Immunomodulating antitumor therapy causing false-positive results of newborn screening for a primary immunodeficiency

Abstract

Introduction. Extended newborn screening will be enrolled in Russia in 2023 including screening for primary immunodeficiencies. The screening will elaborate excision recombinant rings (TREC/KREC) determination. Noteworthy, the TREC/KREC levels may be reduced to critical values not only due to the primary immunodeficiencies of genetic origin but also due to secondary conditions caused by external reasons.

Aim – analysis of the newborn’ TREC/KREC levels reduced to critical values cases revealed in course of an extended newborn screening pilot study. Search for the reasons of the reducing besides the primary immunodeficiencies.

Material and methods. The TREC/KREC levels were determined by real time PCR. The newborn dried blood samples were used obtained during newborn screening routine.

Results. Over 10 000 newborns underwent the screening form March 2021 to September 2022. No cases of true primary immunodeficiencies were observed. Three newborns were revealed showing subthreshold KREC levels. Mothers of all three newborns had undergone chemotherapy using rituximab. Rituximab is suspected to penetrate the placental barrier causing the fetal B cells number reduction. Cases similar to presented had been described. The newborns revealed in the present study are presumed to develop the B cell number reduction by the same mechanism.

Conclusion. Patients showing subthreshold KREC levels should be observed by a pediatrician and immunologist as well as comprehensive examination for serum immunoglobulins and WBC subpopulations. The patients’ TREC/KREC levels must be controlled dynamically.

Keywords:primary immunodeficiency; TREC; KREC; false positive result; antitumor therapy; newborn screening; rituximab

For citation: Vasiliev G.S., Petrova T.V., Nikiforova A.I., Krasheninnikova R.V., Vtorushina V.V., Inviyaeva E.V., Bystritskiy A.A., Donnikov A.E., Balashova E.N., Krechetova L.V., Karetnikova N.A., Trofimov D.Yu. Immunomodulating antitumor therapy causing false-positive results of newborn screening for a primary immunodeficiency. Immunologiya. 2023; 44 (1): 83–92. DOI: https://doi.org/10.33029/0206-4952-2023-44-1-83-92 (in Russian)

Funding. The study was carried out within the framework of State Assignment No. 121092400060-5.

Conflict of interests. The authors declare no conflict of interests.

Authors’ contribution. Concept and design – Donnikov A.E., Krechetova L.V., Karetnikova N.A., Trofimov D.Yu., material collection and processing – Vasiliev G.S., Petrova T.V., Nikiforova A.I., Krasheninnikova R.V., Vtorushina V.V., Inviyaeva E.V., statistical evaluation – Donnikov A.E., Karetnikova N.A., writing the text – Vasiliev G.S., Petrova T.V., Vtorushina V.V., Bystritskiy A.A., Donnikov A.E., Krechetova L.V., Karetnikova N.A., editing – Bystritskiy A.A., Donnikov A.E., Karetnikova N.A., Trofimov D.Yu., finalizing – Trofimov D.Yu., integrity management – Bystritskiy A.A., Trofimov D.Yu.

References

1. Order of the Ministry of Health of the Russian Federation No. 274n dated April 21, 2022 «On approval of the Procedure for providing medical care to patients with congenital and (or) hereditary diseases». (in Russian)

2. Donetskova A.D., Yarilin A.A. T-cell receptor excision circles and their importance in clinical practice. Immunologiya. 2013; 34 (4): 223–32. (in Russian)

3. Deryabina S.S., Tuzankina I.A., Vlasova E.V., Bolkov M.A., Shershnev V.N. Neonatal screening for severe combined immune deficiency in Russia: glorious future or tomorrow’s reality? Voprosy sovremennoy pediatrii. 2017; 16 (1): 59–66. DOI: https://doi.org/10.15690/vsp.v16i1.1696 (in Russian)

4. Khachirova L.S., Barycheva L.Yu., Kubanova L.T., Gordukova M.A., Golubeva M.V., Karaulov A.V. Diagnostic significance of excision rings of T- and B-cell receptor gene rearrangement for the diagnosis of immune disorders in newborns. Meditsinskiy vestnik Severnogo Kavkaza. 2019; 14 (4): 631–5. DOI: https://doi.org/10.14300/mnnc.2019.14157 (in Russian)

5. Gordukova M.A., Korsunsky I.A., Chursinova Yu.V., Byakhova M.M., Oskorbin I.P., Prodeus A.P., Filipenko M.L. Determining reference ranges for TREC and KREC assays in immune deficiency screening of newborns in Russian Federation. Meditsinskaya immunologiya. 2019; 21 (3): 527–38. DOI: https://doi.org/10.15789/1563-0625-2019-3-527-538 (in Russian)

6. Puck J.M.; SCID Newborn Screening Working Group. Population-based newborn screening for severe combined immunodeficiency: steps toward implementation. J. Allergy Clin. Immunol. 2007; 120 (4): 760–8. DOI: https://doi.org/10.1016/j.jaci.2007.08.043

7. Levy H.L. Robert Guthrie and the Trials and Tribulations of Newborn Screening. Int. J. Neonatal Screen. 2021; 7 (1): 5. DOI: https://doi.org/10.3390/ijns7010005

8. Ceyhan-Birsoy O., Murry J.B., Machini K., et al. Interpretation of genomic sequencing results in healthy and ill newborns: Results from the BabySeq Project. Am. J. Hum. Genet. 2019; 104 (1): 76–93. DOI: https://doi.org/10.1016/j.ajhg.2018.11.016

9. Roman T.S., Crowley S.B., Roche M.I., et al. Genomic sequencing for newborn screening: Results of the NC NEXUS Project. Am. J. Hum. Genet. 2020; 107 (4): 596–611. DOI: https://doi.org/10.1016/j.ajhg.2020.08.001

10. Wang H., Yang Y., Zhou L., et al. NeoSeq: a new method of genomic sequencing for newborn screening. Orphanet J. Rare Dis 2021; 16 (1): 481. DOI: https://doi.org/10.1186/s13023-021-02116-5

11. Woerner A.C., Gallagher R.C., Vockley J., Adhikari A.N. The use of whole genome and exome sequencing for newborn screening: challenges and opportunities for population health. Front. Pediatr. 2021; 9: 663752. DOI: https://doi.org/10.3389/fped.2021.663752

12. Chan K., Puck J.M. Development of population-based newborn screening for severe combined immunodeficiency. J. Allergy Clin. Immunol. 2005; 115 (2): 391–8. DOI: https://doi.org/10.1016/j.jaci.2004.10.012

13. Barbaro M., Ohlsson A., Borte S., et al. Newborn screening for severe primary immunodeficiency diseases in Sweden – a 2-year pilot TREC and KREC screening study. J. Clin. Immunol. 2017; 37 (1): 51–60. DOI: https://doi.org/10.1007/s10875-016-0347-5

14. Hazenberg M.D., Verschuren M.C., Hamann D., et al. T cell receptor excision circles as markers for recent thymic emigrants: basic aspects, technical approach, and guidelines for interpretation. J. Mol. Med 2001; 79 (11): 631–40. DOI: https://doi.org/10.1007/s001090100271

15. Trück J., Prader S., Natalucci G., et al. Swiss newborn screening for severe T and B cell deficiency with a combined TREC/KREC

assay – management recommendations. Swiss Med. Wkly. 2020; 150: w20254. DOI:
https://doi.org/10.4414/smw.2020.20254 PMID: 32579701.

16. Cheremokhin D.A., Shinwari K., Deryabina S.S., et al. Analysis of the TREC and KREC levels in the dried blood spots of healthy newborns with different gestational ages and weights. Acta Naturae. 2022; 14 (1): 101–8. DOI: https://doi.org/10.32607/actanaturae.11501

17. Zetterström R.H.; Barbaro M.; Ohlsson A., et al. Newborn screening for primary immune deficiencies with a TREC/KREC/ACTB triplex assay – a three-year pilot study in Sweden. Int. J. Neonatal Screen. 2017; 3 (2): 11. DOI: https://doi.org/10.3390/ijns3020011

18. Bosch X., Ramos-Casals M., Khamashta M.A. (eds). Drugs Targeting B-Cells in Autoimmune Diseases. Springer Science & Business Media, 2013: 1–4.

19. Ochfeld E., Hans V., Marin W., et al. Coding joint: kappa-deleting recombination excision circle ratio and B cell activating factor level: predicting juvenile dermatomyositis rituximab response, a proof-of-concept study. BMC Rheumatol. 2022; 6 (1): 36. DOI: https://doi.org/10.1186/s41927-022-00265-z

20. Naeim F., Rao P.N., Song S.X., Phan R.T. Chapter 2 – Principles of immunophenotyping. In: Atlas of Hematopathology: Morphology, Immunophenotype, Cytogenetics and Molecular Approaches. 2nd ed. Academic Press, 2018: 29–56.

21. Yong P.F.K., Dziadzio M., Grimbacher B. Defects in B cell Survival and Activation. In: M.J.H. Ratcliffe (ed.). Encyclopedia of Immunobiology. Academic Press, 2016L: 466–78.

22. Krüger R., Borte S., von Weizsäcker K., et al. Positive Kappa-Deleting Recombination Excision Circles (KREC) newborn screening in a neonate with intrauterine exposure to rituximab. Scand. J. Immunol. 2018; 87 (1): 54–6. DOI: https://doi.org/10.1111/sji.12627

23. Mandal P.K., Dolai T.K., Bagchi B., et al. B cell suppression in newborn following treatment of pregnant diffuse large B-cell lymphoma patient with rituximab containing regimen. Indian J. Pediatr. 2014; 81 (10): 1092–4. DOI: https://doi.org/10.1007/s12098-013-1336-9

24. Mangasarova Ya.K., Magomedova A.U., Nesterova E.S., et al. Treatment of Aggressive Non-Hodgkin’s Lymphomas in Pregnancy. Clinical oncohematology. 2020; 13(3): 316–21. DOI: https://doi.org/10.21320/2500-2139-2020-13-3-316-321 (In Russian)

25. Routes J.M., Grossman W.J., Verbsky J., et al. Statewide newborn screening for severe T-cell lymphopenia. JAMA. 2009; 302 (22): 2465–70. DOI: https://doi.org/10.1001/jama.2009.1806

All articles in our journal are distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0 license)


JOURNALS of «GEOTAR-Media»