Assessment of Mortality and Its Associated Risk Factors in Patients with Transfusion Dependent Thalassemia in India

Abstract

Introduction: An assessment of morbidity and mortality caused by transfusion dependent thalassemia in India has never really been done despite thalassemia being the most prevalent life threatening non-communicable disorder of childhood. There is little structured understanding identifying the key risk factors feeding into research and policy making for effective management of thalassemia. With an estimated 10,000-12,000 children born with thalassemia each year in India, in addition to increasing focus on early pregnancy targeted screening, it seems critical to increase our understanding of risk factors associated with early mortality and morbidity. This is also relevant to family counselling about management options. Methodology: A retrospective analysis of mortality key risk factors in patients suffering from thalassemia major from 5 thalassemia day care centres in India was carried out. This included a total of 1,087 patients (656 males and 431 females with a median age of 8.6 years) enrolled for care between 1 Jan 2010 - 31 Oct 2018 at these centres. These centres were set up by a non-profit organization in collaboration with blood banks and /hospital facilities with the objective to provide comprehensive thalassemia care; A common web-based application was employed (ThalCare™). This system was used to track information associated with treatment including disease history at enrolment, demographic data and follow-up information. All analyses were performed with R Statistical software (3.5.2). Survival analysis was done from the age at presentation to the centre till October 2018. The reasons for mortality were categorized. Overall survival was also separately analyzed for patients in their 1st,2nd, 3rd or subsequent decades of life. The Cnaan and Ryan approach was used as patients entered and left the study cohort (left censored and right truncated data) and observation began only at enrolment and not at disease onset Results: The median age at enrolment was 5.4 years and the median follow up at the centre was 2.5 years. A total of 86 patients were cured by bone marrow transplantation (BMT), 13 of them moved to other centres for care and 41 patients died during the study period (28 males and 13 females). The median age at death was 15.4 years. Actuarial survival at 26.9 years of age was 50% (Figure 1) and under-five mortality was 7 times higher than the general population. Patients with transfusion-transmitted infections (TTI) had 3.4 times higher risk of death (p=0.031). Serum ferritin >4,000 ng/dL was associated with 4.6 times higher risk of mortality compared to ferritin <1,000 ng/dL (p=0.00063). Hemoglobin drop >2 gm/dL/week had 7.7 times higher mortality risk compared to <1 gm/dL/week (p<0.0001). Social determinants (sex, economic status and distance from centre), splenectomy, age at first transfusion and even cardiac complications were not associated with higher mortality risk. Results are summarized in Table 1. A multivariable analysis of risk factors which emerged as univariately significant showed that Hb drop of > 2 gm/week (hazard ratio 5.58 ,p=0.0007) and lack of attention towards care for possible prevention from TTI (hazard ratio 2.86, p=0.0004) are factors independently associated with high mortality. Table 2 shows that in patients born after the year 2,000 overall survival is 85.2% compared to 29.4% for patients born earlier. Main causes of death were infection, iron overload, TTIs, and alloimmunization; In a quarter of patients the cause of death was unknown (Figure 2). Patients who received more than 4 years of adequate care had more than 66% mortality risk reduction (p<0.0001). Conclusion: Comprehensive care right from an early age at dedicated management centres is key to improving life expectancy of thalassemia patients in India. Optimizing blood transfusion, intensifying chelation and preventing TTIs seem particularly important. Sustained efforts in these areas coupled with increased prevention and access to safe BMT will ease the burden for both families and public healthcare. Disclosures No relevant conflicts of interest to declare.

Global, regional, and national burden of thalassemia during 1990‐2019: A systematic analysis of the Global Burden of Disease Study 2019

“…29 Lastly, the specific burden of thalassemia attributed to relevant risk factors (e.g., bacterial infection, transfusiontransmitted infections, and iron overload) was yet not estimated in the GBD database. 30 Consequently, the population attributable fractions (PAF) of thalassemia burden due to relevant risk factors remain unknown.…”

“…Second, since the clinical technology or thalassemia screening and diagnosis varied across countries and over time, the robustness of burden estimates may present challenges, which depend on the out‐of‐sample predictive validity of the modeling efforts 29 . Lastly, the specific burden of thalassemia attributed to relevant risk factors (e.g., bacterial infection, transfusion‐transmitted infections, and iron overload) was yet not estimated in the GBD database 30 . Consequently, the population attributable fractions (PAF) of thalassemia burden due to relevant risk factors remain unknown.…”

Long-Term Health-Related Quality of Life and Clinical Outcomes in Patients with β-Thalassemia after Splenectomy

“…A significant, sustained fall in annual blood transfusion requirements was also reported as a post-splenectomy outcome in a cohort of 40 Indian TDT patients [ 6 ]. Dhanya et al published data on a broad cohort of 1064 Indian TDT, including 109 splenectomized patients, with the primary aim of detecting any difference in life expectancy between the two approaches: no statistical difference was found in the 25-year survival [ 10 ]. A study from Thailand showed that 56 splenectomized TDT patients had a significantly higher risk of pulmonary hypertension and hypogonadism [ 11 ].…”

“…Due to these restricted indications, the probability of patients undergoing splenectomy is substantially decreased for patients with β-TM born in the last decades, dropping from 57% to 7% for those born in the 1960s and in the 1990s, respectively [ 5 ]. Conflicting data have been reported on the efficacy of spleen removal in prolonging RBC survival and ultimately reducing the need for blood transfusions and heart and liver iron overload [ 6 , 7 , 8 , 9 , 10 , 11 ]. A recent review of randomized and quasi-randomized controlled studies was unable to find good-quality evidence about the efficacy of splenectomy for treating β-TM [ 12 ].…”