Natural History of Swiss Infants with Non-SCID T-cell Lymphopenia Detected by Newborn Screening: A Cohort Study

TL;DR

This study examines the outcomes of Swiss infants with non-SCID T-cell lymphopenia identified through newborn screening, finding that some recover while others require long-term care.

Contribution

The study provides new insights into the natural history and management of non-SCID T-cell lymphopenia in newborns.

Findings

About half of the infants had a confirmed genetic diagnosis of inborn errors of immunity.

Infants without a genetic diagnosis showed faster T-cell recovery and could discontinue prophylaxis by 6 months.

Low initial CD4+ T-cell counts were linked to poor T-cell recovery and ongoing prophylactic care.

Abstract

Newborn screening (NBS) by quantification of T-cell receptor excision circles (TREC) identifies a considerable number of infants with T-cell lymphopenia (TCL) other than severe combined immunodeficiency (SCID). While some of these children have well-defined inborn errors of immunity (IEI), many lack a clear genetic diagnosis, complicating their management and causing prognostic uncertainty.

To characterize the natural history of non-SCID TCL detected through NBS in Swiss infants between 2019 and 2023.

Clinical, genetic and laboratory data from all non-SCID TCL cases were extracted from the national NBS registry and analyzed.

Out of 435 985 screened infants, 42 patients were identified with non-SCID, non-congenital athymia TCL, without an obvious secondary cause. A clear genetic diagnosis of IEI was established in 20 (48%) patients. Infants with confirmed IEI had significantly lower total T-cell, CD4 + T-cell and recent thymic emigrant (RTE) counts on initial lymphocyte phenotyping. In contrast, those with an unclear genetic diagnosis despite full investigations demonstrated faster normalization of total T-cell counts (hazard ratio 5.2, 95% CI 1.9 to 14.5, p = 0.001). All infants with initial CD4 + T-cell < 0.3 × 109/L showed minimal recovery of T-cell counts and remained on long-term prophylactic measures. All infants with an unclear genetic diagnosis despite investigations were able to discontinue prophylaxis at median age 6 months without experiencing opportunistic or severe infections.

Infants with non-SCID TCL identified by NBS represent a heterogenous group, ranging from severe, persistent TCL to mild, transient lymphopenia. Management should be tailored based on individual immunological and genetic profiles.

The online version contains supplementary material available at 10.1007/s10875-025-01945-4.

Initial T-cell counts and genetic diagnosis are key prognostic factors in newborn screening-identified non-SCID T-cell lymphopenia. Patients with milder lymphopenia and no genetic diagnosis are more likely to experience T-cell recovery.

The online version contains supplementary material available at 10.1007/s10875-025-01945-4.

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