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Atypical lymphoid cells circulating in blood in COVID-19 infection: morphology, immunophenotype and prognosis value
  1. Anna Merino1,2,
  2. Alexandru Vlagea3,
  3. Angel Molina1,2,
  4. Natalia Egri3,
  5. Javier Laguna1,2,
  6. Kevin Barrera4,
  7. Laura Boldú1,2,
  8. Andrea Acevedo4,
  9. Mar Díaz-Pavón3,
  10. Francesc Sibina3,
  11. Francisca Bascón1,
  12. Oriol Sibila5,
  13. Manel Juan3,
  14. José Rodellar4
  1. 1 Core Laboratory, Biomedical Diagnostic Center, Hospital Clinic de Barcelona, Barcelona, Spain
  2. 2 Biochemistry and Molecular Genetics, Biomedical Diagnostic Center, Hospital Clinic de Barcelona, Barcelona, Spain
  3. 3 Department of Immunology, Biomedical Diagnostic Center, Hospital Clinic de Barcelona, Barcelona, Spain
  4. 4 Department of Mathematics, Universitat Politecnica de Catalunya, Barcelona, Spain
  5. 5 Institut Clínic del tórax, Hospital Clinic de Barcelona, Barcelona, Spain
  1. Correspondence to Anna Merino, Department of Biochemistry and Molecular Genetics; Core Laboratory; Biomedical Diagnostic Center, Hospital Clinic de Barcelona, Barcelona, Spain; amerino{at}


Aims Atypical lymphocytes circulating in blood have been reported in COVID-19 patients. This study aims to (1) analyse if patients with reactive lymphocytes (COVID-19 RL) show clinical or biological characteristics related to outcome; (2) develop an automatic system to recognise them in an objective way and (3) study their immunophenotype.

Methods Clinical and laboratory findings in 36 COVID-19 patients were compared between those showing COVID-19 RL in blood (18) and those without (18). Blood samples were analysed in Advia2120i and stained with May Grünwald-Giemsa. Digital images were acquired in CellaVisionDM96. Convolutional neural networks (CNNs) were used to accurately recognise COVID-19 RL. Immunophenotypic study was performed throughflow cytometry.

Results Neutrophils, D-dimer, procalcitonin, glomerular filtration rate and total protein values were higher in patients without COVID-19 RL (p<0.05) and four of these patients died. Haemoglobin and lymphocyte counts were higher (p<0.02) and no patients died in the group showing COVID-19 RL. COVID-19 RL showed a distinct deep blue cytoplasm with nucleus mostly in eccentric position. Through two sequential CNNs, they were automatically distinguished from normal lymphocytes and classical RL with sensitivity, specificity and overall accuracy values of 90.5%, 99.4% and 98.7%, respectively. Immunophenotypic analysis revealed COVID-19 RL are mostly activated effector memory CD4 and CD8 T cells.

Conclusion We found that COVID-19 RL are related to a better evolution and prognosis. They can be detected by morphology in the smear review, being the computerised approach proposed useful to enhance a more objective recognition. Their presence suggests an abundant production of virus-specific T cells, thus explaining the better outcome of patients showing these cells circulating in blood.

  • morphological and microscopic findings
  • lymphocytes
  • immunophenotyping
  • viruses

Data availability statement

All data relevant to the study are included in the article.

This article is made freely available for personal use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

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Data availability statement

All data relevant to the study are included in the article.

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  • AM and AV are joint first authors.

  • Handling editor Mary Frances McMullin.

  • Correction notice This article has been corrected since it was published Online First. Details of first authorship has been added.

  • Funding This work is part of a research project funded by the Ministry of Science and Innovation of Spain, with reference PID2019-104087RB-I00.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.