1 J I M D C 2 0 1 8 1 Address of Correspondence: Lawrence Faulkner Email: lawrence.faulkner@cure2children.org The Rising Global Burden of Hemoglobinopathies, A Challenge and an Opportunity for Health Care in Pakistan Lawrence Faulkner Medical Coordinator, Cure2Children Foundation, Florence, Itlay Severe hemoglobinopathies, namely thalassemia major and sickle cell disease, are the most frequent life- threatening non-communicable disease of children globally: A minimum estimate of 300.000 newborns yearly have some symptomatic globin disorder, these births occur largely in low- and middle-income countries (LMICs) where prevention and management programs are often lacking or insufficient1,2. Hematopoietic stem cell transplantation, also known as blood or marrow transplantation (BMT), is the only established curative modality with success rates over 85% in low risk children with a compatible sibling3–5, moreover, BMT can normalize long-term health-related quality of life (HRQoL)6,7 and be highly cost effective8,9. However, there is a dire shortage of BMT centers in hemoglobinopathy-prone regions10 which often fall in the low- and middle-income country (LMIC) strata, so that many families have to migrate to affluent countries seeking cure for their beloved ones; this not only aggravates misery, psychological and economical burden but perpetuates the hemorrhage of professional and financial resources to high-income countries (HIC). Within structured collaboration programs low-risk matched-related BMT can be associated with very good results even in startup centers directly in LMICs11,12 and thus may provide a unique opportunity for saving lives, improve HRQoL, decrease financial burden of disease and promote capacity-building, research & development, and health care strengthening13. BMT indications and outcomes: HICs vs. LMICs: The spectrum of BMT indications and procedures differ between West and East10: in North America and Europe hematological malignancies are the most frequent indication and unrelated donors are often employed because of small average family size. In the Middle East and Asia non-malignant disorders, e.g. hemoglobinopathies and aplastic anemia, tend to be most common indications and matched related donors more frequently available14–16. Moreover, in addition to financial and logistic issues, the very limited use of unrelated volunteer donors in the East is also due to the fact that non-malignant disorders require stringent HLA matching and non-Caucasian ethnicities are generally underrepresented in donor registries17. Lastly, results using partially matched family doors for so called haploidentical transplantation, typically the mother or father, are increasingly encouraging18. There is no evidence that, at least for low-risk matched related BMTs, outcomes are substantially different in HICs compared to LMICs. Gliebel et al. assessed the impact of Human Development Index (HDI) on BMT results in adults with acute leukemia and found that transplantations performed in countries with an upper HDI were associated with improved leukemia-free survival, this however was not due to higher transplant-related mortality (TRM) but rather to higher relapse rates in LMICs, suggesting that the survival differences were probably related to patient selection and residual disease assessment rather than the BMT procedure itself19, and thus may not apply to non-malignant disorders. In the experience of the Cure2Children Foundation (C2C) in supporting the startup of centers in Pakistan and India performing primarily low-risk matched-related BMTs for severe thalassemia aided by a structured peer to peer collaborative platform20, outcomes where comparable to those obtained in Western centers21. There is also no E D I T O R I A L 2 J I M D C 2 0 1 8 2 evidence that in LMICs the spectrum of transplant-related infections is substantially different compared to the West22,23. Cost issues BMT is one of the most expensive tertiary care procedures with costs generally above 150.000 USD in HICs24. Figure 1 compares the relative cost breakdown of BMT for adult leukemia in HICs to the one for childhood thalassemia in LMICs underlining several interesting points: a) the major difference is related to follow up costs, probably because chronic GVHD is far more common, and to some extend therapeutically desirable, in adult leukemia; b) the second major difference is in hospitalization charges, which are related mostly to differences in salaries but also to BMT units construction and maintenance, in fact, complex infection control environments may not be needed for low-risk matched- related BMT in children with non-malignant diseases who arrive to transplant with no prior exposure to chemotherapy, no previous prolonged neutropenia episodes, no infections and in good general conditions12; c) diagnostics are also much less expensive in BMT for thalassemia since, for example, residual leukemia quantification or frequent chimerism analysis post BMT are not an absolute requirement as long as transfusion- independency is achieved; d) drugs and transfusion support is also different because of patient size and complication frequency, particularly fungal infections, the treatment of which may substantially impact on final costs. In fact, in the C2C experience in Pakistan and India the incidence of possible, probable or proven fungal infections25 in young thalassemic children undergoing matched-related BMT is less than 2%23. Within an existing hospital facility, less than 100,000 USD where sufficient to renovate and fully equip a 4-bed start up BMT unit26. Increasing evidence suggest that complex and costly infection control environments may not be required27–29 and established international guidelines do not call for stringent air control systems, at least for low-risk BMTs30. The cure of severe hemoglobinopathies as a capacity-building opportunity Optimal supportive care if often not available or not accessible in LMICs so that most children with severe hemoglobinopathies do not survive beyond 20 years of age and the risk of blood-borne infections, primarily hepatitis C, is still substantial32. Figure 1. Cost breakdown comparison of matched- related BMT in HIC (adult leukemia24) and LMIC (children with thalassemia31); total cost $116,000* and $11,200 respectively (family support program not included) As paradoxical as it may seem, BMT may actually be the best option for many patients with thalassemia in developing countries: It is a one-time procedure not depending on long-term access to appropriate medical care and at the same time greatly improves the quality of life for both patients and families by decreasing medical, psychological and financial burdens6,7. Buccal swab-based HLA-typing technology has greatly facilitated centralized compatibility testing so that there is no need to set up HLA laboratories locally, and patients can be easily typed worldwide and referred to BMT centers within South-South cooperation programs offering effective and cost-conscious BMT33. In the C2C-supported BMT network in Pakistan and India hinging on focused training and intensive online cooperation, low-risk matched-related BMT in children younger than 15 years is currently delivered with more than 95% thalassemia-free survival, a result at least as good as that obtained in HIC3, for an average cost of 12.000 USD per BMT4,31. The realistic prospect of a definitive cure also improved compliance with supportive care and engaged families in cascade screening and prevention programs, e.g. most mothers of thalassemic children accepted the offer of free prenatal diagnosis for subsequent pregnancies. Because of large patient loads, there is great potential for expertise on specific disease curable by BMT, for 3 J I M D C 2 0 1 8 3 example, Pakistan has at least 100 times the incidence of thalassemia compared to the West, and many cases have a compatible sibling donor due to large family size. As a result, many more transplants for young thalassemic children with a compatible donor are currently carried out in LMICs compared to Europe or North America34. However, to take advantage of this opportunity, Increasing efforts will have to focus on quality assurance platforms20 and outcome reporting programs as a means of reassuring national and international patients, patient advocates, insurances and other sponsoring bodies. It seems reasonable to assume that if quality standards are assured, expertise is higher and costs are much lower, there might be the potential for patient attraction. Why should an insurances or national health systems refuse to cover a patient willing, for example, to go from the UK to Pakistan in centers that have much more experience on specific diseases, e.g. Thalassemia, where appropriate quality standards are assured, outcome reporting is transparent and BMT costs are much less BMT for thalassemia offers several advantages for startup centers in LMICs: a) it is the least expensive and simplest form of allogeneic BMT with relatively basic technology requirements; b) being a chronic disease there is enough time to adequately prepare patients in order to maximize initial success rates; c) high commitment and compliance of affected families; d) children generally enjoy high cure rates and excellent HRQoL; e) high cost-effectiveness; f) potential for leading expertise and patient attraction. C o n c l u s i o n BMT consists of a wide array of procedures which have very different complexities, outcomes and costs. The one used to cure young children with severe hemoglobinopathies having a compatible sibling sits on the simplest side of this spectrum, it's far less expensive than long-term supportive care and can restore a normal quality of life in most patients. It does not require complex hospital environments or undue sophisticated technologies. It can save the life of many children while being a great opportunity for health care strengthening, professional motivation and higher medical education. BMT may have positive ripple effects on institutions taking over the challenge as well as on screening and prevention programs in LMICs R e f e r e n c e s 1. Modell, B. & Darlison, M. Global epidemiology of haemoglobin disorders and derived service indicators. (WHO website, 2009). 2. Weatherall, D. J. The inherited diseases of hemoglobin are an emerging global health burden. Blood 115, 4331–4336 (2010). 3. Angelucci, E. Hematopoietic Stem Cell Transplantation in Thalassemia. 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