The rapid and wide spread of SARS-CoV-2 infection in China and in the world has resulted in a tremendous loss of safety in peoples’ lives . In this study, we systematically analyzed clinical characteristics, dynamic changes in the immune response including changes in proinflammatory cytokines, in 74 patients with different degrees of disease severity. Although the number of patients included in our study is limited, our study provides several novel findings, including the observations that SARS-CoV-2 might mainly act on lymphocytes, induces an inflammatory cytokine storm in the body, and generates a series of immune responses. In addition, the dynamic changes in multiple immune cells and cytokines that we have observed, as well as their association with disease severity and outcomes during hospitalization, might help us develop effective treatment strategies and a preventive vaccine to treat and control COVID-19 in the near future. Our research helps us more clearly delineate the progression of COVID-19 in humans, and also provide a scientific basis for a better understanding of its pathogenesis.
In total, old age and shortness of breath were more common in severe patients. Lymphopenia, including T cells, B cells, and NK cells and an increase in NLR were common among patients with COVID-19, and were more pronounced in the severe patients. These results are in accordance with other studies [12, 13, 14]) and the findings of limited autopsies and biopsies, which reported markedly shrunken spleens and a significant reduction in lymphocytes (Chinese Clinical Guidance for COVID-19 Pneumonia Diagnosis and Treatment, 7th edition). Immune cells are important effectors of a host’s immune system, and play crucial roles in anti-viral infections . CD4 + T helper cells coordinate immunity by releasing various cytokines, while CD8 + suppressor T cells directly kill the target cells during viral infections . B cells perform their humoral immune function by releasing neutralizing antibodies, presenting antigens, and regulating immune function. NK cells can kill non-specific target cells infected by virus, and play an important role in the early anti-viral response . The reduction in lymphocyte counts may allow SARS-CoV-2 to spread and progress in the early stages of an infection. Based on these data, we suggest that COVID-19 might damage immune cells, including T cells, B cells, as well as NK cells, and that the immune system is impaired to various degree and this correlates with disease severity.
We also noted that the most severe patients presented higher neutrophils counts and lower lymphocytes counts, i.e., there was an increase in NLR, compared to that in the non-severe patients. Transient or persistent leukocytosis, primarily due to increased levels of neutrophils, is a well-known phenomenon in systemic inflammation and infections [17, 18]. Our results are consistent with data from several studies [2, 12], suggesting that there is a serious disturbance in the internal environment, secondary bacterial infections, and potential critical condition in these severe patients. These significant changes in white blood cells prompted us to quantify inflammatory cytokines. Consistently, a wide range of inflammation-related biomarkers and cytokines, were elevated and this was more evident in severe patients, suggesting that an inflammatory cytokine storm may have a role in disease progression.
Eosinophils are generally considered as multifunctional cells that function as part of the innate immune system and are associated with allergic and parasitic inflammation responses. However, several studies have shown that there is an intricate correlation between eosinophils and severe infectious diseases, including bacterial and viral infections [19, 20]. The translocation of eosinophils from the lungs of mice infected with influenza virus has been shown to reduce morbidity and viral burden, improve lung function, and increase the levels of CD8(+) T cell in the airways . Our study found that eosinopenia was common among patients with COVID-19, and this was more significant in the severe patients. Moreover, the number of eosinophils steadily increased as the patient’s condition improved. These data imply that eosinopenia might be considered to be a potential marker of disease severity in COVID-19 patients, and that eosinophils might have a protective role in SARS-CoV-2 infections.
In order to investigate dynamic changes in the immune response, we further analyzed the kinetics of the immune response that were associated with clinical resolution of COVID-19. All of the recovered patients exhibited a gradual and persistent increase in lymphocyte counts, including helper T cells, suppressor T cells, and NK cells, strongly suggesting that both innate and adaptive immune system play a protective role in fighting the SARS-CoV-2 infection. Additionally, as the patients improved the levels of most of inflammatory cytokines examined, including IFN-γ, IL-10, IL-17A, IL-2, IL-4, IL-6, and TNF–α generally decreased, indicating their potential as biomarkers and indicators of disease severity and prognosis.
Collectively, our study provides novel information towards understanding the kinetics of the immune response in a cohort of COVID-19 patients with different degrees of disease severity. Furthermore, our study indicates that both innate and adaptive immune responses are correlated with clinical outcomes. However, there are several limitations in our study. First, it is a retrospective, single center study with a relatively small sample size. We propose that a larger cohort of patients with COVID-19 should be used to assess the dynamic changes in the immune response to avoid any potential bias. Second, all the patients studied here recovered from COVID-19, thus we do not have any information on the processes that occur in patients who do not recover from COVID-19. Third, as a result of our limited testing ability, only part of the immune response could be analyzed in our hospital. The immune response to SARS-CoV-2 in humans should be characterized in much more detail in the future. We hope that this study has provided evidence that sets the stage for identifying the predictors of outcomes and also potential intervention strategies for COVID-19.