Advancing sickle cell disease care in India from prevention to management: Challenges and way forward

INTRODUCTION

Sickle cell disease (SCD) is a major public health concern in India with highest prevalence amongst the tribal ethnic groups.^[1] It is an autosomal recessive disorder caused by point mutation in β-globin gene on chromosome 11, resulting in substitution of valine for glutamic acid at the sixth position of the β-globin gene.^[2] It leads to the development of an abnormal hemoglobin variant-hemoglobin S (HbS). The hallmark of pathophysiology of SCD is hemoglobin polymerization which results in sickle shaped red blood cells. This, in turn, leads to erythrocyte rigidity contributing to vaso-occlusion, reduced blood flow, and chronic hemolysis which eventually results in progressive damage to brain, kidneys, lungs, bones, and cardiovascular system.^[2]

Homozygous sickle cell disease (HbSS), sickle cell trait (SCT) and sickle β-thalassemia (HbS/β-thal) are three main forms of sickle cell-related disorders. HbSS can present as most severe form of disease, whereas SCT is a heterozygous state, individuals are largely asymptomatic but can transmit the disease to offspring. HbS/β-thal is a compound heterozygous condition and can present either as HbS/β-thal, when there is no production of normal β-globin chains and clinical presentation is similar to HbSS whereas HbS/β⁺-thal has reduced but not absent β-globin chain production resulting in a milder clinical phenotype.

Given the diversity of clinical presentation and the high prevalence in tribal communities, SCD poses a considerable burden on health care system. National Sickle Cell Anaemia Elimination Mission (NSCAEM) launched by Government of India (GOI) in 2023 proposes comprehensive public health initiative linking screening, early diagnosis, management, and preventive aspects to promote Universal Health care (UHC) for all affected population in India. This article provides an overview of SCD burden in India, recent trends in diagnosis and care, existing programmatic challenges and future directions for advancing sickle cell care in India and strengthening national response.

DISEASE BURDEN AND CLINICAL SPECTRUM

Despite perceived as mild disease earlier due to presence of the Arab-Indian HbS haplotype-characterized by relatively high levels of fetal hemoglobin (HbF) and variable frequencies of α-thalassemia, SCD can present with severe manifestations similar to many other regions of the world.^[3] Nevertheless, complications such as vaso-occlusive crises, acute chest syndrome, avascular necrosis, renal involvement, and stroke often present at a younger age in Indian SCD patients.^[4] Moreover, during early years, splenomegaly, severe anaemia, dactylitis (hand-foot syndrome), and repeated fever episodes are most common clinical manifestations. Importantly, children with SCD are at increased risk of bacterial infections including invasive pneumococcal disease, pneumonia, and meningitis resulting in increased risk of mortality during the first 3 years of life.^[5,6] HbS/β-thal may result in vaso-occlusion episodes, and often, patients have no symptoms until puberty.^[7] SCT or carriers are typically asymptomatic but may result in increased red blood cell sickling and polymerization under conditions of severe tissue hypoxia, acidosis, dehydration, and hypothermia.^[8]

The perinatal complications are likely to be related to chronic fetal hypoxia associated with decreased placental perfusion which leads to preterm birth, low birth weight, small for gestational age babies, and intrauterine growth retardation.^[9,10] However, newborns with SCD are healthy and asymptomatic at birth and characteristically develop clinical signs after HbF levels decline after first few months.^[11]

EPIDEMIOLOGY IN INDIA

Nearly, 14.5% of the global burden of SCD is contributed by India^[12,13] and it ranks second in the world for the number of predicted SCD births.^[14,15] SCD presents a substantial public health burden, particularly in central, western, and southern regions of India (Maharashtra, Madhya Pradesh, Chhattisgarh, Odisha, Jharkhand, Gujarat, and parts of Andhra Pradesh and Tamil Nadu).^[16] Further, the central zone and the east zone have a higher prevalence as compared to the western and the southern zone.^[12] HbS/β-thal is more prevalent in western parts, Uttar Pradesh and Odisha where the β-thalassemia mutation is co-endemic.^[12]

The prevalence of HbSS varies from 1% to 2% in high-burden districts of India.^[1,17,18] A recent systematic review by Rao et al. has reported prevalence of SCD, SCT, and HBS-beta-thalassemia as 1.17%, 5.9%, and 0.37%, respectively.^[12] Further, the prevalence of SCD is 4.05% in tribal communities, whereas it is relatively lower (0.84%) among the non-tribal populations of India.^[12]

SCREENING, DIAGNOSIS, AND EARLY DETECTION

Early detection is a cornerstone of SCD management to initiate timely intervention and guiding prenatal decisions.^[19] SCD screening is mainly conducted at community level (through outreach activities) and facility level (through primary health centers, district, subdistrict, and rural hospitals).

COMPREHENSIVE DISEASE PREVENTION AND MANAGEMENT STRATEGIES

The advancements in comprehensive management strategies have evolved significantly over past few decades. The primary goals of SCD management are to promote a healthy lifestyle, to reduce crises, and minimize complications by providing timely treatment. These goals are best accomplished by adapting combination of primary prevention (promotive strategies), secondary prevention (prophylactic and therapeutic approaches), and rehabilitation as stated below.^[3]

SECONDARY PREVENTION

Immunization, newborn screening for hemoglobinopathies, pre-conceptional genetic counseling, and subsequent prenatal diagnosis are important dimensions of secondary preventive strategies.

PRENATAL DIAGNOSIS AND GENETIC COUNSELLING IN SCD

Genetic counseling is a key pillar of SCD preventive strategy which enables prenatal diagnosis to prevent detrimental outcomes of future pregnancies.^[32] It can aid to make informed decisions regarding continuation of pregnancy for at-risk couples, explaining 50% chances of SCD and SCT in a baby if one parent is SCD and another SCT, whereas 50% chances of SCT and 25% SCD in a baby if both parents are trait [Figure 1]. If one of the parent is SCD and another normal, then there is 100% chances of baby being born with SCT. 50% SCT and 25% SCD if both the parents are trait. Prenatal diagnostic procedures such as amniocentesis or chorionic villus sampling (CVS) may be used in the early stages of pregnancy. Importantly, premarital and preconception counseling, along with community awareness activities, are crucial in tribal populations, having high rates of consanguinity.^[33]

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Figure 1:

Inheritance pattern of sickle cell disease. SCD: Sickle cell disease, SCT: Sickle cell trait, AS/SA: Sickle cell heterozygous/sickle cell trait, and SS: Sickle cell homozygous, AA: Normal.

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PUBLIC HEALTH INTERVENTIONS AND POLICY LANDSCAPE

National Sickle Cell Anaemia Elimination Mission (NSCAEM) was launched by GOI in 2023, with the overarching goal of eradicating SCD as a public health concern by 2047 with release of operational guidelines for comprehensive management of SCD.^[31] The strategy involves three pillars, namely, health promotion-emphasizing primary prevention through pre-marital genetic counseling, secondary prevention, focusing on universal screening and early detection, and lastly holistic management and continuum of care which includes management of SCD across all healthcare levels with community engagement mechanisms along with provision of social protection. Figure 2 depicts a framework consisting of different aspects of SCD including pathophysiology, clinical horizon, and different dimensions of prevention and management which are being considered for planning research, policy integration, and strengthening NSCAEM in India.

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Figure 2:

Comprehensive model of sickle cell disease prevention, management, and rehabilitation under India’s national sickle cell elimination mission. This framework depicts the comprehensive strategy for managing SCD in India, in accordance with the NSCAEM. The upper section represents the disease pathophysiology and clinical horizon whereas lower section represents multipronged strategy focused on primary prevention, secondary prevention with rehabilitation with focus on holistic approach along with continuum of care. NSCAEM: National Sickle cell anaemia elimination mission, SCD: Sickle cell disease, HbS: Hemoglobin S, HbSS: Homozygous sickle cell disease, HbS/β: Thal sickle cell β-thalassemia, IEC: Information, education, and communication, SBCC: Social and behavior change communication, CBC: Complete blood count, TCD: Transcranial Doppler, LFTs: Liver function tests, RFTs: Renal function tests, RPWD Act: Rights of persons with disabilities act (2016), and PPP: Public–private partnership.

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NSCAEM recommends universal population-based screening of SCD in 17 states with higher SCD prevalence (Madhya Pradesh, Gujarat, Maharashtra, Rajasthan, Chhattisgarh, Bihar, Jharkhand, West Bengal, Odisha, Tamil Nadu, Telangana, Karnataka, Assam, Andhra Pradesh, Uttarakhand, Uttar Pradesh, and Kerala) in its initial stage and subsequently expanding to all states/UTs in a phased manner. A targeted screening strategy is being considered in non-tribal districts for newborns, children (6 months to 10 years), adolescents, and pregnant mothers followed by cascade screening for extended family members.

This mission emphasizes intersectoral collaboration across the Ministries of Health, Tribal Affairs, Education, and Women and Child Development to promote effective implementation in remote tribal areas. Early detection and treatment for SCD is being strengthened through Rashtriya Bal Swasthya Karyakram by screening school going children, adolescents, and facilitating management through District Early Intervention Centers. Likewise, integration Ayushman Bharat Health and Wellness Centers is also playing a key role in providing community care, follow-up, counseling, and distribution of HU and folic acid.

Further, considering significant lifelong health, economic and psychosocial implications of SCD, social protection, and disability provisions have been recommended. Sickle cell cards are being issued post-screening with color coding (Male-Blue and Females-Pink) and as per status (Traits/ Disease). The cards are also used as tools for premarital and pre-conceptional counseling to explain genetic risks of children being born with SCD or SCT.

NSCAEM also proposes an innovative strategies as shown in Table 1 at different levels of health care facilities, along with integrating AYUSH for reducing oxidative stress and its related complications at different organ and systems level.^[31] It also recommends creating Patient Support System and community adoption to enhance community participation.^[31]

Further, SCD also imposes significant economic burden on families due to chronic health issues which also reduce productivity and absenteeism at workplaces resulting in significantly lower health-related quality of life.^[34] It is recognized as one of the 21 benchmark disabilities under Rights of Persons with Disability Act (RPWD), 2016. Those with 40% and above disability are entitled for time flexibility at school and workplaces, additional leaves for medical care, relaxation in attendance norms, and more time for assessments. It also provides financial assistance for medical expenses, and consideration of employment in proximity to comprehensive care. In addition to other rights under the RPWD Act of 2016, any person with SCD is also entitled to free education (from age 6 to 18), 4% reservation in education and government jobs, and 5% reservation in higher education.^[31] RPWD act also mandates non-discrimination, the right to equality and right to live with respect and dignity. It also holds provision of offering incentives to employers to employ individuals with a disability.

These provisions advocate a rights-based approach to SCD management, evolving beyond medical management, and paving toward an integrated social justice framework to ensure UHC enabling equity and opportunities.

CHALLENGES AND WAY FORWARD

Despite significant initiatives embarked by GOI, there are several systemic challenges which need to be addressed to achieve reduction in SCD cases. Although geospatial epidemiology has been well understood, the reach at the grassroots level has been impacted by delayed adoption, lapses in implementation and geographical disparities leading to difficulty in health care access especially in remote tribal regions.^[35]

Substantial research is being undertaken in India to characterize genetics affecting disease severity utilizing genomic techniques with specific emphasis on newborn screening which is an integral aspect of management.^[36] However, it is important to understand diversity in clinical spectrum of SCD in Indian context.^[37] There are significant gaps in collative research addressing implementation gaps or systematic appraisal of quality of care for patients with SCD. Notably, the absence of long-term studies substantially restricts the availability of evidence on healthcare outcomes in SCD.^[35] Implementation research (IR) is crucial to identify context-specific gaps and challenges and to develop evidence-based optimal model for SCD screening, diagnosis, treatment, and care. It will provide useful information about treatment adherence, community perceptions, and equity in health care. The iterations in the implementation models can strengthen outreach and penetration of program at all levels in health system. IR focusing on feasibility and acceptability of POC devices for screening will be very useful to achieve the target of universal screening of vulnerable populations especially in regions with high prevalence of SCD.

While newborn screening and other targeted screening for SCD are being given much emphasis, it is intriguing to note that health-seeking and treatment initiation are relatively poor during infancy, as newborns diagnosed at birth remain asymptomatic for the first few months due to high fetal hemoglobin. Thus, despite timely diagnosis at birth, parents do not adhere to timely follow-up and prophylactic treatment. Therefore, achieving targeted screening coverage should not be the only indicator to assess program effectiveness. There needs to be a composite care continuum index for every diseased child tracking from diagnosis till treatment initiation. However, currently, NSCAEM portal only depicts data on status of SCD and SCT patients and there is absence of a nationwide registry tracking clinical details, immunization, and treatment status of SCD patients. In this regard, a portal developed as a part of multicentric study of Indian Council of Medical Research (ICMR) on newborn sickle cell screening can be upscaled and further integrated for use under the NSCAEM.^[38] The scale up of newborn screening clubbed with timely follow-up ensuring continuum of care can be a paradigm move. A proposed framework by multicentric newborn screening study by ICMR can be adopted in low resource settings.^[36] Further, standard post-screening management protocols should be easily available as reference guide for medical officers. Increasing availability of POC tests, expanding the screening coverage, and advancements with respect to treatment options can also help to improve community acceptance. Recent innovations such as liquid oral formulation of hydroxyurea can prove beneficial in pediatric population. Moreover, the promising results of Clustered Regularly Interspaced Short Palindromic Repeats-(CRISPR) Associated technologies hold a great potential for treating SCD by directly modifying the faulty gene.

There is also need of a dedicated SCD-specific immunization program having linkages with national immunization schedule as few vaccines recommended for SCD patients such as PPSV23, meningococcal vaccines are not part of universal immunization schedule.

Subsequent follow-ups of SCD patients need integrated care involving multidisciplinary approach involving pediatricians, hematologists, psychologists, nutritionists, and social workers. However, lack of specialized care at remote facilities is important concern. Further, access to molecular diagnostics and laboratory support is also limited in such settings. Establishment of centers of excellence for multidisciplinary management of SCD to provide holistic care, genetic counseling, and community engagement in remote areas can enhance the quality of life and reduce the disease burden.^[39] Considering, lack of specialist care in remote facilities, the use of virtual platforms, digital health tools for tracking patients, and advocating public-private partnerships can be an effective strategy.^[40,41]

Although, prenatal screening for SCD using chorionic villus sampling and amniocentesis are available in tertiary facilities through Government funds, its utilization is largely impacted by limited access to care in geographically remote populations due to lack of trained personnel and adequate infrastructure.^[3] This restricts opportunities for early identification and informed reproductive decisions among high-risk couples. Similarly, newborn genome sequencing including hemoglobinopathies is very helpful in early detection and timely management but cost is currently a big constraint.

Another important aspect which needs to be addressed is socio-cultural and behavioral dimensions of SCD management, which are largely unaddressed. The cultural barriers and social stigma prevailing in tribal population result in delays in timely diagnosis and treatment, eventually exacerbating complications. There is a need for adopting a strong social and behavior change communication (SBCC) and advocacy, communication, and social mobilization (ACSM) approaches to address diverse cultural, traditional, religious, and socio-economic concerns, particularly among tribal populations.^[42] SBCC interventions, such as culturally tailored IEC materials, creating community role models and community ambassadors, may contribute to reshape perspectives, promote early screening, and improve treatment adherence. The Ministry of Tribal Affairs has recently introduced a new initiative, “Going Online as Leaders” as part of the health for all for making turning community members into ambassadors for spreading knowledge.^[37] Simultaneously, ACSM initiative can bring together local leaders, frontline workers, and grassroots organizations on same platform to advocate for policy implementation, increased utilization of health facilities, and community participation.^[43] Philanthropists and civil societies can also be involved for enhancing outreach, funding, and healthcare infrastructure to bridge the gaps in remote areas.

CONCLUSION

Notwithstanding recent advancements in screening, diagnosis, and management of SCD, there is an imperative need of efforts toward improving overall quality of life of SCD individuals, spanning beyond medical management. Integrating SBCC and ACSM through programs may culminate in the socio-cultural transformation required for long-term success. With a robust political commitment, microplanning strategies, intersectoral collaboration, and community participation, NSCAEM, India can serve as a global model for sickle cell control in low-resource settings.