This paper is based on the beta-thalassaemia programme at the Duchess of Kent Hospital, Sandakan, Sabah. It seeks to show that a hypertransfusion regimen which improves the quality of life of children with thalassaemia major can be practised in district and general hospitals if there is an organised blood recruitment programme, at least at departmental level. Such a programme reduces the demand on the hardpressed hospitals' blood banks. Frequent and regular transfusions can be given with minimal interference with the school and family life of affected children and reduces immeasurably the social, emotional and financial strain on the affected families. There is also an urgent need to define the magnitude of the problem of beta-thalassaemia through population studies so that genetic counselling can be given and adequate resources can be allocated to improve the quality of life of affected patients.
Two hundred and eleven blood transfusions were administered to 26 multi-transfused thalassemic children (aged 9 months-13 years) over a 6-month period. Eighteen children were receiving buffy coat-poor packed red cells (PRC) prepared by centrifuge while 8 children received filtered blood through a leucocyte-filter (Sepacell R-500A). Transfusion reactions occurred in 8.5% (n = 18) of transfusions and in 42.3% (n = 11) of patients. 11.9% (n = 16) and 2.6% (n = 2) of reactions occurred in 50% (n = 9) and 25% (n = 2) of patients receiving buffy coat-poor PRC and filtered blood respectively. Transfusion reactions in toto were significantly reduced in the group receiving filtered blood (p < 0.05). However, febrile reaction alone was not significantly reduced (p > 0.1). The median onset and duration of reaction were 2 hours (range 10 minutes-18 hours) and 4 hours (range 1/2-24 hours) respectively. 72.2% (n = 13) of the reactions occurred occurred during transfusion. 88.8% (n = 16) of the reactions caused only one symptom. 19.2% (n = 5) of all patients had recurrent reactions, all of them receiving buffy coat-poor PRC. The commonest clinical manifestation was fever (n = 7), followed by urticaria (n = 5) and petechial rash (n = 2). The outcome was good, with no patient experiencing symptoms exceeding 24 hours. Only 0.9% (n = 2) of the transfusions were discontinued.
A specific enzyme immunoassay (EIA) for the diagnosis of hepatitis C virus (HCV) infection was developed by recombinant DNA technology. Abbott HCV EIA was used to detect antibody to HCV (anti-HCV) in non-transfused and multiply-transfused thalassemia patients. None of 11 non-transfused patients had anti-HCV but 3 of 52 (5.8%) multiply-transfused patients had anti-HCV. This study showed that the prevalence rate of HCV infection is low in thalassemia patients. However, it is still important to identify hepatitis C virus infected patients in high risk groups because hepatitis C is associated with chronic hepatitis, cirrhosis and hepatocellular carcinoma.
Patients with the Hb beta + [IVS 1-5 (G-->C)] clinically presented as beta-thalassaemia intermedia and remained asymptomatic in the absence of blood transfusions. With or without blood transfusions the patients were short and had moderate to marked thalassaemia facies. Children who received blood transfusions showed progressive iron loading with age. The serum ferritin and serum alanine transaminase levels were significantly raised in the patients who were given blood transfusions. In the presence of blood transfusions, and absence of adequate iron chelation therapy, splenectomy became an inevitable event at some stage of the disease because of increasing transfusing requirements.
In many of the parts of the world where thalassaemia is common, the blood supply is inadequate or unsafe, and desferrioxamine is too expensive for routine use. We classify some patients as having 'severe thalassaemia intermedia', i.e. those with moderately severe thalassaemia who can survive without regular transfusions, but who are at risk of many complications which are reviewed here. These include bone deformity and fractures, extramedullary haemopoietic tumours, leg ulcers, autoimmune haemolysis and, especially after splenectomy, thromboembolism and infection. An increase in the quality and safety of the blood supply, and a cheaper and/or oral iron chelator, would enable more of these patients to be treated as thalassaemia major and have improved survival and quality of life.
Regular blood transfusions for patients with thalassemia have improved their overall survival although these transfusions carry a definite risk of the transmission of certain viruses. Infection with hepatitis B virus (HBV), hepatitis C virus (HCV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV) leads to complications which contribute to the morbidity and mortality of patients with thalassemia. We analyzed the blood samples taken from 85 transfusion dependent thalassemics receiving treatment at the day care center in Hospital Universiti Kebangsaan Malaysia and found that the seroprevalence rates for HBV, HCV and CMV were 2.4%, 22.4% and 91.8% respectively. None of the patients tested positive for HIV. Those positive for HBV and HCV will require further tests and treatment if chronic hepatitis is confirmed.
A 25-month-old boy with beta-thalassaemia major was presented with an opportunity for umbilical cord blood transplantation when his unborn sibling was diagnosed in utero to be a beta-thalassaemia carrier and also human leucocyte antigen compatible. A barely adequate amount of cord blood was collected at the birth of his sibling and infused into the patient after appropriate chemo-conditioning. Engraftment occurred without major complications. The subject is now alive and well 9 months post-transplant, thus marking our first success in umbilical cord blood transplantation.
The advent of leukocyte filters has enabled effective removal of leukocytes from certain blood products thus avoiding many adverse effects of blood transfusion. Many different materials have been incorporated into these filters to achieve >95% leukocyte removal. In this study we evaluated the efficacy of leukocyte removal of two different filters, using actual bedside transfusion settings involving patients with transfusion dependent thalassaemia. Fifty-one transfusion events were randomised to use either a polyurethane filter or a non-woven polyester filter. We found that the two filters achieved 98.4% and 96.2% leukocyte removal respectively (p = 0.022). We also found no significant correlation between pre-filtration white blood cell count and the volume transfused with the efficacy of leukodepletion. No untoward events or transfusion reactions were observed during the study.
One of the major complications in patients with transfusion dependent thalassemia is growth impairment secondary to iron overload. We studied the growth status in 66 patients with beta-thalassemia major and HbE-beta thalassemia who were transfusion dependent, aged from 2 to 24 years, and 66 controls matched for sex and age. The prevalence of short stature in transfusion-dependent thalassemics was 54.5% compared to 4.5% in control group (p<0.001). Short stature was more prevalent in those above the age of 10 years in this study group (83.3% vs 16.7%). Transfusion dependent thalassemics with short stature were found to have significantly lower mean standing height standard deviation scores (SDS), sitting height SDS and subischial leg length SDS values (p<0.001). There was also a significant difference between the mean sitting height SDS and the mean subischial leg length SDS in our thalassemics with short stature, suggesting that the short stature was due to disproportionate truncal shortening. Serum ferritin levels were significantly higher in transfusion dependent thalassemics who were short compared to those who were of normal height (p = 0.002). However, the mean pre-transfusion hemoglobin levels did not differ significantly between patients with short stature and those with normal height (p = 0.216). The prevalence of short stature also did not differ significantly between those with beta-thalassemia major and those with HbE-beta thalassemia (p = 0.32). This study highlighted the importance of providing optimal treatment in these patients, including monitoring of growth parameters and optimizing iron chelation therapy.
The current treatment options for beta thalassaemia major patients include conservative treatment with blood cell transfusions and iron chelation or stem cell transplantation. Regular blood transfusions inevitably lead to multi-organ haemosiderosis and are attended by risks of blood-borne infections. Results from stem cell transplantation are good and suggest that this should be offered as first line therapy when a matched sibling donor is available because the patient is often cured and able to live a normal life. Of 38 Malaysian children who underwent bone marrow or cord blood transplantations using matched sibling donors, 29 (76%) are now cured.
Molecular characterization of the compound heterozygous condition - (G)gamma((A)gammadeltabeta)(o)/beta-thalassemia - in four families showing mild beta-thalassemia intermedia was carried out using DNA amplification techniques. Using the Amplification Refractory Mutation System (ARMS) to confirm the beta-mutations and DNA amplification to detect the 100-kb Chinese-specific (G)gamma((A)gammadeltabeta)(o)-deletion, ()two families were confirmed to possess (G)gamma((A)gammadeltabeta)(o)/beta-thalassemia with the IVSII No. 654 beta(+)-allele. In the third family, the (G)gamma((A)gammadeltabeta)(o)-deletion was confirmed in the father and the mother was a beta-thalassemia carrier with the cd 41-42 beta(o)-allele. Their affected child with (G)gamma((A)gammadeltabeta)(o)/beta-thalassemia was found to be transfusion dependent. The same (G)gamma((A)gammadeltabeta)(o)-deletion and beta-thalassemia (cd 41-42) was also confirmed in a fourth family. In addition, the mother was also diagnosed with Hb H disease (genotype -alpha(3.7)/-(SEA)). Both the children were found to possess (G)gamma((A)gammadeltabeta)(o)/beta-thalassemia but they were not transfusion dependent and this could be due to co-inheritance of alpha-thalassemia-2 (genotype-alpha(3.7)/alphaalpha) in the children together with their compound heterozygous condition.
The aim of this study was to: (1) determine the prevalence and patterns of lung dysfunction among transfusion dependent thalassemics; (2) determine the associated factors that might contribute to this problem. This was a cross-sectional study involving 66 patients with transfusion dependent thalassemia aged 10 years and above. All patients underwent physical examination, standardized pulmonary function tests including spirometry, lung volume, and the carbon monoxide diffusion capacity. A restrictive pattern of lung dysfunction was observed in 22 patients (33.3%) and none showed the presence of obstructive ventilatory impairment. A reduction in the carbon monoxide diffusion capacity (DLCO) was seen 87.9% of the patients, including 7.6% who had evidence of hypoxemia. Ten patients showed a reduction in the FEF25-75% although they did not fulfil the criteria for small airway disease. No correlation was found between lung dysfunction and serum ferritin levels in the patients. Restrictive lung dysfunction and diffusion impairment were the predominant abnormalities found in our cohort of patients.
Study site: Thalassemia clinic, Pusat Perubatan Universiti Kebangsaan Malaysia (PPUKM), Kuala Lumpur, Malaysia
OBJECTIVES: To estimate the risks of seroconversion of hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency viruses (HIV) in children with multitransfused thalassaemia at a thalassaemic clinic in Kuala Lumpur, Malaysia.
METHODS: Seventy-two children (39 males, median age 11.3 years, 2.5th-97.5th centile: 1.4-19.2 years) with thalassaemia major were studied. The risks of seroconversion of HBV, HCV and HIV were estimated by comparing the seroprevalences of hepatitis B surface antigen (HBsAg), anti-HCV and anti-HIV between a defined starting point and an end point. The end point was the point when latest serological results were available while the starting point was when regular transfusion was commenced, or approximately 5 years before the end point when the duration of transfusion was longer.
RESULTS: The median duration of the study was 49 months (range 8-69 months, total 2953 patient-months). There were 2605 transfusion episodes and 4154 units of blood transfused (0.88 transfusion episode/patient per month, 1.41 units of blood transfused/patient per month). There were three new seroconversions for anti-HCV but none for HBsAg and anti-HIV. The risk of seroconversion for HCV was one in 1384 units of blood transfused (95% CI: 4000-472). The seroprevalence rates at the starting and end points were: HBsAg (1%, 1%), anti-HCV (10%, 13%) and anti-HIV (0%, 0%), respectively.
CONCLUSIONS: The estimated risk of acquiring HCV infection in children receiving multiple blood transfusions in this study is surprisingly higher than the generally accepted estimated risk. Other routes of transmission may be important. A prospective, multicentre study to estimate such risks more precisely is needed.
The development of red blood cell (RBC) isoimmunization with alloantibodies and autoantibodies complicate transfusion therapy in multiply transfused thalassemia patients. Thus, the frequency, causes and prevention of these phenomena were studied among these patients. Clinical and serological data from 58 Malay multiply transfused thalassemic patients who sought treatment at Hospital University Sains Malaysia were collected and analyzed prospectively. Blood samples were subjected to standard blood bank procedures to screen for antibody and subsequent antibodies identification. All patients in our hospital received blood matched for only ABO and Rh (D) antigens. There were 46 (79.3%) patients with Hb E/beta thalassemia, 8 (13.8%) with beta thalassemia major, 3 (5.2%) with Hb H Constant Spring and 1 (1.7%) with Hb H disease. Overall, 8.6% of the patients had alloantibodies and 1.7% had autoantibodies. The alloantibodies identified were anti-E, anti-c, anti-K, anti-Jka, anti-N and anti-S. In conclusion, the transfusion of matched blood is essential for chronically multiply transfused patients in order to avoid alloimmunization. Considering the high frequency of anti E at our hospital, it is advisable to genotype patients and match the red cells for E antigens in multiply transfused thalassemia patients.
Health Related Quality of Life (HRQoL) studies on children with chronic illness such as thalassaemia are limited. We conducted the first study to investigate if children with thalassaemia have a lower quality of life in the four dimensions as measured using the PedsQL 4.0 generic Scale Score: physical, emotional, social and role (school) functioning compared to the healthy controls allowing for age, gender, ethnicity and household income.
Frequent blood transfusions can lead to iron overload which may result in several endocrine complications especially in the absence of adequate chelation therapy. The objectives of this study are to determine the prevalence of endocrine complications in transfusion dependent thalassaemia patients and the correlation of endocrine complications with the degree of iron chelation. This retrospective study looked at cases of adult patients with transfusion dependent thalassaemia treated in the Haematology Unit, Penang Hospital. Of the 25 transfusion dependent thalassaemia patients, there were 10 male and 15 female patients respectively with almost equal number of Malay and Chinese patients (13 and 12 patients respectively). Short stature was seen in 36.0% of our patients. In our cohort, 12 patients had delayed puberty (male 70.0% and female 33.3%). Prevalence of osteoporosis was 36.0%. Hypogonadism was noted in 40.0% of males and 46.7% of females. 53.4% of the female population had menstrual abnormalities with prevalence of primary and secondary amenorrhoea at 26.7% each. The prevalence of other endocrinopathies was much lower: 8.0% had diabetes mellitus and only one patient had hypocortisolism. Iron chelation appeared insufficient in our study population. The high frequency of endocrine complications noted in our study supports the rationale for regular follow-up of transfusion dependent thalassaemic patients to ensure early detection and timely treatment of associated complications.
Growth impairment is commonly seen in children with thalassemia despite regular blood transfusions and desferrioxamine treatments. We investigated the growth velocity of 26 prepubertal patients with beta-thalassemia or HbE-beta thalassemia who were transfusion dependent aged between 2 and 13 years. The prevalence of impaired growth velocity (ie, growth velocity less than the third percentile) amongst the transfusion dependent prepubertal thalassemics was 57.7% compared to 19.2% in the control group. The mean height velocity of the thalassemics was 11.1% less than controls but this difference was not statistically significant (4.23cm/year vs 4.76cm/year, p = 0.08). The mean serum ferritin level of the thalassemics with a height < 3rd percentile was higher compared to those with a height > 3rd percentile (4,567.0 vs 2,271.0, p = 0.01). Our study showed that there was a high prevalence of impaired growth velocity amongst our transfusion dependent prepubertal thalassemics. This highlights the problem of inadequate chelation therapy, and compliance with chelation therapy amongst our patients. This study emphasizes the importance of monitoring growth parameters and optimal iron chelation therapy in these patients.
The quality of life of transfusion-dependent thalassaemia patients is affected by the disease itself and iron overload complications from repeated blood transfusion. Desferrioxamine has been used to remove the excess iron, resulting in decreased mortality and morbidity. In Malaysia, a significant proportion of the transfusion-dependent thalassaemia patients are not prescribed desferrioxamine, due to its high cost, especially as it is not subsidized by the government. The aim of this study was to measure the quality of life of thalassaemia patients on desferrioxamine treatment.