in HbE beta thalassemia than in other forms of thalassemia. A systematic approach to treatment will be needed to document the prevalence and factors placing such patients at risk for leg ulcers. Controlled trials to evaluate the optimal treatment of this common complication are indicated.

Thalassemia in Sri Lanka.

The island nation of Sri Lanka with 22 million people (in 2020) has an estimated 2000 patients with severe thalassemia. The majority have ß-thalassemia (ß-thal) major (ß-TM), and Hb E (HBB: c.79G>A)/ß-thal accounts for most of the remainder. Carrier rate for α+-thalassemia (α+-thal) trait is 9.9% and ß-thal trait is 2.5%, with very similar rates in the three major ethnic groups (Sinhalese, Tamils and Moors). The distribution of thalassemia type reveals a remarkable variation, even in this small island, mirroring historical distribution of malaria. Even though healthcare is provided free by the state including blood transfusions and chelation, the overall survival of patients of ß-TM is still not on a par with that of the Mediterranean countries. A national thalassemia prevention program was set up in 2007, but overall success of the exercise based essentially on dissuasion of marriages is not very promising.

Anemia in Sri Lanka: A Literature Review.

Anemia is a global health problem. This paper reviews literature on the prevalence of anemia in Sri Lanka. We searched EBSCO (Elton Bryson Stephens Company), Cochrane Library, and Medline for articles on prevalence and molecular basis of anemia in Sri Lanka from January 2000 to May 2021. Forty articles were selected. Most of the studies were on prevalence of anemia among children and pregnant women. All the studies had restricted themselves to assess the contributing factors for anemia in limited age categories. Most articles had attempted to determine the overall prevalence of anemia and the contribution of iron deficiency to it. There were only a few studies on prevalence and molecular basis of hemoglobinopathies and even fewer on the prevalence of anemia of chronic disease. None of the studies had attempted to assess the national prevalence of red cell membranopathies and enzymopathies. The published data on prevalence of anemia in Sri Lanka are incomplete. This review emphasizes the value of a much broader survey on anemia covering all age categories including the elderly and conducting a national survey including anemia of chronic disease and on red cell membranopathies and enzymopathies in Sri Lanka.

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

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.

Marriage patterns in Sri Lanka and the prevalence of parental consanguinity in patients with ß-thalassaemia: a cross-sectional descriptive analysis.

Consanguineous marriages potentially play an important role in the transmission of ß-thalassaemia in many communities. This study aimed to determine the rate and socio-demographic associations of consanguineous marriages and to assess the influence on the prevalence of ß-thalassaemia in Sri Lanka. Three marriage registrars from each district of Sri Lanka were randomly selected to prospectively collect data on all couples who registered their marriage during a 6-month period starting 1st July 2009. Separately, the parents of patients with ß-thalassaemia were interviewed to identify consanguinity. A total of 5255 marriages were recorded from 22 districts. The average age at marriage was 27.3 (±6.1) years for males and 24.1 (±5.7) years for females. A majority (71%) of marriages were 'love' marriages, except in the Moor community where 84% were 'arranged' marriages. Overall, the national consanguinity rate was 7.4%. It was significantly higher among ethnic Tamils (22.4%) compared with Sinhalese (3.8%) and Moors (3.2%) (p < 0.001). Consanguinity rates were also higher in 'arranged' as opposed to 'love' marriages (11.7% vs 5.6%, p < 0.001). In patients with ß-thalassaemia, the overall consanguinity rate was 14.5%; it was highest among Tamils (44%) and lowest among Sinhalese (12%). Parental consanguinity among patients with ß-thalassaemia was double the national average. Although consanguinity is not the major factor in the transmission of the disease in the country, emphasis should be given to this significant practice when conducting ß-thalassaemia prevention and awareness campaigns, especially in high-prevalence communities.

Role of red cell distribution width in screening for Hb E trait in population screening for hemoglobin disorders.

The national screening policy for hemoglobinopathies uses the cutoffs for red cell indices mean corpuscular volume >80 and mean corpuscular hemoglobin >27, a strategy known to miss some individuals with Hb E trait (EBT), the most common abnormal hemoglobin in Sri Lanka. We wanted to determine if red cell distribution width (RDW) cutoff values would help in increasing the sensitivity of screening for Hb E trait. High-performance liquid chromatography was carried out as the gold standard to detect hemoglobinopathies and red blood cell parameters with colter counter. Receiver operating characteristic curve was drawn to determine the cutoff value for EBT against ß-trait (BTT) and other anemias. Of the 504 patients, 246 had BTT, 110 had EBT, and 151 had other types of anemias. Mean (SD) RDW among patients with BTT was 16 (2.8), with EBT 14.5 (2.9), and with other anemias 15.8 (4.2) (P>0.001). With 14.45 as the cutoff for RDW and considering accepted values for mean corpuscular volume >80 and mean corpuscular hemoglobin >27, it gave a predictive sensitivity of 98.2% for EBT. By using RDW cutoff at 14.45 in addition to the accepted screening indices, sensitivity of Hb E trait detection went up to 98.2% from 86.6%. This study highlights the importance of taking RDW into consideration for screening.

Survival and complications in patients with haemoglobin E thalassaemia in Sri Lanka: a prospective, longitudinal cohort study.

BACKGROUND: Worldwide, haemoglobin E ß-thalassaemia is the most common genotype of severe ß-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. FUNDING: Wellcome Trust, Medical Research Council, US March of Dimes, Anthony Cerami and Ann Dunne Foundation for World Health, and Hemoglobal.