Aveolar Macrophage Activation and Cytokine Storm in the Pathogenesis of Severe COVID-19

Abstract

The coronavirus disease-19 (COVID-19) caused by SARS-CoV-2 infection can lead to a series of clinical settings from non-symptomatic viral carriers/spreaders to severe illness characterized by acute respiratory distress syndrome (ARDS)1,2. A sizable part of patients with COVID-19 have mild clinical symptoms at the early stage of infection, but the disease progression may become quite rapid in the later stage with ARDS as the common manifestation and followed by critical multiple organ failure, causing a high mortality rate of 7-10% in the elderly population with underlying chronic disease1-3. The pathological investigation in the lungs and other organs of fatal cases is fundamental for the mechanistic understanding of severe COVID-19 and the development of specific therapy in these cases. Gross anatomy and molecular markers allowed us to identify, in two fatal patients subject to necropsy, the main pathological features such as exudation and hemorrhage, epithelium injuries, infiltration of macrophages and fibrosis in the lungs. The mucous plug with fibrinous exudate in the alveoli and the activation of alveolar macrophages were characteristic abnormalities. These findings shed new insights into the pathogenesis of COVID-19 and justify the use of interleukin 6 (IL6) receptor antagonists and convalescent plasma with neutralizing antibodies against SARS-CoV-2 for severe patients.Authors Chaofu Wang, Jing Xie, Lei Zhao, Xiaochun Fei, Heng Zhang, and Yun Tan contributed equally to this work. Authors Chaofu Wang, Jun Cai, Rong Chen, Zhengli Shi, and Xiuwu Bian jointly supervised this work.

Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19

“…We have noticed that HCQ has in vitro antiviral effects on several viruses, including SARS and SARS-CoV-2 (Al-Bari, 2015; Bian et al, 2020;Gautret et al, 2020;Yao et al, 2020), which may contribute directly to its therapeutic effect on COVID-19 patients. However, the anti-SARS-CoV2 action of HCQ requires a much higher concentration of HCQ than the dose used in this study, and cannot account for the significant efficiency on critically ill patients in our cohort.…”

“…COVID-19 patients displayed apparent immunity disorders, showing marked reduction in lymphocyte numbers in peripheral blood and lymphatic tissues, but large amounts of lymphocyte infiltration in lungs as well as in other critical organs such as the heart. Many patients showed symptoms of cytokine storm with markedly elevated levels of the proinflammatory cytokine IL-6, suggesting over-activated immune responses (Bian et al, 2020). Anti-IL-6 antibody, Tocilizumab, has been shown to be an effective treatment option for COVID-19 patients with a risk of cytokine storms (Luo et al, 2020).…”

“…CQ and HCQ also have antimicrobial effects and were used to treat infections by bacteria and viruses. Recently, HCQ was reported to be effective in inhibiting SARS-CoV-2 infection in cell-based assays (Bian et al, 2020), and treatment with HCQ was significantly associated with reduction and disappearance of viral load in COVID-19 patients in a small-sized sample (Gautret et al, 2020), which instigated new hope for an effective treatment for COVID-19.…”

Analysis of Mortality in Patients With COVID-19: Clinical and Laboratory Parameters

“…First, SARS-CoV-2 infection may affect hematopoietic stem/ progenitor cells via CD13 or CD66a directly or through development of auto-antibodies or immune complexes, as seen in SARS [8]. Atrophy of bone marrow hematopoietic tissue has been seen in SARS and COVID-19 [9,10]. Second, glucocorticoid treatment can induce lymphocytopenia in some patients [8].…”

Single-cell RNA Analysis on ACE2 Expression Provides Insight into SARS-CoV-2 Blood Entry and Heart Injury

“…Analysis of single-cell RNA-Seq (scRNA-seq) data in normal human lung tissues demonstrated that ACE2 is mainly expressed in type II alveolar cells (AT2) 7 . The pathological investigation of COVID-19 fatal cases showed exudation and hemorrhage, epithelium injuries, infiltration of macrophages, and fibrosis in the lungs 8 . Pulmonary fibrosis is not only due to that SARS-CoV-2 directly attacking the lung as its target organ, while the activation of cytokine storm in COVID-19 patients also contributes 9,10 .…”