Neutrophilia, lymphopenia and myeloid dysfunction: a living review of the quantitative changes to innate and adaptive immune cells which define COVID-19 pathology

Abstract

Destabilization of balanced immune cell numbers and frequencies is a common feature of viral infections. This occurs due to, and further enhances, viral immune evasion and survival. Since the discovery of the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), which manifests in coronavirus disease 2019 (COVID-19), a great number of studies have described the association between this virus and pathologically increased or decreased immune cell counts. In this review, we consider the absolute and relative changes to innate and adaptive immune cell numbers, in COVID-19. In severe disease particularly, neutrophils are increased, which can lead to inflammation and tissue damage. Dysregulation of other granulocytes, basophils and eosinophils represents an unusual COVID-19 phenomenon. Contrastingly, the impact on the different types of monocytes leans more strongly to an altered phenotype, e.g. HLA-DR expression, rather than numerical changes. However, it is the adaptive immune response that bears the most profound impact of SARS-CoV-2 infection. T cell lymphopenia correlates with increased risk of intensive care unit admission and death; therefore, this parameter is particularly important for clinical decision-making. Mild and severe diseases differ in the rate of immune cell counts returning to normal levels post disease. Tracking the recovery trajectories of various immune cell counts may also have implications for long-term COVID-19 monitoring. This review represents a snapshot of our current knowledge, showing that much has been achieved in a short period of time. Alterations in counts of distinct immune cells represent an accessible metric to inform patient care decisions or predict disease outcomes.

Keywords: B cells; SARS-CoV-2; cell counts; clinical; lymphocytes; lymphopenia; monocytes; neutrophilia; neutrophils; prognosis; recovery; severity.

Figure 1:

Changes in innate and adaptive immune cell numbers in severe and mild/recovered COVID-19. (a) Altered immune cells in the peripheral blood. Top left, severe disease: neutrophils, inflammatory intermediate monocytes (Mµ) and the NLR are increased in severe COVID-19. Increased plasmablasts have been reported in both severe and mild disease. Bottom left: Many cells of the innate and adaptive immune system are depleted in severe COVID-19: non-classical monocytes (M2), pDC and basophils. Lymphopenia is widely reported in COVID-19, largely due to depletion of T cells; reductions in CD4⁺ and/or CD8⁺ T cells (CD4, CD8) have been reported and innate lymphocytes and unconventional T cells are also decreased: NK cells, NKT cells, γδ T cells and MAIT cells. Centre, unchanged: some studies suggest eosinophils are unchanged in COVID-19 disease but may increase in the course of recovery. Classical monocytes (M1) are largely unchanged in COVID-19, however, changes in expression of certain phenotypic proteins are associated with severe disease. Top right, mild COVID-19/recovery: Increasing basophils and eosinophils are also associated with recovery or mild COVID-19, along with higher numbers of cDCs, NK cells and T cells which are indicative of an effective anti-viral immune response contributing to a milder form of COVID-19 and/or recovery. Bottom left: decreased neutrophils and recovery of lymphocyte numbers, resulting in a reduction of the NLR, are associated with recovery from COVID-19. (b) Altered immune cells in the lungs. Top left: Severe disease is largely characterized by inflammation in the lungs in association with increased neutrophils, M1 and Mµ monocytes. NK cells, cDCs and M2 monocytes are also increased, whereas basophils are decreased. Despite decreases in the blood, pDCs are rarely detected in the lung in severe COVID-19. In mild disease or recovery, neutrophils return to normal ranges. Increased T cells, in particular CD8⁺ T cells, occur as part of the recovery from COVID-19, although some studies have reported delayed recovery trajectories based on disease severity. DCs also increase with recovery. This figure was created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com.