ORIGINAL ARTICLE Lymphopenia and Severe Combined Immunodeficiency (SCID) - Think Before You Ink Jahnavi Aluri 1 & Maya R. Gupta 1 & Aparna Dalvi 1 & Snehal Mhatre 1 & Manasi Kulkarni 1 & Mukesh Desai 2 & Nitin K. Shah 3 & Manisha R. Madkaikar 1 Received: 17 July 2018 /Accepted: 13 February 2019 # Dr. K C Chaudhuri Foundation 2019 Abstract Objectives Severe combined immunodeficiency (SCID) represents one of the most severe forms of Primary immunodeficiency (PID) disorders, characterized by T cell lymphopenia (TCL) and lack of cellular and humoral immune responses. However, not all patients with low T cell lymphocyte counts may have an abnormal T cell immunity and the observed TCL may be a temporary suppression resulting from transient lymphopenia secondary to severe infections. In such cases, it is necessary to estimate the severity of the observed TCL by assessing thymic capabilities. Methods In this study, patients clinically suspected of SCID were evaluated for lymphocyte subsets analysis, naïve T cells and T cell receptor excision circles (TREC). Results Patients with transient lymphopenia had detectable TREC levels and normal naïve T cells subsets. Normalization of absolute lymphocyte counts, and T cells was seen in the patients after a short duration. Conclusions The authors highlight the importance of detailed immunological investigations in an infant with severe infections and lymphopenia before labeling the infant as SCID. Keywords SCID . TREC . Naïve T cells . Transient lymphopenia Introduction Neonates have little immunological memory and a developing immune system, which increases their vulnerability to infec- tious agents [1]. While neonates with an intact immune system can handle these infections well on administration of appro- priate antibiotics, immunodeficient infants come to attention due to recurrent and severe infections that respond poorly to antibiotics. After ruling out the secondary causes of immuno- deficiency, such as Human immunodeficiency virus (HIV) infection, a strong suspicion for Primary immunodeficiency (PID) diseases is made in a pediatric practice. Primary immu- nodeficiency (PID) diseases are a rare group of disorders that affects different components of the immune system. Severe combined immunodeficiency (SCID) represents the most severe and heterogenous form of PID which is suspected in a clinical scenario of recurrent infections, an early age of presentation (<6 mo), a finding of low absolute lymphocyte count (ALC) and T cell lymphopenia [2]. SCID diagnosis is challenging due a varied spectrum that ranges from severe forms referred to as BTypical SCID^ with absolutely reduced lymphocyte subsets to Batypical^ or Bmilder^ phenotypes where the subsets may appear normal, but cells may be dys- functional. In such cases, diagnosis is further supported by advanced immunological studies like studying the expression of disease associated proteins, functional assays, and T cell proliferation assay [2]. Through newborn screening program (NBS) for SCID, the potential of T cell receptor excision circle assay (TREC) followed by measurement of naïve T cell counts for early diagnosis of SCID was realized. TRECs are produced during the process of T cell receptor (TCR) rear- rangement, hence, considered as biomarkers of thymic output. * Manisha R. Madkaikar madkaikarmanisha@gmail.com 1 Department of Pediatric Immunology and Leukocyte Biology, National Institute of Immunohematology (ICMR), Mumbai, Maharashtra, India 2 Division of Immunology, Bai Jerbai Wadia Children’ s Hospital, Mumbai, Maharashtra, India 3 Pediatric Hematology-Oncology, P. D. Hinduja National Hospital & Research Center, Mumbai, Maharashtra, India The Indian Journal of Pediatrics https://doi.org/10.1007/s12098-019-02904-9