Sickle cell disease in India: the journey and hope for the future

Visual Abstract

Abstract

India, the most populous nation in the world, also has a high frequency of the sickle hemoglobin (HbS) allele globally. The Arab Indian HbS haplotype in India is characterized by a relatively high percentage of fetal Hb, with widely varying frequencies of α-thalassemia. Hence, sickle cell disease (SCD) in India was perceived to be mild. Advances in the past decade in screening and SCD management have revealed that the severity of SCD in India is comparable to many other parts of the world. Clinical features in India include vaso-occlusive crisis, acute chest syndrome, avascular necrosis, renal involvement, stroke, etc, at a relatively young age. Once a fatal disease of childhood, the majority of patients born with SCD are expected to survive into adulthood, largely because of improvements in comprehensive care programs including newborn screening, penicillin prophylaxis, transcranial Doppler, and hydroxyurea therapy. Several centers are performing hematopoietic stem cell transplants successfully for SCD. To address the urgent need to control and manage SCD in India's population, the Government of India launched the National Sickle Cell Anaemia Elimination Mission, with significant funding for large-scale measures to screen, treat, counsel, educate, and develop technologies and novel therapies and gene therapies.

Learning Objectives

• Summarize the current status of SCD in India, which has a high percentage of fetal hemoglobin accompanied by mild to severe complications

• Discuss the milestones and progress in understanding the SCD phenotype, accelerated by the National Sickle Cell Anaemia Elimination Mission 2023

CLINICAL CASE

A 16-year-old girl with HbSS (sickle homozygous) receiving comprehensive care since diagnosis at newborn screening (NBS) had a persistent HbF level of 21.8%. Hydroxyurea (HU) was started at the age of 10 years, and the dose was escalated to 20  mg/kg. Transcranial Doppler was normal. She presented with fever and respiratory distress with hypoxia, with pulse oximetry revealing an oxygen saturation of 92%; hemoglobin [Hb], 7.9  g/dL; a white blood cell count, 18 200; a platelet count of 72.00; bilateral lung infiltrates on chest x-ray; and negative blood cultures. She received oxygen, a packed red cell transfusion, and antibiotics. On day 5, the patient developed left hemiparesis, and magnetic resonance imaging of the brain revealed acute infarcts in the left parietal lobe. She developed bilateral lower-extremity deep vein thromboses, which were managed with anticoagulants. The patient was discharged without residual neurological damage. She continues to be followed up in the sickle cell clinic.

Introduction

Sickle cell disease (SCD) is a global disorder, with the highest number of births in Nigeria and the Democratic Republic of the Congo, followed by India, with the third-highest number of births with HbSS disease.^1-3 Sickle cell trait (SCT) was first described in the aboriginal communities of Southern India, and the focus was on the anthropological investigation of potential ancient migrations between India and Africa (Figure 1). The severity of the sickle cell phenotype and disease prevalence in India were underestimated.^4,5 Because of the high percentage of HbF in persons with SCD in India, the disease was mistakenly considered mild.^6,7 We trace its progress from these uncertain beginnings to the current status of SCD prevalence, morbidity, mortality, management, and the recent impressive efforts of the Government of India (GOI) to screen, manage, and control SCD through its National Sickle Cell Anaemia Elimination Mission (NSCAEM) 2023 (Figures 2 and 3).^8,9 These developments are driven and sustained by the federal and state governments and partnership with for-profit and nonprofit institutions, industry, and academia to mitigate the suffering from this debilitating condition in India. The progress in SCD care in India has the potential to positively impact other low- and middle-income countries globally.

Figure 1.

Historic milestones in the detection and progress of SCD in India. AS, heterozygous; CSIR, Council of Scientific and Industrial Research; HSCT, hematopoietic stem cell transplantation.

Figure 2.

Various components of the Sickle Cell Management Program of the NSCAEM 2023. Adapted with permission from the Ministry of Health and Family Welfare⁹ and the Ministry of Tribal Affairs, GOI, Government of India; POC, point of care.

Figure 3.

Consort diagram showing the well-organized Sickle Cell Management Program of the NSCAEM 2023. AB-HWC, Ayushman Bharat-Health and Wellness Center; CZE, capillary zone electrophoresis; HPLC, high-performance liquid chromatography; IEF, isoelectric focusing. Adapted with permission from the Ministry of Health and Family Welfare.⁹

History of SCD and diversity of the βS-globin gene haplotypes in India (Figure 1)

In 1952, Lehmann and Cutbush first reported the presence of sickle cell trait in the aboriginal communities of Southern India.¹⁰ Dunlop and Mazumder reported the presence of HbS in migrant tribal workers in the eastern states of Bihar and Odisha and in the tea gardens of Assam in the Northeast.¹¹ Findings of the βS-globin (β^S) trait formed the basis of a hypothesized population exchange between India and Africa and the milder phenotype. Subsequently, it was reported that SCD also affected nonaboriginal populations,¹² with significant morbidity and mortality despite high HbF amid the heterogenous presentation of SCD in the culturally and geographically diverse landscape of India (Figures 4 and 5).^5,13-16 It is not clear if the origin of the β^S mutation in India is related to migration from Africa or the Middle East or represents an independently arising mutation in areas where malaria is endemic in India.¹⁷

Figure 4.

Map of India showing states with a high and partial prevalence of SCD. Reproduced with permission from Prevention, management and elimination of sickle cell disease: a strategic road map, Ministry of Tribal Affairs, GOI, Government of India.

Figure 5.

Regional distribution of SCD among the tribal population of India. Reproduced with permission from the Ministry of Health and Family Welfare.⁹ AA, without sickle; AS, heterozygous/trait.

In late 20th century, studies first documented the severity of the clinical phenotype of SCD in India. Kar et al reported that the sickle cell gene was widespread and presented with moderate to severe anemia, vaso-occlusive episodes (86.5%-89.36%), splenic sequestration (8.43%-12.76%), crippling avascular bone necrosis (5.7%-35.08%), and osteomyelitis (5%).^18-25 Jain et al in Nagpur observed that a significant proportion of children with SCD from central India presented with severe symptoms and required regular medical attention.^{5,13-16,26-36}

The major β-globin haplotype in India is the Arab Indian, but other haplotypes also exist in lower proportions. In a newborn cohort in Nagpur, out of the 150 infants with HbSS, 141 (94.0%) were linked to the AI haplotype.²⁸ Similar genotypic prevalences were reported in a cohort of 100 subjects from Chhattisgarh in central India.²⁹

Since SCD was most prevalent in aboriginal (scheduled tribes) and disadvantaged communities, it is likely that many remained undiagnosed and/or did not survive because of lack of access to care, which may have led to the poor understanding of the disease phenotype. Recent studies have revealed that SCD is not confined to these communities.

Early studies of disease phenotype following NBS

NBS was initiated in early 2000 and revealed the high frequency of sickle cell mutation in central India.^29,33,37-42 Since then the NBS cohort has been followed by the Government Medical College, Nagpur, with comprehensive multidisciplinary care including pneumococcal prophylaxis and immunization, HU, and screening for cerebral blood flow velocity proteinuria, retinopathy, avascular necrosis and cholelithiasis. Of 2178 newborns screened with a mother positive for β^S (targeted NBS), 104 were sickle homozygous (SS), 7 sickle β-thalassemia, 5 sickle D^Punjab, and 1978 SCT.²⁸ Pain, severe anemia requiring blood transfusions, and acute febrile illness were the major complications with 59.7, 45.1, and 42.6 cases/100 person-years.²⁹ Some of the barriers to follow-up included low literacy and seasonal migration for work.

Comparison of SCD cohorts in India with clinical phenotypes in other parts of the world

Generalizing the clinical features of SCD in India may be challenged by the tremendous genetic, cultural, socioeconomic, and geographical diversity of India and limited access to care. We conducted a single-center study in Nagpur in a large cohort of 833 children to examine the rate of complications and define the phenotype of SCD in India and to determine whether clinical phenotype was actually milder in aboriginal tribes.¹⁵ We compared the rate of complications per 100 person-years for 1954 person-years to those reported by the Cooperative Study of Sickle Cell Disease.¹⁵ The rates of vaso-occlusive crises, severe anemia, stroke, splenic sequestration, and meningitis were more frequent in Nagpur compared to the Cooperative Study of Sickle Cell Disease. Notably, non-aboriginals presented with more frequent complications compared to aboriginal tribal populations.

We also compared the disease phenotype in the long term follow-up of children in Nagpur with Jamaica.¹⁶ Compared to the Jamaican cohort, the Nagpur cohort had lesser α-thalassemia; higher HbF, hypersplenism, and persistent splenomegaly; and lesser dactylitis (Table 1). There were also high admission rates for febrile illness and marked anemia in the Nagpur cohort. Invasive pneumococcal disease occurred in 10% of Jamaicans but was not seen in Nagpur, perhaps because the Nagpur cohort received a pneumococcal vaccine and penicillin prophylaxis from birth until 5 years of age.

Table 1.

Comparison of HbF between Jamaican and Central Indian cohorts of persons with SCD

	Untransformed percentage mean HbF		Transformed mean difference, 95% CI	P
Age in years	Jamaica	Nagpur Central India
1 year	15.5	25.2	2.51, 2.35-2.68	<0.001
2 years	12.1	22.5	2.58, 2.42-2.73	<0.01
3 years	11.2	22	0.89, 0.18-1.60	<0.05

Adapted with permission from Jain et al.¹⁶

Despite high HbF levels, there is a prevalence of the severe SCD phenotype in India, but to the best of our knowledge, no data are available to explain this. We speculate that in addition to HbF other genetic and epigenetic factors—environmental factors such as social determinants of health, health care availability/ utilization, concomitant infections and infestations, nutrition, environmental exposure, maternal health, etc, and biological factors such as hemolysis, hydration, and coexistence with other diseases may modulate disease severity. There is an urgent need to unravel the paradox of both very high HbF and mild disease and severe disease in the presence of high HbF.

Malaria is endemic in many regions of India, particularly those with large SCD cohorts, and may contribute to disease severity. While sickle cell trait is known be protective against malaria, individuals with SCD may have more severe manifestations of malaria. High mortality has been reported in patients with HbSS with Plasmodium falciparum malaria.⁴³ Further clinical and epidemiological studies are indicated to determine the effect of malaria on the morbidity and mortality of SCD in India. Preliminary data show a high rate of mortality and serious complications among patients with SS, with those contracting P. falciparum developing fatal outcomes and serious complications.

Current status of comprehensive care

Prevention of pneumococcal infections

Immunization against Streptococcus pneumoniae and Haemophilus influenzae infections has improved survival and decreased the morbidity associated with invasive pneumococcal disease and H. influenzae.

Prenatal screening for SCD

Prenatal screening for SCD using chorionic villus sampling and amniocentesis is available at GOI's expense. However, utilization of these services may be impacted by limited access to care in geographically remote populations.

Social support and special protection

Thalassemia, hemophilia, and SCD are the 3 hematological disorders included in the Rights of Persons with Disabilities (RPWD) Act of 2016. Those with 40% and above disability are entitled to accommodation at school and work, including time flexibility, extra leave for medical care, relaxation in attendance requirements, extra time for timed exams, financial assistance for medical expenses, and consideration of employment in proximity to comprehensive care. The RPWD act also mandates nondiscrimination, the right to equality, and life with dignity and respect and provides incentives to employers to employ individuals with a disability. The act also establishes preferences in admission to courses of higher education.

Disease-modifying therapies

Hydroxyurea

Hydroxyurea (HU) has been used in patients with SCD in India since 2008.^34-36,44-48 HU is manufactured in India by several pharmaceutical companies and is readily available there. HU is dispensed free of charge through the government health system and is commercially available at a very low cost for a 200- or 500-mg/tablet or capsule. A 500-mg dose costs from approximately Rs 2.5 to Rs 15 (equivalent to US $0.03 to $0.18). An oral liquid formulation of HU that is stable at room temperature is being manufactured in India at a sale price of Rs 600 (USD $7.18)/100  mL. This formulation offers a major benefit for treating children in remote areas in the tropical climates of India and Africa.

HU has been shown to be effective in decreasing painful episodes, blood transfusion requirements, and rates of hospitalization. Initially, a low fixed dose of HU at 10  mg/kg/d was started in persons with severe SCD. Several studies from different regions in India found that HU treatment from 6 months to 24 months led to a statistically significant increase in total Hb, HbF, MCV, MCH, and MCHC levels and a significant reduction in HbS, leukocytes, platelets, reticulocytes, total serum bilirubin, and lactate dehydrogenase; it also decreases hemolysis, improves anemia, leads to fewer VOCs and hospitalization, and reduces the transfusion requirement.^{34,36,45,47,49-51}

Currently, HU is offered to all patients with SS starting at 2 years of age, irrespective of symptoms. Most of the published literature from India reports that a low and fixed dose of HU (10  mg/kg/d) in children affected with severe disease leads to a significant reduction in recurrent painful episodes, the need for frequent blood transfusions, and the frequency of hospitalization, along with other sickle cell anemia–related comorbidities. This may in part be due to high basal levels of HbF. However, dose escalation is undertaken only if there is no reduction in pain crises and depending upon the requirement for blood transfusions. A multicentric randomized trial is ongoing to assess the efficacy of 10  mg/kg/d vs 20  mg/kg/d and dose escalation of HU in the treatment of SCD.

Crizanlizumab is currently available in India, and L-glutamine is expected to become available shortly.

Curative therapies

Hematopoietic cell transplantation

Hematopoietic cell transplantation (HCT) has steadily grown in India over the last 4 decades. Currently, there are 114 HCT centers in the country, of which 89 report results to a bone marrow transplant registry.⁵² To date, over 27 000 HCT procedures, including 16 000 allogeneic HCTs, have been performed, with 65% of the HCTs occurring in adults. Thalassemia is prevalent in many ethnic groups in India but has no predilection for disadvantaged communities. There are several available programs to support HCT for thalassemia, which has led to the initiation and success of HCT for SCD. It is encouraging to note that novel strategies have been used in customizing the standard HCT protocols in India for SCD.⁵³ Nationally, complete data from different centers are not yet available for transplants in SCD patients from India, but efforts to provide regular updates are being organized through the NSCAEM registry. There is increasing interest among patients and health care providers in considering transplants for SCD. Thus far, a significant number of patients have traveled from Africa to India to receive HCT. Pre- and post-HCT care, which is critical for successful outcomes, may be limited in their home countries. Resources to meet the demand for bone marrow transplants in Africa are urgently needed.⁵⁴ Therefore, a global strategy is required to harness the technically advanced resources in India in synergy with other low- and middle-income countries to successfully utilize curative therapies in a cost-effective manner.

Clinical trials

Approximately 47 clinical trials are registered in the Clinical Trial Registry India for SCD, including but not limited to HU, haploidentical transplant conditioning regimens, decitabine- tetrahydrouridine, crizanlizumab, and ayurvedic and integrative medications/strategies such as yoga, omega-3 fatty acids, nutraceuticals, plant extracts, and homeopathic interventions (https://ctri.nic.in/Clinicaltrials/pubview2.php). Of 18 ongoing clinical trials for SCD, 12 are randomized controlled trials. With large numbers of patients with SCD and medical services in private and academic hospitals, India has the potential to serve as a source for conducting interventional clinical trials.

A vision for the future and a national initiative

The NSCAEM, implemented since 2023, focuses on addressing the significant health challenges posed by SCD, with special emphasis on tribal populations of the country.²⁶ The mission is designed to improve the care of all SCD patients and to lower the prevalence of the disease through a multifaceted coordinated approach toward screening and awareness strategies with the ambitious target of eliminating SCD as a public health problem in India before 2047 (Figures 2 and 3).⁹

The mission includes support for increasing awareness of the disease in the community, implementing mass screening activities for early identification, building a strong network for diagnosis and treatment and a robust monitoring system, strengthening the existing primary health care mechanism to incorporate SCD-related strategies, forming primary, secondary, and tertiary health care teams, and creating cost-effective intensive interventions at quaternary care facilities. The main pillars of the mission are i) health promotion through awareness generation and premarital genetic counseling, ii) prevention by universal screening and early detection, iii) holistic management and continuing care at primary, secondary, and tertiary health care levels, (iv) treatment facilities at tertiary and quaternary health care facilities, and (v) implementation of a patient support system and community engagement to encourage adoption. Mass screening has been undertaken in 17 high-prevalence states with the goal of screening 70 million individuals aged under 40 years in 3 years. To date 36 million individuals have been screened, and 150 000 individuals with SCD and 1 million individuals with sickle cell trait have been detected. Screening metrics are updated in real time to a live public online portal to guide resource allocation at the district, state, and national level (https://sickle.nhm.gov.in/home/guest_dashboard) (Figure 6).

Figure 6.

Dashboard showing updated sickle cell screening data in real time. Reproduced with permission from the Ministry of Health and Family Welfare,⁹ accessed 7 July 2024, https://sickle.nhm.gov.in/home/guest_dashboard.

All individuals screened are provided with a standardized color-coded identity card with holes punched according to their sickle cell status that also reveals reproductive risk in a health literacy-friendly format (Figure 7). All pregnant women attending antenatal clinics are screened for SCD; if both partners test positive, chorionic villus sampling or amniocentesis is offered free of charge.

Figure 7.

Sickle cell cards for every individual showing their status as normal, as a carrier, or as a person with SCD. The blue is for males and the pink for females. “Front of the card bears the special QR code and identifying information specific to the individual. Back of the card shows the possible outcomes of conception between 2 individuals depending upon their status. For matchmaking the couple's cards are held together against the light and the coinciding holes show the possibility of having a child with Trait or SCD.” Reproduced with permission from the Ministry of Health and Family Welfare.⁹

Research support for gene therapies

While disease-modifying therapies such as HU have been shown to prevent or reduce complications, gene therapies offer the hope of a transformative therapy moving toward a cure. The approval by the US Food and Drug Administration of Lyfgenia and Casgevy offers the hope of wide implementation of these therapies.⁵⁵ Serious concerns remain about the feasibility and cost of gene therapies in low- and middle-income countries.⁵⁶ It is encouraging to note that the GOI has already made major investments in research to develop gene therapies for SCD in India.⁵⁷

Conclusions

India is home to a large proportion of those with the β^S allele globally. Heterogeneity in geography, cultural and ethnic diversity, and variability in the health system contributes to the challenges of providing quality SCD care. The severity of disease phenotype is similar to that described elsewhere in the world, though there may be variations among ethnic groups. India has seen tremendous progress in newborn and population screening, comprehensive care, pneumococcal prophylaxis, and disease- modifying therapy with HU, all available free in government-run clinics. Government and philanthropic support is available for curative therapies, and research is ongoing to develop gene therapies. There is a large capacity to manufacture disease- modifying drugs, safe blood products, vaccines, and genomic therapies at low cost and to scale. Political will at the federal and state levels has led to the initiation of the largest comprehensive effort anywhere for alleviating SCD at the personal to the population level, with the ambitious goal of eliminating SCD as a public health problem by 2047.

Implications for clinical case

The patient developed acute chest syndrome despite receiving comprehensive care per the current standard, a high baseline level of HbF and a moderate dose of HU. She was able to access timely quality treatment including transfusions, antibiotics, and supportive care. Stroke has been observed in patients with severe acute chest syndrome. Deep vein thrombosis likely resulted from the immobilization related to her severe hospital course. She may be a candidate for escalation of HU dosing, but recurrent thrombocytopenia (platelets <80 000) prevented her health care team from accelerating the dose. HCT or gene therapy at a regional center of excellence may be considered.

Conflict-of-interest disclosure

Kalpna Gupta: no competing financial interests to declare.

Lakshmanan Krishnamurti: no competing financial interests to declare.

Dipty Jain: no competing financial interests to declare.

Off-label drug use

Kalpna Gupta: nothing to diclose.

Lakshmanan Krishnamurti: nothing to disclose.

Dipty Jain: nothing to disclose.