Factors affecting health-related quality of life in Thai children with thalassemia

Thalassemia is an inherited blood disease. It is a serious public health problem throughout the Mediterranean region, the Middle East and the Indian subcontinent, as well as in Southeast Asia [1]. Out of approximately 300 million carriers of this hemoglobin disorder worldwide [2], 55 million live in Southeast Asia [3]. In Thailand, with a population of 65 million, about 40% have thalassemia traits or are carriers, while 1% of the population is afflicted with this disease [4].

Thalassemia is a chronic disease that presents a range of serious clinical and psychological challenges. The effects of thalassemia on physical health can lead to physical deformity, growth retardation, and delayed puberty [5–7]. Its impact on physical appearance, e.g., bone deformities and short stature, also contributes to a poor self-image [6, 7]. Severe complications such as heart failure, cardiac arrhythmia, liver disease, endocrine complications, and infections are common among thalassemia patients [8, 9]. The problems mentioned do not only affect patients' physical functioning but also their emotional functioning, social functioning and school functioning, leading to impaired health-related quality of life (HRQOL) of the patients [6, 7, 10–14].

Although thalassemia is recognized as a genetic blood disorder which can be fatal if proper treatment is not received, during the past decades the development of new treatments and clinical management has markedly improved the prognosis as well as the survival rates of the patients [9, 15–18]. However, the positive impact of these treatments is likely to be diminished, especially in terms of HRQOL, if they interfere with daily activities or are less tolerable. These may be the cases of regular blood transfusions that require frequent visits to the hospital, and nightly subcutaneous injections of iron chelation therapy [14].

For chronic diseases such as thalassemia, where a cure is not attainable and treatment may be prolonged, HRQOL is likely to be an essential outcome when considering options for treatment for individual patients and the allocation of health care resources. In child health service research, HRQOL is also recognized as an important health outcome [19–21]. As children are less able to voice their concerns and are more vulnerable than adults, the assessment of HRQOL in children is essential for the provision of proper care, since it helps in identifying the impacts of the disease and treatment from the children's perspective. Moreover, a recent study found that HRQOL of children can be used as a predictor of health care costs, and can also help identify at-risk groups of children who are candidates for proactive care coordination [22].

Due to the effects of the disease and its treatment, as mentioned previously, existing evidence indicates that thalassemia has a negative impact on HRQOL [6, 11–13]. A previous study revealed that thalassemia patients experienced more depressive symptoms and reported lower HRQOL [6]. In addition, it was found that not only transfusion-dependent patients but also transfusion-independent patients suffered from impaired HRQOL [12]. By using EuroQoL (EQ-5D), a prior study [13] found that the pain domain of patients was affected the most, followed by the depression and mobility domains, with an equal score. One study [12] found that the most commonly affected domains were feelings such as depression, anxiety, and concern about overall health status; while another study [11] found that quality of life in the school domain was affected the most.

Presently, there is limited research examining the factors associated with HRQOL in children and adolescents with thalassemia. A previous study conducted in adults with thalassemia found that treatment and cultural difference did not affect HRQOL [7]. Other studies have found that age [11] and side effects of iron chelation [13, 14] are predictors of HRQOL in children with thalassemia; while gender, ethnicity and household income are not [13]. A better understanding of the factors associated with HRQOL among children and adolescents with thalassemia could have a direct effect on the development of more suitable clinical, counseling, and social support programs to enhance treatment outcomes, especially in terms of HRQOL of these patients. In addition, at-risk groups of children and adolescents could be identified as candidates for proactive care assistance. Given the insufficient research in this area, this study aims to examine factors associated with HRQOL among thalassemic children and adolescents with the focus on patient perspective.

Regarding clinical characteristics, having severe condition, pre-transfusion Hb level, age at onset of anemia and age at first transfusion were found to be significant predictors of total summary scores, as indicated in table 5. The study revealed that patients whose Hb level was higher than 9 g/dL had significantly higher total summary score (mean = 79.82; SD = 10.21) than those with Hb levels of 7-9 g/dL (mean = 75.59; SD = 11.09) or less than 7 g/dL (mean = 73.51; SD = 13.06). In addition, It was found that patients whose age at onset of anemia was <2 years and age at first transfusion <4 years had significantly low total summary scores. With regard to severity, it was found that the patients who were classified as having a severe condition had significantly low total summary score than their non-severe counterparts. On the other hand, diagnosis, complication, and serum ferritin level were not associated with HRQOL scores.

For treatment characteristics, receiving a blood transfusion during the previous three months was significantly associated with the total summary score, as shown in table 6. The study indicated that patients who had received a blood transfusion during the three months prior to HRQOL assessment had significantly lower total summary scores, as compared to those who did not receive a blood transfusion. On the other hand, frequency of blood transfusion was not associated with HRQOL scores.

When looking at each summary score, it was found that two factors - age at onset of anemia and age at first transfusion, and receiving a blood transfusion during the previous three months - were significantly related to the Physical Health summary score; while age and pre-transfusion Hb level were significantly related to the Psychosocial Health summary score. For the social and school functioning subscales, age, pre-transfusion Hb level, age at onset of anemia and age at first transfusion, and severity were significant predictors of HRQOL. In addition, iron chelation treatment was significantly associated with impaired HRQOL in the school functioning subscale.

Since the focus of this study was on patient perspective then only HRQOL scores obtained from child self-report were examined. While data on parent proxy- report were also collected they will be the focus of subsequent manuscript and will be available upon request.

Similar to what was found in a previous study [11], the assessment of HRQOL of thalassemia patients in this study showed that psychosocial health had a lower score than physical health. Also, as with the previous study [11], the school functioning subscale scored the lowest. This could be explained by the fact that frequent absenteeism from school for hospital visits, and a lack of energy when performing academic activities, had a significant negative impact on the children's HRQOL [11, 31–33].

Although the pattern of HRQOL scores was found to be the same as in a previous study [11], HRQOL scores obtained from this study were somewhat higher. Based on the previous study[11], the mean total summary score (SD), mean Physical health summary score (SD), and mean Psychosocial health summary score (SD) were 67.70 (12.40), 69.17 (15.34), and 67.39 (13.24), respectively. However, due to the absence of HRQOL scores of healthy children in Thailand as well as differences in country-specific characteristics, direct comparisons could be made with caution. Nevertheless, possible reason that could account for the difference in HRQOL scores between the two studies was that the patients in this study represented milder cases of thalassemia, as compared to those in the previous study [11]. About 60% of patients in the previous study were diagnosed with homozygous β-thalassemia, and 77% were transfusion-dependent. In contrast, only 4.8% of the patients in this study were diagnosed with homozygous β-thalassemia, and only 42% had received a blood transfusion during the previous three months.

Consistent with the findings from several studies conducted on other diseases [34–37], this study found that pre-transfusion Hb level and receiving a blood transfusion during the three months prior to HRQOL assessment were significant predictors of HRQOL among thalassemia patients. This could be explained by the fact that lower Hb level is associated with a number of symptoms, such as fatigue, general weakness, and decreased mental alertness, which might lead to impaired HRQOL of the patients in several domains. Similar to the recommendation for blood transfusion mentioned earlier - that pre-transfusion Hb level should be monitored routinely to maintain an optimal level of 9-10.5 g/dL [15, 29] - the findings of this study indicated that patients with a pre-transfusion Hb level >9 g/dL had significantly higher HRQOL than patients whose pre-transfusion Hb level was <9 g/dL. In the case of blood transfusion, one possible explanation for the significant relationship between receiving a blood transfusion and lower HRQOL is that patients who received blood transfusions during the three months prior to HRQOL assessment were those with low pre-transfusion Hb levels. In contrast, this study found no significant relationship between frequency of blood transfusion per year and HRQOL. This non-significant relationship could be due to the fact that the questions used to assess HRQOL of the patients were related to the feelings and conditions of the patients during the previous month; therefore the number of transfusions per year might not be relevant to the HRQOL score.

Consistent with a previous study [11], age was a significant predictor of HRQOL among thalassemia patients. Although transitioning from adolescence to adulthood presents many new challenges - a more independent lifestyle, choosing a successful career path, and marriage [32] - this study found that adolescent patients had significantly higher HRQOL than their younger counterparts. This finding was similar to that of a previous study which revealed that older children with thalassemia experienced fewer symptoms of depression, reflecting a process of adjustment and coping [6].

Although existing evidence indicates that long-term iron overload might result in severe morbidity and mortality [15, 16, 28, 38], and that a serum ferritin level higher than 2,500 ng/dL is associated with cardiac complications and mortality [15], this study found no relationship between serum ferritin level and HRQOL. This contradictory result could possibly be due to the fact that damaging, long-term iron overload occurs gradually; so short-term iron overload, as represented by an elevated serum ferritin level, did not cause significant visible symptoms or complications, and hence had no impact on their HRQOL. Similar to the findings of previous studies [13, 14], this study found that, due to the burden of nightly subcutaneous injections of desferrioxamine 5 to 7 days per week [29], iron chelation treatment was significantly related to impaired HRQOL.

Complications and type of diagnosis were not related to HRQOL level in this study. This could be because the number of patients having complications was too small (only 6.1%) to detect a significant difference. Similarly, although patients diagnosed with homozygous β-thalassemia were expected to have significantly lower HRQOL since they were transfusion-dependent, a non-significant relationship between type of diagnosis and HRQOL was found in this study. This could possibly be due to the small number of patients diagnosed with homozygous β-thalassemia (< 5%) that were included in this study. Concordant with the findings from a previous study conducted on children with thalassemia [11], gender was not associated with HRQOL in this study.

One limitation of this study, as previously mentioned, is the absence of HRQOL scores of healthy children in Thailand. As a result, the true magnitude of thalassemia's impact on HRQOL was hardly estimated. Other limitation is that purposive sampling of the settings might limit the extent to which the results could be extrapolated to patients in other settings. In addition, failure to recruit adequate subjects, as stated in sample size calculation may be a potential limitation of the study. Lastly, as there was no consensus on how to determine severity of thalassemia patient, the criteria to assess severity of thalassemia varied across studies, ranging from only referred to patients with homozygous β thalassemia [39] to other different criteria [30, 40, 41]. As the result, the direct comparison across studies should be made with caution. The definition of severity used in this study was developed based on local expert opinions. As only data on type of diagnosis, hemoglobin level, age onset of anemia, and age at first transfusion were required to assess severity, this definition seemed to be feasible in less developed countries, where data on laboratory value or genetic information were unavailable in general practice.

The findings of this study highlight the significant negative impact of thalassemia and its treatment on HRQOL in terms of physical functioning and psychosocial functioning, especially in the school functioning subscale. In light of this, and considering the prevalence of thalassemia in Thailand, our study suggested that modification of existing thalassemia management could be beneficial. Psychosocial and counseling programs aimed at helping patients discuss and accept their illness, facilitating a normal lifestyle, and providing a link between patients, school officials, the family and the physician may be helpful in alleviating these difficulties, especially academic performance. In addition, modification of health care services for children with thalassemia to become more patient-centered, flexible and comprehensive may reduce time spent at hospitals and also improve treatment outcomes, including HRQOL of the patients.

In the meantime, while stem cell transplantation is not considered as a standard treatment, blood transfusion and iron chelation therapy are required for thalassemia patients. The findings of this study confirmed the importance of maintaining pre-transfusion Hb level above 9 g/dL. Therefore, effective strategies aimed at promoting access to blood transfusions should be employed in several developing countries, where at present there is limited access to this essential treatment. In addition, given the fact that long-term iron overload leads to severe complications and increase mortality, a more convenient regimen of iron chelation that would prevent the long-term consequences of iron overload is essential and could help improve HRQOL of the patient [40–42], even in the situation where no significant relationship between the elevation of serum ferritin and HRQOL is found.

Furthermore, patients whose age at onset of anemia <2 years and age at first transfusion <4 years; those receiving blood transfusions whose pre-transfusion Hb <7 g/dL; those receiving iron chelation therapy; and those diagnosed with homozygous β-thalassemia deserve special attention and proactive care, since their HRQOL scores were relatively low.