key: cord-337127-pc9hez28
authors: García-Salido, Alberto; García-Teresa, María Ángeles; Leoz-Gordillo, Inés; Martínez de Azagra-Garde, Amelia; Cabrero-Hernández, Marta; Ramirez-Orellana, Manuel
title: Innate cell response in severe SARS-CoV-2 infection in children: expression analysis of CD64, CD18 and CD11a
date: 2020-09-30
journal: Med Intensiva
DOI: 10.1016/j.medin.2020.09.003
sha: 
doc_id: 337127
cord_uid: pc9hez28

nan

In January 2020, a new coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was described in Wuhan, China. The virus, which produces coronavirus disease 2019 (COVID-19), has been declared a global health emergency and pandemic by the World Health Organization. Spain is one of the more severely affected countries 1 .

The immune response to SARS-CoV-2 infection appears to be a critical factor in the development and prognosis of COVID-19 patients 2 . In children, severe forms of the disease like the pediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 appears to be related with some immune dysregulation 3 . So, increase knowledge about the innate cellular immune response to SARS-CoV-2 is of great interest. To this, the study by flow cytometry (FC) may provide critical data and further understanding of this novel disease 3 .

In this paper we study three molecules which are part of the innate cellular response to infection: CD64, CD18 and CD11a. The CD64 is a type I high-affinity receptor for the Fc fraction of the immunoglobulin G, located on the surface of monocytes, macrophages, dendritic cells, and neutrophils. Increased CD64 density on the cell surface is directly related to the intensity of stimulation received by inflammatory cytokines 4 . Additionally, CD18, also known as integrin β2, participates in leukocyte adhesion and signalling. CD11a associates with CD18 to form the lymphocyte function-associated antigen 1, or LFA-1. Expressed on leukocytes, this T cell integrin plays a central role in leukocyte cell-cell interactions and lymphocyte stimulation.

We study in this report three children with severe SARS-CoV-2 infection. Also, we compare them with a healthy control, a case of severe influenza infection and a case of Neisseria meningitidis sepsis. All cases included had SARS-CoV-2 infection confirmed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) on nasopharyngeal swab samples. The cases trajectories, complementary tests, and therapy approaches are summarized in Table 1 . The children were studied after informed consent was obtained. One 0,5 ml sample of peripheral blood was extracted on admission to the pediatric intensive care unit (PICU). The samples obtained were collected in sterile EDTA at room temperature or refrigerated at 4°C, after which they were used for CD45+ cell-marker studies and analyzed by FC within 24 hours. Cell surface expression of CD64, CD18, and CD11a was measured by BD FACS Canto II flow cytometer 7 . Our group carried out CD64 expression studies in acute bronchiolitis and severe viral and bacterial infections 5 . As can be seen in Figure 1 children with SARS-CoV-2 show levels of CD64 expression that are higher than in previous published reports of bacterial or viral infections or autoinflammatory diseases 5 . Regarding the CD11a and CD18 complex or LFA-1, it is known that plays a key role in migration. Through these, leukocytes are mobilized from the bloodstream into tissues. One of the main findings in COVID-19 patients is the presence of lymphopenia 8 . It can be seen in our cases. This may be linked to the migration of CD8+ lymphocytes to the infected tissues. As seen in Figure 1 , the CD11a upregulation in CD8+ is clear and could be linked to this process. The LFA-1 is also involved in the process of cytotoxic T cell-mediated killing as well as antibody-mediated killing by granulocytes and monocytes 9 . The upregulation of both leukocyte populations is also observed in our cases (Figure 1 ).

The nonantimicrobial COVID-19 therapies proposed to date are intended to downregulate the immune system. The use of immunoregulatory therapies in infectious context should be based on a risk-benefit analysis. In SARS-CoV-2 infections the cytokine storm theory coupled with analytical data are used to justify these approaches 2,10 . Our FC results introduce a new approach to analyzing the immune response to this new virus. We confirm the activation of the innate cellular response. Besides we observed that is different and maybe higher than in other infections. The description of this immune status using FC could individualize the diagnosis and optimize the therapies applied.

In summary, we describe the immunophenotype of three children with severe SARS-CoV-2 infection. We observed significant upregulation of CD64, CD18, and CD11a expression on leukocytes. Compare to previous papers and to other types of infection it appears to be higher.

This could inform about immune dysregulation triggered by SARS-CoV-2. The use of FC may lead to a better understanding of this response and optimize the therapies applies. Prospective studies with a higher number of cases should be conducted to confirm this observation. lymphocytes is also upregulated compared to previous data. 

Screening and Severity of Coronavirus Disease 2019 (COVID-19) in Children in

Clinical infectious diseases : an official publication of the Infectious Diseases Society of

Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection

Accuracy of neutrophil CD64 expression in diagnosing infection in patients with autoimmune diseases: a meta-analysis

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Increased Complement Receptor-3 levels in monocytes and granulocytes distinguish COVID-19 patients with pneumonia from those with mild symptoms

Neutrophil CD64 expression as a longitudinal biomarker for severe disease and acute infection in critically ill patients

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) distinctly regulate neutrophil extravasation through hotspots I and II

Reducing mortality from 2019-nCoV: host-directed therapies should be an option