Clinical diagnosis
Case 228
【Progress】
He was transported to the hub hospital supplying ECMO (extracorporeal membrane oxygenation) respirator.
【Discussion】
Neutrophils attack bacillus by phagocytosis, granules release and extracellular trap. Macrophages also own the ability of phagocytosis. Natural killer cells also own the ability of granules and natural killer T cell own the ability of releasing chemokine. All white cells except lymphocytes have the ability of extracellular trap. Extracellular trap means DNA in nucleus is released to prevent growth of microbes (1-5). Namely, the cell releases self-DNA like a net to catch microbes at the sacrifice of cell life. Extracellular trap is the last attack to the pathogens for macrophages and neutrophils. Of all kinds of white cells, neutrophils alone have three kinds of weapon to attack pathogens. They are like strong soldiers but their granules release causes to damage not only pathogens but also host cells. Then, neutrophils are not always called in any case: neutrophils are silent in virus infection.
Approximately 5 days after macrophages switch from the common state (first line defense) to the second defense line, in other words, macrophages release cytokine of interleukin 5, Ig M production reaches a peak and thereafter, it is decreased (6, 7). Meanwhile, Ig G production begins at the peak of Ig M and it reaches to its peak two or three weeks later (6, 7). When these immunoglobulins are sufficient to control pathogen, the pathogen are eradicated, leaving the memory of pathogen in the memory T cells and B cells. However, when the production of Ig G is not sufficient, viral infection continues to be vigorous to host cells. Infected host cells of type I and II pulmonary cells and other cells release cytokine to appeal they are infected and ask a favor of phagocytic cells. When macrophages realize the existence of much-volume pathogens through cytokine storm, macrophages challenge the last attack to the pathogens at the sacrifice of its life, releasing self-DNA to catch pathogens called macrophage extracellular trap.
Macrophage extracellular trap occurs in the pulmonary branch artery causing thrombus formation, leading decreases of counts of both macrophage and platelet (8). At the same time, count of neutrophils increases probably because of cytokine storm. As a result, neutrophils damages to the infected host cells via phagocyte, granulation release and extracellular trap, causing diffuse alveolar cell damage and resulting in acute respiratory distress syndrome.
Disseminated intravascular coagulation has been well-known at the late stage of sepsis. It was once thought that endothelial damages are caused by thromboplastin release from endothelial cells stimulated by endotoxin and/or cytokine. Neutrophil extracellular trap might be related to DIC.
In our case, laboratory test 7 days vs 13 days after the onset of slight fever revealed marked decrease count of lymphocytes, monocytes and platelets and increase count of neutrophils and D dimmer. Contrast-enhanced chest CT depict expanding ground glass opacity with patchy consolidation with thrombus of pulmonary branch artery. Note reparation mechanism of fibrous formation was not observed. When virus infection power is potent, reparation mechanism might not work.
【Summary】
We present a sixty five-year-old male with COVID19. Chest CT 5 days and 7 days after showed the expanding ground glass opacity and contrast-enhanced CT showed thrombosis of pulmonary branch artery. Laboratory test revealed counts of lymphocytes, monocytes and platelets decreased and count of neurocytes and D dimer values elevated 13 days after compared to 7 days after. Thrombus of pulmonary branch artery is formed by macrophage extracellular trap and platelets accumulation. Insufficient produce of IgM and IgG induces virus infection vigorously to host cells of type 1 pulmonary cells. The infected host cells release cytokine whose accumulation of cytokine is called cytokine storm. It let macrophage conduct the last battle at the sacrifice of its life, macrophage extracellular trap by its DNA. Further it brings about increasing count of neurocytes, inducing activated attack to the virus and host cells, leading ARDS.
【References】
1.Brinkmann, et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303: 1532– 1535
2.Brinkmann, V, et al. Beneficial suicide: why neutrophils die to make NETs. Nat. Rev. Microbiol. 5, 577– 582.
3.Papayannopoulos, V, et al. NETs: a new strategy for using old weapons. Trends Immunol. 2009; 30: 513– 521.
4.Doster RS et al. Macrophage Extracellular Traps: A Scoping Review. J Innate Immun 2018;10(1):3-13.
5.Yu Zuo Y, et al. Neutrophil extracellular traps and thrombosis in COVID-19. Journal of Thrombosis and Thrombolysis (2020)
6.Komatsuda A, et al. Discrete renal deposition of IgM heavy chain and κ light chain in Waldenström macroglobulinemia (IgM-κ). Clin Kidney J. 2012 Oct; 5(5): 438–441
7.Zhang YM, et al. Clinical Significance of IgM and C3 Glomerular Deposition in Primary Focal Segmental Glomerulosclerosis. Clin J Am Soc Nephrol. 2016 Sep 7; 11(9): 1582–1589.
8.Kazancioglu S, et al. Lymphocyte Subset Alteration and Monocyte CD4 Expression Reduction in Patients with Severe COVID-19. Viral Immunology Published Online:23 Nov 2020https://doi.org/10.1089/vim.2020.0166
2021.4.14