Experiences from inborn errors of immunity registry of India: A preliminary report

Methods

The “National Registry for Rare and Other Inherited Disorders” is a prospective hospital-based registry which collects data of the diagnosed rare disease patients from the centres which expressed interest in contributing to this national database. As per the IUIS classification, the IEI have been classified into 10 main categories: (I) immunodeficiencies affecting cellular and humoral immunity, (II) combined immunodeficiencies with associated or syndromic features, (III) predominantly antibody deficiencies, (IV) diseases of immune dysregulation, (V) congenital defects of phagocyte number or function, (VI) defects in intrinsic and innate immunity, (VII) autoinflammatory diseases, (VIII) complement deficiencies, (IX) bone morrow failure, and (X) phenocopies of IEI. Centre of Excellence at ICMR-National Institute of Immunohaematology (NIIH) and Post Graduate Institute of Medical Education and Research (PGIMER) Chandigarh, the designated nodal centres for IEI registry by ICMR, jointly developed a detailed data collection instrument, SOPs for data entry and quality criteria for validation of data entered by the contributing centres. The ethical clearance was obtained from the Institutional Ethics Committee of all the participating institutes and written informed consent was obtained from all the participants. Written informed consent from parents and oral assent from children aged 7-12 yr was obtained and for children above 12 yr, written assent along with parental consent was obtained.

Results

Six participating centres, including the nodal centres ICMR-NIIH Mumbai, PGI Chandigarh, Apollo Chennai, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER) Pondicherry, Nizam’s Institute of Medical Sciences (NIMS), Hyderabad, and Sir Gangaram Hospital Delhi, have together contributed data for 708 IEI patients into the registry. After exclusion of incomplete entries, data of 676 patients enrolled between January 2019 - October 2024 was analysed. Immunodeficiencies affecting cellular and humoral immunity (CID) and CID with associated or syndromic features taken together were the most frequent PID (n=187, 27.6%) with 94 (13.9%) and 93 (13.7%) patients, respectively ( Figure).

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Figure.

Pie-chart showing distribution of patients with inborn errors of immunity across IUIS categories.

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Demographic and clinical details of these patients are provided in Table I. Median diagnostic delay was 16 (3, 55) months and was maximum in antibody deficiencies, [53 (IQR 12,129) months].The presenting clinical manifestations comprised of recurrent infections in 459 (67.9%) patients, autoimmune or autoinflammatory in 292 (43.2%) patients, adverse effects following immunisation in 38 (5.6%), allergies in 45 (6.7%) and malignancy in 5 (0.73%). The commonest infectious manifestations were respiratory and gastrointestinal infections. The commonest autoimmune and autoinflammatory presentations involved abdominal symptoms followed by skin infections ( Table I). The category-wise genetic diagnosis is presented in Table II.

Of 146 and 187 patients diagnosed with antibody deficiency and combined immunodeficiency, respectively, 103 and 47 patients had received IVIG therapy ever, and 90 (13.3%) IEI patients underwent hematopoietic stem cell transplantation (HSCT), of which 80 are doing well on follow up. On follow up of these patients in 2024, 118 (17.4%) of 676 patients who could be followed up had died due to infections. The underlying diagnosis in these patients were immunodeficiencies affecting cellular and humoral immunity (n= 46, 38%) followed by diseases of immune dysregulation (n= 25, 21%), congenital defects of phagocyte number or function (n= 23, 19%), antibody deficiency (n= 10, 8%), combined immunodeficiency with associated or syndromic features (n=9, 7%), defects of intrinsic and innate immunity (n=3, 2.5%) and (n=1, 0.84%) each from complement deficiencies and bone marrow failure.

Patients who had failure to thrive, haemoglobin less than 10 g/dL, absolute lymphocyte count<1000 per mm³ at presentation and history of consanguinity had two times higher odds of death. The odds of dying were less than half if patient was on IVIg or had received HSCT ( Table III).

Discussion

This registry is part of the first national level effort by the ICMR to collate data on patients diagnosed with rare diseases. Our registry highlights an effort towards collating observations of IEI diagnoses, genetics, treatment, and survival trends among Indian patients. Largest current IEI cohorts from Asian countries include registry data from Iran, China, and Turkey with reported prevalence of 3.9, 0.2 and 7.2 per 100000 population respectively.⁷ As observed with the USIDNET and European registries which are the largest IEI databases globally, antibody deficiencies are the most frequent IEI followed by combined immunodeficiencies taken together.^11,12

We identified combined immunodeficiencies taken together to be most frequent followed by predominantly antibody deficiencies, followed by congenital phagocytic defects of number and function. Despite being the most prevalent IEI, many studies^13-15 including our registry data reports the delay in diagnosis among antibody deficiency to be longer than most other IEIs, emphasising the need of increasing awareness among the clinicians.

Many IEIs can be diagnosed using two simple blood tests - a complete blood count and immunoglobulin level assessment which are easily available. These tests can help identify antibody deficiencies and immunodeficiencies characterised by a severe lack of lymphocytes or granulocytes, which taken together constituted almost half of the diagnosed patients. Two out of five patients had autoimmune or autoinflammatory manifestations, and a high index of suspicion among patients presenting with these manifestations may help in early diagnosis.

The registry database will help determine the burden of IEIs in India and help policy makers make informed decisions. The Ministry of Health and Family Welfare of the Government of India has made provision for the treatment of IEIs under the Rare Disease Policy 2017.¹⁶ However, it was observed from our registry data that there is a mismatch between demand and supply of IVIG among our patients diagnosed with antibody deficiency, hence, there is a need for advocacy for sufficient provision of IVIG by the State government. In addition, majority deaths were observed among our patients diagnosed with combined immunodeficiencies, highlighting the need for timely diagnosis and availability of HSCT and prophylactic antibiotics. Hence, data from the registry can help identify gaps in access to diagnostics and treatment of IEIs and also help gather information on availability of expertise for management of these disorders which can help streamline processes under the National Rare Disease Policy. In this direction, the Government of India has also recognised Centres of Excellence across the country for management of different rare diseases; these centres will also eventually serve as sentinel sites for these disorders and also help build capacity in the management of these disorders. The gaps or leads identified in registry data will also help identify areas for future research.

High consanguinity¹⁷ highlights that autosomal recessive conditions might be more prevalent in some geographical areas among the Indian population. Cord blood screening or newborn screening in these at-risk highly consanguineous populations might help in early diagnosis and initiating timely management. In addition, genetic counselling and prenatal screening¹⁸ for families with an identified genetic defect might help in preventing birth of affected babies. In addition, live vaccine BCG may be deferred in babies born in affected families until IEI has been ruled out.¹⁹

Haematopoietic stem cell transplantation (HSCT) is a currently available curative option for patients with IEI in India. There are now over 200 centres in the country performing these lifesaving procedures and over 500 have been performed in the country with 65% overall survival.²⁰ Ninety patients among those enrolled in the registry underwent HSCT. HSCT can now be performed from a matched family donor, matched unrelated donor or a haploidentical donor. Recent advances in graft manipulation have resulted in T cell depletion techniques particularly suited for small babies with comorbidity like children with IEI. Access to care has also improved with government and non-government organisations willing to fund these curative options. The future will see gene therapy available in our country, newborn screening, and early referral with over 90% survival.^21,22

The major limitation of the current database is the limited number of participating centres contributing to this national database although IEI patients are being diagnosed and managed by many more institutions across the country. The burden of IEIs is clearly underestimated and improved registration efforts could help in more accurately estimating the burden of the disease and allowing for the allocation of appropriate resources for these disorders. Missing data for family history including consanguinity and affected male members in extended family can be attributed to recall limitation, missing data regarding affected sibling/sibling death may be attributed to sociocultural factors including hesitancy of parents to disclose these details.