Lymphopenia in the COVID-19 Patient: More than a Predictor of Poor Prognosis?

  • Julián Rondón-Carvajal Internal Medicine Specialist, Internal Medicine Department, Pontificia Universidad Javeriana, Bogotá DC, Colombia. https://orcid.org/0000-0001-9804-8990
  • Vaneza Ávila-Rodríguez Internal Medicine Department, Pontificia Universidad Javeriana, Bogotá DC, Colombia.cia Universidad Javeriana https://orcid.org/0000-0002-0050-6883
  • María José López-Mora Internal Medicine Specialist, Infectious Diseases Specialist, Professor Adjunt, Internal Medicine Department, Pontificia Universidad Javeriana, Bogotá DC, Colombia. https://orcid.org/0000-0002-9955-8973
Keywords: Coronavirus Disease, SARS-Cov-2, Lymphopenia, Biomarker, Prognosis

Abstract

The COVID-19 pandemic, caused by the infectious agent SARS-CoV-2, has claimed the life of thousands of people around the world following its rapid expansion from Wuhan, China, in early January 2020. Since then, multiple groups worldwide have attempted to describe predictive models for adverse clinical outcomes in patients affected by this disease. Within laboratory findings, the first Chinese cohorts described an inverse relationship between the absolute lymphocyte count and disease severity, and about 80% of severe patients exhibited lymphopenia. However, there are discrepancies regarding the predictive value of this clinical manifestation, as well as in the pathophysiological mechanisms involved. Here, we review current evidence regarding lymphopenia in patients with COVID-19, and the potential utility of this hematological finding as a disease biomarker.

How to cite this article:
Rondón-Carvajal J, Ãvila-Rodríguez V, López-Mora M. Lymphopenia in the COVID-19 Patient: More than a Predictor of Poor Prognosis? J Commun Dis 2021; 53(1): 96-103.

DOI: https://doi.org/10.24321/0019.5138.202116

References

Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez- Ocampo E et al. Clinical, laboratory and imaging features

of COVID-19: A systematic review and meta-analysis. Travel Medicine and Infectious Disease 2020; 34.

Cao C, Chen M, Li Y et al. Clinical features and predictors for patients with severe SARS-CoV-2 pneumonia: a

retrospective multicenter cohort study. SSRN Electronic Journal 2020.

Di Gennaro F, Pizzol D, Marotta C et al. Coronavirus diseases (COVID-19) current status and future

perspectives: A narrative review. International Journal of Environmental Research and Public Health 2020;

(8).

Wynants L, Van Calster B, Bonten MMJ et al. Prediction models for diagnosis and prognosis of covid-19

infection: systematic review and critical appraisal. The BMJ 2020; 369.

Lovato A, de Filippis C. Clinical Presentation of COVID-19: a systematic review focusing on upper

airway symptoms. Ear, Nose and Throat Journal 2020.

Liu J, Li S, Liu J et al. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the

peripheral blood of SARS-CoV-2 infected patients. EBioMedicine 2020: 55.

Giamarellos-Bourboulis EJ, Netea MG, Rovina N et al. Complex Immune Dysregulation in COVID-19 patients

with severe respiratory failure. Cell Host and Microbe 2020; 27(6): 992-1000.e3.

Zhu J, Ji P, Pang J et al. Clinical characteristics of 3,062 COVID-19 patients: a meta-analysis. Journal of MedicalVirology 2020: 0-1.

Gandhi RT, Lynch JB, del Rio C. Mild or moderate Covid-19. New England Journal of Medicine 2020: 1-9.

Berlin DA, Gulick, RM, Martinez FJ. Severe Covid-19. New England Journal of Medicine 2020: 1-10.

Lu R, Zhao X, Li J et al. Genomic characterization and epidemiology of 2019 novel coronavirus: implications

for virus origins and receptor binding. The Lancet 2020; 395(10224): 565-74.

Zhou P, Yang X-L, Wang XG et al. A pneumonia outbreak associated with a new coronavirus of probable bat

origin. Nature 2020; 579(7798): 270-273.

Hoffmann M, Kleine-Weber H, Schroeder S et al. SARSCoV-2 cell entry depends on ACE2 and TMPRSS2 and

is blocked by a clinically proven protease inhibitor. Cell 2020; 181(2): 271-80.e8.

Zhang L, Sun W, Chen L et al. Clinical features and a simple model for predicting the mortality of coronavirus

disease 2019 patients on admission. SSRN Electronic Journal 2020.

Zhang G, Hu C, Luo L et al. Clinical features and shortterm outcomes of 221 patients with COVID-19 in

Wuhan, China. Journal of Clinical Virology 2020; 127:104364.

Chen G, Wu D, Guo W et al. Clinical and immunological features of severe and moderate coronavirus disease

Journal of Clinical Investigation 2020; 130(5): 2620-9.

Diao B, Wang C, Tan Y et al. Reduction and functional exhaustion of T cells in patients with coronavirus

disease 2019 (COVID-19). Frontiers in Immunology 2020; 11: 1-7.

Ziegler CGK, Allon SJ, Nyquist SK et al. SARS-CoV-2 receptor ACE2 is an interferon- stimulated gene in

human airway epithelial cells and is detected in specific cell subsets across tissues. Cell, 2020.

Zhao Y, Zhao Z, Wang Y et al. Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan

-nCov. BioRxiv 2020.

Zhang H, Kang Z, Gong H, et al. The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes. BioRxiv 2020.

Xiong Y, Liu Y, Cao L et al. Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood

mononuclear cells in COVID-19 patients. Emerging Microbes and Infections 2020; 9(1): 761-770.

Xu H, Zhong L, Deng J et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral

mucosa. International Journal of Oral Science 2020; 12(1): 1-5.

Gu J, Gong E, Zhang B et al. Multiple organ infection and the pathogenesis of SARS. Journal of Experimental

Medicine 2005; 202(3): 415-424.

Chu H, Zhou J, Wong BHY et al. Middle East Respiratory Syndrome Coronavirus Efficiently Infects Human

Primary T Lymphocytes and Activates the Extrinsic and Intrinsic Apoptosis Pathways. Journal of Infectious

Diseases 2016; 213(6): 904-14.

Zhou X, Jiang W, Liu Z et al. Virus infection and death receptor-mediated apoptosis. Viruses 2017; 9(11).

Doitsh G, Galloway NLKK, Geng X et al. Pyroptosis drives CD4 T-cell depletion. Nature 2014; 505(7484): 509-514.

Wang Y, Liu L. The membrane protein of severe acute respiratory syndrome coronavirus functions as a novel

cytosolic pathogen-associated molecular pattern to promote beta interferon induction via a toll-likereceptor-

related TRAF3-independent mechanism. MBio 2016; 7(1): 1-14.

Kulkarni R, Behboudi S, Sharif S. Insights into the role of Toll-like receptors in modulation of T cell responses.

Cell and Tissue Research 2011; 343(1): 141-152.

Henderson LA, Canna SW, Schulert GS et al. On the alert for cytokine storm: Immunopathology in COVID-19.

Arthritis and Rheumatology 2020; 0(0): 1-5.

D’Ambrosio D, Mariani M, Panina-Bordignon P et al. Chemokines and their receptors guiding T lymphocyte

recruitment in lung inflammation. American Journal of Respiratory and Critical Care Medicine 2001; 164(7):

-75.

Mehta A, Gracias DT, Croft M. TNF Activity and T cells. Physiology & Behavior 2016; 176(1): 100-6.

Falschlehner C, Schaefer U, Walczak H. Following TRAIL’s path in the immune system. Immunology 2009; 127(2): 145-54.

Xu Z, Shi L, Wang Y et al. Pathological findings of COVID-19 associated with acute respiratory distress

syndrome. Journal of the Formosan Medical Association 2020.

Kuba K, Imai Y, Rao S et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirusinduced lung injury. Nature Medicine 2005; 11(8): 875-879.

Crowley SD, Rudemiller NP. Immunologic effects of the renin-angiotensin system. Journal of the American

Society of Nephrology 2017; 28(5): 1350-1.

Liu Z, Huang XR, Chen HY et al. Loss of angiotensinconverting enzyme 2 enhances TGF-Î’/Smad-mediated

renal fibrosis and NF-κB-driven renal inflammation in a mouse model of obstructive nephropathy. Laboratory

Investigation 2012; 92(5): 650-661.

Thomas MC, Pickering RJ, Tsorotes D et al. Genetic Ace2 deficiency accentuates vascular inflammation

and atherosclerosis in the ApoE knockout mouse. Circulation Research 2010; 107(7): 888-897.

Imai Y, Kuba K, Rao S et al. Angiotensin-convertingenzyme 2 protects from severe acute lung failure.

Nature 2005; 436(7047): 112-116.

Green DR, Droin N, Pinkoski M. Activation-induced cell death in T cells. Immunological Reviews 2003;

: 70-81.

Ju S-T, Panka, DJ, Cui H et al. Fas (CD95)/FasL interactions required for programmed cell death after T-cell

activation. Nature 1995; 373(6513): 444-448.

Lissy NA, Davis PK, Irwin M et al. A common E2F-1 and p73 pathway mediates cell death induced by TCR

activation. Nature 2000; 407(6804): 642-625.

Huang I, Pranata R. Lymphopenia in severe coronavirus disease-2019 (COVID-19): systematic review and metaanalysis. Journal of Intensive Care 2020; 8(1): 1-10.

Zhou F, Yu T, Du R et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in

Wuhan, China: a retrospective cohort study. The Lancet 2020; 395(10229): 1054-1062.

Yang X, Yu Y, Xu J et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia

in Wuhan, China: a single-centered, retrospective, observational study. The Lancet Respiratory Medicine

; 8(5): 475-481.

Wang D, Hu B, Hu C et al. Clinical Characteristics of 138 Hospitalized Patients with 2019 Novel Coronavirus-

Infected Pneumonia in Wuhan, China. Journal of the American Medical Association 2020; 323(11): 1061-9.

Dong Ji, Zhang D, Xu J et al. Prediction for progression risk in patients with COVID-19 pneumonia: the CALL

score. Frontiers in Plant Sci 2012; 0954162(478): 1-4.

Chen J, Qi T, Liu L, et al. Clinical progression of patients with COVID-19 in Shanghai, China. Journal of Infection

; 80(5): e1-6.

Zhao Q, Meng M, Kumar R et al. Lymphopenia is associated with severe coronavirus disease 2019

(COVID-19) infections: A systemic review and metaanalysis. International Journal of Infectious Diseases

; 96: 131-5.

Huang W, Berube J, McNamara M et al. Lymphocyte subset counts in COVIDâ€19 patients: a metaâ€analysis.

Cytometry Part A, 2020.

Published
2021-03-31