Lymphopenia and Cytokine Storm are Common in COVID-19 and Act as Markers of Disease Severity

Written by: Parker Davis
Edited by: Jina Zhou and Esther Melamed
4/7/2020

The host immune response to SARS-CoV-2 infection has been documented and characterized to some extent over the course of the last few months. Still in the early stages of understanding, there is some contention about the exact mechanism of the coronavirus infection. The earliest retrospective studies characterized a cytokine storm of pro-inflammatory mediators, suggesting a superantigenic component of the novel coronavirus. More recent papers, however, have demonstrated a more nuanced view of the disease progression, even noting a dampening effect on some subsets of T cells and other innate cells (Huang, et al., 2020). The particular mechanism by which SARS-CoV-2 mediates this dampening effect is not yet understood, though it may be the case that it utilizes a pathway similar to that of previous coronaviruses (Prompetchara, et al., 2020).

Despite the uncertainty of the host response, impressive progress todate has been made toward developing a vaccine and identifying clinical manifestations that could potentially serve as biomarkers of disease progression and severity. Several studies have looked at differences between ICU and non-ICU patient cases and scientists have begun to tease apart the immunological profile at different stages of infection (Liu, et al., 2020). Similarly, immune responses to potential therapies have been characterized, and the knowledge gleaned will be useful in directing care for infected patients, especially those with underlying conditions that may be affected by the host response to infection. Much more information will become available as more and more researchers turn their attention to stemming the spread of the COVID-19 disease.

Adaptive Immunity

Convalescent plasma trials have shown promise as potential therapy for SARS-CoV-2 infection, both in vitro and in vivo. A preliminary study out of Shenzhen, China treated 5 “critically ill” patients presenting with COVID-19 and acute respiratory distress syndrome (ARDS) with convalescent plasma (no controls), showing marked reduction in organ failure (SOFA scores), harmful proinflammatory cytokine hypersecretion, and pulmonary lesions, with increased specific antibody titers, indicating successful transfusion and the safety of plasma from previously infected patients. ARDS also resolved in 4 out of the 5 patients, likely as a result of cleared infection. Future testing against control cases will be necessary before plasma therapy can be considered a viable treatment option. (Shen, et al., 2020).

So far, five CTL and eight B cell epitopes have been identified as potential targets for vaccines. The epitopes exhibit non-covalent interactions with MHC I/II molecules, demonstrating their efficacy as presentable antigens by professional antigen-presenting cells (APCs: B cells, dendritic cells, macrophages). Artificial neural network software was used to identify and score potential epitopes within the full amino acid sequence of the surface glycoprotein of SARS-CoV-2. All the epitopes identified but one (a CTL epitope) were found to be at least partially unique to SARS-CoV-2. Of note, further characterization will be required to determine whether mapping of these epitopes is complete given the transient covalent attachment of glycans to some epitopes in question. The immediate implementation of these epitopes into vaccines is important due to the high rates of mutation seen in typical RNA viruses. (Baruah, Bose, 2020).

Th1 and Th17 cells have been implicated in immune response in various ways, though the connections are not strong yet. Importantly, chloroquine – and hydroxy-chloroquine to a lesser extent – has been shown to induce IL-23 expression in monocyte-derived cells in the skin, stimulating secretion of IL-17 subsets by CD4+ T cells. COVID-19 therapies targeting these pathways will be very important in patients with multiple sclerosis and other autoimmune conditions characterized by Th1/Th17 responses. (Prompetchara, et al., 2020).

A study (n = 16) from the Sichuan Province of China characterizing the adaptive immune response to COVID-19 has shown that several clusters of CD8+ and dendritic cells are increased, and that B cell and helper T cell clusters seem to be downregulated. Specifically, interferon-producing plasmacytoid dendritic cells are upregulated in the response, and the interferon-MAPK pathway has been suggested as one of the primary response pathways in host cells, though the details are still unclear. If this is the case, supplementation with exogenous interferon may further stimulate and enhance the immune response to SARS-CoV-2 infection. The study also performed a preliminary profile of TCR and BCR expression in vivo and demonstrated that severe cases of COVID-19 seem to be related to strong autoimmune responses, potentially indicating some cross-reactivity between human and viral antigens. (Huang, et al., 2020).

Innate Immunity

In general, infected patients present with lymphopenia and a cytokine storm of proinflammatory cytokines – IL-6, TNFa, IL-1B, C-reactive protein – suggesting a super antigen component of SARS-CoV-2. There has also been a significant difference documented between severe – admitted to the ICU – and non-severe cases in the levels of these cytokines. The cytokine response may therefore be a potential biomarker of disease progression and severity and may serve to inform treatment plans specific to a patient. (Zhang, et al., 2020). A study looked specifically at hypoalbuminemia, lymphopenia, and percentage of total neutrophil count among other indicators and found multiple specific measurements to be highly indicative of disease severity. (Liu, et al., 2020).

The disease presentation of lymphocytopenia was seen previously in the MERS outbreak of 2011 as a result of necrosis/apoptosis induced by the MERS coronavirus. It is hypothesized that SARS-CoV-2 may utilize a similar mechanism to dampen the immune response. The presentation of lymphocytopenia with hypercytokinemia is characteristic of lymphopenic community acquired pneumonia (L-CAP). The degree of L-CAP has been correlated with disease severity, increased mortality and dysregulated immune responses. Endothelial dysfunction has been hypothesized as a primary predisposing factor to low lymphocyte/high cytokine counts leading to more severe disease and novel coronavirus pneumonia (NCP). Drugs targeting endothelial dysfunction – leakage or tearing, etc. – and lymphocyte apoptosis are potential therapies for mitigating disease progression to more severe stages. (Bermejo-Martin, et al., 2020).