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Multicenter Study
. 2021 Feb 8:11:619146.
doi: 10.3389/fimmu.2020.619146. eCollection 2020.

Clinical, Immunological, and Molecular Features of Severe Combined Immune Deficiency: A Multi-Institutional Experience From India

Pandiarajan Vignesh  1 , Amit Rawat  1 , Rajni Kumrah  1 , Ankita Singh  1 , Anjani Gummadi  1 , Madhubala Sharma  1 , Anit Kaur  1 , Johnson Nameirakpam  1 , Ankur Jindal  1 , Deepti Suri  1 , Anju Gupta  1 , Alka Khadwal  2 , Biman Saikia  3 , Ranjana Walker Minz  3 , Kaushal Sharma  1 , Mukesh Desai  4 , Prasad Taur  4 , Vijaya Gowri  4 , Ambreen Pandrowala  5 , Aparna Dalvi  6 , Neha Jodhawat  6 , Priyanka Kambli  6 , Manisha Rajan Madkaikar  6 , Sagar Bhattad  7 , Stalin Ramprakash  8 , Raghuram Cp  8 , Ananthvikas Jayaram  9 , Meena Sivasankaran  10 , Deenadayalan Munirathnam  10 , Sarath Balaji  11 , Aruna Rajendran  11 , Amita Aggarwal  12 , Komal Singh  12 , Fouzia Na  13 , Biju George  13 , Ankit Mehta  14 , Harsha Prasada Lashkari  15 , Ramya Uppuluri  16 , Revathi Raj  16 , Sandip Bartakke  17 , Kirti Gupta  18 , Sreejesh Sreedharanunni  19 , Yumi Ogura  20 , Tamaki Kato  20 , Kohsuke Imai  20   21 , Koon Wing Chan  22 , Daniel Leung  22 , Osamu Ohara  23 , Shigeaki Nonoyama  20 , Michael Hershfield  24 , Yu-Lung Lau  22 , Surjit Singh  1
Affiliations
Multicenter Study

Clinical, Immunological, and Molecular Features of Severe Combined Immune Deficiency: A Multi-Institutional Experience From India

Pandiarajan Vignesh et al. Front Immunol. .

Abstract

Background: Severe Combined Immune Deficiency (SCID) is an inherited defect in lymphocyte development and function that results in life-threatening opportunistic infections in early infancy. Data on SCID from developing countries are scarce.

Objective: To describe clinical and laboratory features of SCID diagnosed at immunology centers across India.

Methods: A detailed case proforma in an Excel format was prepared by one of the authors (PV) and was sent to centers in India that care for patients with primary immunodeficiency diseases. We collated clinical, laboratory, and molecular details of patients with clinical profile suggestive of SCID and their outcomes. Twelve (12) centers provided necessary details which were then compiled and analyzed. Diagnosis of SCID/combined immune deficiency (CID) was based on 2018 European Society for Immunodeficiencies working definition for SCID.

Results: We obtained data on 277 children; 254 were categorized as SCID and 23 as CID. Male-female ratio was 196:81. Median (inter-quartile range) age of onset of clinical symptoms and diagnosis was 2.5 months (1, 5) and 5 months (3.5, 8), respectively. Molecular diagnosis was obtained in 162 patients - IL2RG (36), RAG1 (26), ADA (19), RAG2 (17), JAK3 (15), DCLRE1C (13), IL7RA (9), PNP (3), RFXAP (3), CIITA (2), RFXANK (2), NHEJ1 (2), CD3E (2), CD3D (2), RFX5 (2), ZAP70 (2), STK4 (1), CORO1A (1), STIM1 (1), PRKDC (1), AK2 (1), DOCK2 (1), and SP100 (1). Only 23 children (8.3%) received hematopoietic stem cell transplantation (HSCT). Of these, 11 are doing well post-HSCT. Mortality was recorded in 210 children (75.8%).

Conclusion: We document an exponential rise in number of cases diagnosed to have SCID over the last 10 years, probably as a result of increasing awareness and improvement in diagnostic facilities at various centers in India. We suspect that these numbers are just the tip of the iceberg. Majority of patients with SCID in India are probably not being recognized and diagnosed at present. Newborn screening for SCID is the need of the hour. Easy access to pediatric HSCT services would ensure that these patients are offered HSCT at an early age.

Keywords: BCG; India; hematopoietic stem cell transplantation; newborn screening; severe combined immune deficiency.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Bar graph depicting the rise in number of cases diagnosed over last 10 years.
Figure 2
Figure 2
Bar graph depicting the clinical manifestations and microbiological profile. (A) Clinical manifestations noted at first clinical presentation; (B–D) Microbiological profile of the organisms isolated—bacteria (B), fungi (C), and viruses (D).
Figure 3
Figure 3
Clinical manifestations of children with SCID. (A, B) BCG site ulceration and pus discharge (Pt. 46 and 34); (C–F) Features of Omenn syndrome such as generalized erythema, scaling, loss of hair, and eyebrows (Pt. 34); (G, H) Chest radiograph of a child with ADA SCID showing radiological abnormalities—scapular spur and flattening of lower border of scapula (Pt. 39); (I) Chest radiograph of a child with CORO1A defect showing normal thymus shadow (Pt. 49).
Figure 4
Figure 4
Chimerism analysis using dual colour FISH probes targeting centromeres of X (DXZ1; green) and Y (DYZ1, orange) chromosomes in a male child suspected with transplacental-acquired maternal T cell engraftment (Pt. 44). (A) Immunomagnetically sorted CD19 positive cells (B cells) showing XY pattern in all cells while; (B) Immunomagnetically sorted CD3 positive cells showing XX pattern in two out of three cells suggesting maternal T cell engraftment. Inset shows XX pattern in a lymphocyte and XY pattern in neutrophils.
Figure 5
Figure 5
MLPA data was analyzed using Coffalyser software. (A) Healthy control sample having a Dosage Quotient (DQ) between 0.80 and 1.20; (B) A patient with T-B-NK+ SCID (pt. 66) showing a homozygous deletion and DQ=0; (C, D) Parents of index child showing a heterozygous deletion with DQ Score in range of 0.40 to 0.65.
Figure 6
Figure 6
Survival curve comparing the outcome of children who underwent HSCT (n=23) and children who were not transplanted (n=213), p < 0.001 (Log Rank Mantel-Cox). Total person follow-up months—629.13 months.
See this image and copyright information in PMC

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