Thalassemia, as a regional and global problem, is widespread in Southeast Asia, the Mediterranean, and southern China (1). About 1.5% of the global population (about 80–90 million people) were heterozygotes or carriers of β-thalassemia, and ~26,000 patients with β-thalassemia major (β-TM) were born yearly (2). Globally, the annual prevalence of symptomatic patients with β-thalassemia is ~1 in 100,000, up to 90% of these births occur in low- or middle-income countries (2). In China, an epidemiological study with a population of nearly 600,000 revealed that the prevalence of β-thalassemia was 0.67% (3), and the overall prevalence in high-incidence provinces was roughly 2.21% (4); however, there was still lacking accurately regional epidemiological distribution.

β-TM, as the most severe form, required regular blood transfusions and iron chelation therapy throughout life (5). Lifetime transfusions would lead to serious iron overload, which led to organ damage, dysfunction, complications, and eventually death (1). It was reported that 89% of patients with β-TM lived beyond 40 years in Greece, and 80% of patients lived beyond 45 years in the United Kingdom (6), while patients between 2011 and 2017 in Guangxi province, China, could just live to 28 years averagely (7). With recent advances in treatment technology in China, the overall life expectancy of patients seems to have improved, but it remains to be revealed through further epidemiological data. But the extension of life expectancy has led to an increase in the prevalence of co-morbidities, resulting in a serious deterioration of quality of life (QoL) of patients (8).

The healthcare cost for patients with β-TM is proportional to their age and weight, and long-term treatment imposes a prohibitive financial burden of the disease on individuals and families (9). Hematopoietic stem cell transplantation offers a cure for thalassemia, but the optimal age for the procedure has been missed in adult patients (10). The amount and frequency of blood transfusions and iron chelation increase with age and weight, and so did the direct medical costs (11). Meanwhile, limitations in physical function and mobility prevented adult patients from managing their daily lives and undertaking normal tasks. The short transfusion cycle resulting in frequent outpatient clinics and hospitalization took up a lot of time, and adult patients had to choose some casual jobs with less stringent requirements on working hours which even were rejected by many employers, adult patients had difficulty in obtaining stable employment (12). They faced more challenges from work and employment which further aggravated the financial strain on patients and their families. It was estimated that the lifetime medical burden for patients in the UK was £803,000 (13), the annual financial burden for patients in Iran was $8,321.8 (11), the mean 1-year healthcare cost for patients in the US was $128,062 (14), and the annual direct financial burden of disease for patients in Guangdong Province, China was CNY 43,058.7 (15).

The WHO (16) defined the QoL as: “An individual's perception of their position in life in the context of the culture and value systems in which they live and concerning their goals, expectations, standards, and concerns” (17). Patients with β-TM had a substantially lower QoL in comparison with the general population (18). Many studies have shown that the diagnosis of β-TM negatively impacted the QoL of patients (19, 20). However, most of studies have been limited to the pediatric and adolescent β-TM population. With aging, adult patients have a worse disease burden and financial burden, and a significantly lower QoL than pediatric patients (21). Moreover, the treatment options for adult patients were limited, and the government and society lacked targeted efforts to help and support them. Thus, the suboptimal survival environment and condition of adult patients with β-TM seriously affects their QoL and warrants further study.

In addition, the identification of HSU and its predictors, especially modifiable ones such as social support and caregiver burden, is of practical significance to further improve the QoL with β-TM in China and to continuously increase their life expectancy. As for the social support, Shumaker and Brownell (22) defined it as “an exchange of resources between two individuals perceived by the provider or the recipient to be intended to enhance the wellbeing of the recipient” (23). Thalassemia patients need more social support than the general population (17). One study pointed out that improving social support for thalassemia patients and raising public awareness about the incidence and treatment of thalassemia could be useful to improve the condition of patients and their QoL (23). Caregiver burden has been defined by Zarit (24) as the attitudes and emotional-affective reactions from the experiences of the role with repercussions in the personal, family, and social spheres (25). Parents of thalassemia patients suffer higher levels of distress compared to others (26). The caregiver burden affects the adherence of thalassemia patients and their families to the treatment of the disease, which in turn impacts the QoL and the ability of patients to integrate into society, and ultimately the health of the patients (27).

To our knowledge, based on the existing literature, numerous studies have been conducted worldwide to assess QoL in β-TM patients (18), while rarely in terms of health status utility (HSU). In addition, almost all the recently published analyses on the QoL in β-TM patients were from middle eastern countries, mainly focusing on children (19, 20). There has been no study describing HSU values and its predictors for adult patients with β-TM in mainland China.

Therefore, we aimed to investigate the QoL of adult patients with β-TM using the SF-36 in mainland China, to measure HSU by the SF-6D algorithm with Hong Kong population norms based on the response of each patient, to compare mean utility scores for subgroups of adult patients with β-TM, and to develop a multivariable regression model to identify the factors associated with the HSU values.

To our knowledge, this study is the first study measuring HSU values and identifying the influencing factors for adult patients with β-TM in mainland China. The QoL and HSU among adult patients with β-TM was poor. Diagnosis with comorbidity was significantly negatively associated with HSU values, and pre-transfusion hemoglobin levels and social support were significantly positively associated with HSU values. It would assist policymakers in the decision-making process related to disease management in the thalassemia patients, especially considering β-TM has become a public health problem in areas with high prevalence in China (28).

Soheir et al. found the presence of chronic pain was closely associated with lower QoL outcomes of thalassaemia patients (38). This is consistent with our finding that the mean score for PCS was lower than MCS and the BP dimension had the lowest score among all domains. BP in patients with β-TM was strongly associated with lower PCS scores, limited their daily activity and affected SF (38), which could be attributed to low hemoglobin concentration, low bone mass, and/ or iron overload (39). Physical health effects of thalassemia may lead to physical malformation, growth retardation, delayed puberty, poor self-image, and patients with serious complications such as heart failure, cardiac arrhythmia and liver disease (39). The absence of certain blood groups or the shortage of blood in some situations had affected the blood-dependent life of thalassemia patients (8). Blood reactions, alloimmunization and antibody formation in the blood, as well as viral infections through infected blood had threatened the physical health of patients (8). Thus, Francesca et al. suggested that compliance with treatment contributes to the health of patients, not only physically, but also psychologically (40).

In addition, although the result of the highest MCS score was in line with the finding of Bazi et al. (19), it is essential to emphasize the importance of mental health in patients with β-TM. The minimum value of SF observed in the MCS was contrary to the published meta-analysis of 26 studies (18). A large quantity of evidence confirmed that psychological problems were the main problem in thalassemia patients (41, 42). It was found that Greek thalassemia patients suffered more psychological problems than physical functioning (43). One study reported that thalassemia patients had the most mental health and role emotional problems, had no life satisfaction and suffered from depression and anxiety (44). Khani et al. reported that 64.9% of patients were candidates for psychiatric medication (44). Uncertainty about the future of the disease and treatment, on the one hand, and worries about the high cost of treatment, on the other hand, worries about playing a social role and the future of the family, can cause psychological stress for thalassemia sufferers and endanger their mental health (8).

We found that SF-6D HSU values in our study (0.598) was obviously lower than the HSU value of 0.95 for EQ-5D in the all-age Chinese general population (45). In addition, it was reported that thalassemia patients were 0.893 HSU values measured by EQ-5D in Malaysia (1). In another study, Iranian patients with transfusion-dependent thalassemia (TDT) using iron chelation therapy had HSU values ranging from 0.81 to 0.86 as measured by the time-weighted value set (46), which were higher than the result in our study. Differences in HSU values may be related to the different instruments used to measure QoL, the different characteristics of study population in different countries, and the different treatments received by patients.

The EQ-5D focuses primarily on the physical domain of measuring QoL with four dimensions reflecting physical aspects and one dimension for mental health. β-TM has a direct impact on patients' physical health, and other complications from frequently administered blood transfusions and iron chelation therapy increase the psychological burden. SF-6D provides a more comprehensive physical, psychological, social, and emotional reflection of QoL. Therefore, it is an appropriate tool to measure the impact of β-TM on patients' health. Results from other studies in the UK and the US indicated that the SF-6D was more discriminative than the EQ-5D-5L (47). Brazier and colleagues developed the SF-6D scale based on the SF-36 scale (48) and extracted utilities from the SF-36 by using the utility weights of the UK population (35). The SF-6D has subsequently seen widespread use in many countries. Lam conducted a pre-test in Hong Kong, China, in 2008 (34) and developed a more sophisticated SF-6D utility value score system in 2011 (33).

We found that respondents tended to report the most severe problems on the RL dimension. Although no performance of the SF-6D in the population of thalassemia was reported in previous studies, research on other patients showed similar findings. For example, a UK study indicated that 38.4% of patients with seven different disorders reported extreme problems with RL (49). Longworth et al. found that 42.4% of liver transplant patients reported the most severe problems on the RL dimension (47). Therefore, the performance of SF-6D in populations from different countries or regions requires further examinations.

This study indicated that co-morbidities among adult patients with β-TM were associated with lower HSU values. There was a similar result reporting that co-morbidities had a significantly negative effect on HSU scores in an Iranian study (46). In addition, several studies supported the association between adherence to iron removal therapy and QoL (40, 50), which highlighted the importance of regular iron removal therapy (50). However, it was reported that patients with β-TM were associated with poor adherence of transfusion treatment and iron removal treatment, which was similar to the result in our study (40).

This study found that lower pre-transfusion hemoglobin levels negatively affected QoL, which is consistent with the result of previous studies (51, 52). Several studies indicated that patients with more severe anemia tended to have a worse QoL (51, 53). One study using PedsQL 4.0 Generic Core Scale reported that patients with pre-transfusion hemoglobin levels >90 g/L had significantly higher QoL scores than those with the level of 70–90 g/L or < 70 g/L (51). One study conducted in Omani children found that those with higher pre-transfusion hemoglobin levels were associated with better QoL scores (53). Another study from Thailand showed that most patients with β-TM died from anemia, suggesting that a high proportion of patients received inadequate transfusion (54). Patients with β-TM would be exposed to the progressive effects of chronic anemia if they did not receive a timely transfusion or transplantation, and die within a few months of diagnosis (55). Therefore, regular blood transfusions and chelation therapy could improve survival rate and QoL in patients with β-TM (5, 56) and transform a previously fatal disease with death into a chronic disease compatible with prolonged survival. However, the poor compliance to blood transfusion and iron chelation were reported in this study, which was consistent with the finding of another Egyptian study (57). If without regular transfusion and iron chelation therapy, the morbidity and mortality of thalassemia would be similar to or higher than leukemia in the future (55).

This study showed that adult patients with β-TM had low social support scores, which is in alignment with many studies (23, 58, 59). Social support would help relieve and catharsis of negative psychological emotions, allowing patients and families to reduce anxiety and fear of illness (60). As compared to other patients, this group frequently exhibits maladaptive coping strategies and highly anxious psychosocial dysfunction due to the distress from the illness itself and the need for iron chelation (8). The lack of appropriate social status for them and poor acceptance of thalassemia patients in society have made these patients feel frustrated, fearful and uncertain about the future (8). Society generally did not accept these patients appropriately. Such inequalities with their healthy peers added to the mental abnormalities of thalassemia patients (44). Khani et al. found that 87 and 35% of thalassemia patients were usually single, having marital and occupational problems, respectively (44), which might be one of the leading causes of anxiety and depression. Kumar et al. study in Singapore also showed that thalassemia major patients feared disclosure of their disease that was due to the concern about the stigma of the inability to marry and work, as well as the fear of social and occupational discrimination (61). Access to social support and health care indicated better QoL in a combined intercontinental study designed to measure QoL and care for thalassemia patients in Lebanon, Canada and Iran (58). These findings emphasize the need for social support for thalassemia major patients and the need for social destigmatization.

In addition, nearly 40.7% of the caregivers in this study had moderate to severe caregiving burdens, which was consistent with another study (62). A cross-sectional study from Malaysia indicated that nearly half of the caregivers experienced psychiatric problems of anxiety or depression (42). This chronic and unending illness is a source of stress for the parents and the rest of the family, and also places a clinical burden on the whole family which includes psychological and social consequences (62). Fully mobilizing and utilizing other social support resources and those of relatives aimed at reducing the burden of the parents, and strengthening their coping strategies for better integration in daily life, is therefore essential for adult patients and caregivers with β-TM.

Concordant with the findings from a previous study, gender was not related to QoL (63). However, we observed the QoL to be significantly higher in males than in females between gender subgroups, as in previous studies (19, 41). Contrary to what Floris et al. reported, they thought females were better at adhering to treatment plans and lifestyles (40). A higher educational level was not found to be a predictor of QoL, while HSU values were significantly better in patients with higher education levels. In Egypt and Sardinia, significantly higher QoL scores were reported for patients with higher education levels (40, 59). The possible explanation is that patients with higher education levels were more likely to have a better understanding of the disease and superior adherence to treatment. We did not find a significant association between patient's age and QoL, which was inconsistent with the previous studies (38, 46, 51). Seyedifar et al. indicated that age was also an important factor affecting QoL in thalassemia patients, and increasing age was accompanied by increasing anxiety and depression, as well as an increasing prevalence of diabetes and hepatitis (46). Dahlui et al. demonstrated that age growth with a decrease in HSU (63). The studies of Teawtrakul et al. (21) and Haghpanah et al. (41) found that older age was correlated with increased comorbidities and reduced QOL. However, in our study, we only included adult patients, and most patients were in their early adulthood, so it was difficult to observe differences in QoL across age subgroups.

This study has a few limitations. First, as a cross-sectional design, the association between QoL and factors cannot be interpreted as causal. Second, the sample size was relatively small, and it might limit the generalization of the results. There were some possible reasons: (1) the lack of epidemiological distribution information nationwide, which made it difficult to conduct effective sample estimation and field survey; (2) under the effects of rather scattered patient residence, COVID-19, patients' reluctance to participate in face-to-face surveys and other factors, it was difficult to conduct onsite surveys, we had to choose online survey by snowball sampling through referrals from physicians and patients. However, as adult patients were a fairly small group, the sample in this study was still representative to reflect their situation. Third, this study was an online survey, and might be susceptible to information bias; however, we conducted two-rounds quality control follow-ups to mitigate this effect. Further empirical prospective studies with large sample size are needed in the future.

Adult patients with β-TM were associated with lower QoL and HSU in mainland China. Comorbidity, pre-transfusion hemoglobin level, and social support were independent risk factors for the HSU value among adult patients with β-TM. It highlights the importance of adherence to transfusion treatment and iron chelation treatment. The findings are usable in the disease management decision-making process and will be useful for researchers to employ in future clinical and health economic studies, including decision analysis and cost-effectiveness analysis.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

This study was approved by the Medical Ethics Committee of the Center for Health Management and Policy Research, Shandong University. All patients and caregivers were voluntary and signed an online informed consent form before collecting data. The patients/participants provided their written informed consent to participate in this study.

RZ participated in the conception, design of this study, data collection, data analysis, interpretation of data, and drafted and revised the manuscript. JM, RZ, JX, and BL performed the data analysis, interpretation of data, and drafted and revised the manuscript. CC assisted in the data collection. XZ participated in the conception, design of the study, data collection, interpretation of data, and drafted and revised the manuscript. XS participated in the conception, design of the study, and helped in the revising the manuscript. All authors contributed to the article and approved the submitted version.