Acute Immune Mediated Lung Injury in COVID 19: A Review

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A. S. V. Prasad


There are many gaps in our present understanding of the of the SARS CoV 2 related matters like its PAMPs,(pathogen associated molecular patterns),antigenic profile, immune evasive mechanisms and also other host related matters, like PRR s(pattern recognizing receptors) and the deranged host defense mechanisms, that cause self-damage. These constraints come in way of accurately delineating the pathogenesis of COVID19 lung disease. Hence is the speculative nature of any concept trying to explain the same. An integrated approach is embarked upon, taking into account the known clinical, radiological, laboratory, and autopsy findings, in search of clues that may suggest a possible mechanism, that explains the underlying lung damage in COVID 19. It is seen that no single mechanism or syndrome could explain fully the pathology and pathogenesis of lung damage in COVID19. Hence, multiple mechanisms consistent with each known facet of the pathology are explored. Thus the inflammatory damage of the alveolar tissue is sought to be explained by the3 complement activation pathways i.e. the alternative pathway, the MBL/Lectin pathway/ and Tissue factor/extrinsic pathway(of the classical complement activation), the contact cascade involving the kallikrein-kinin pathway, and the cytokine mediated pro and anti inflammatory mechanisms. The vascular pathology like hemorrhages and small blood vessel micro-thrombi as observed at autopsy , are viewed from the point of view of simple activation of the coagulation cascade to small vessel vasculitis (leucocytoclastic vasculitis) and coagulative micro angiopathy. Besides, the role of TM-PC-EPCR SYSTEM (Thrombomodulin-Protein C-EPCR System) is explored. The points in favour and against of each of the above are discussed.The central role played by the macrophage polymorphism is focused in the context of the simultaneous presence of active inflammation in the lung tissue and the interstetium and healing by interstitial fibrosis, seen in the lungs of COVID 19 patients. The role played by the other humoral and cellular elements of both innate and adaptive immunity is briefly reviewed. The uniqueness and diversified features of COVID 19 lung pathology, suggests two things - that the immune mediated damage seems more probable than could be explained by the viral infectivity and that the pathology seems to stem from a mixture of different underlying and overlapping syndromes. Hence, the author prefers to call all the COVID 19 related features of lung pathology as “Acute immune mediated Lung injury". (AILI) than trying to bunch them under a single syndrome.

Pathogen associated proteins (PAMPs), pathogen recognizing receptors (PRRs) complement, cytokines, phagocytosis, antibody, ARDS, immune evasion, capillaritis, microangiopathy

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Prasad, A. S. V. (2020). Acute Immune Mediated Lung Injury in COVID 19: A Review. Asian Journal of Immunology, 4(2), 11-30. Retrieved from
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Li X, Ma X. Acute respiratory failure in COVID-19: Is it “typical” ARDS? Crit Care. 2020;24:198.

Peter G, Gibson, Ling Qin, Ser Puah. COVID-19 ARDS: Clinical features and differences to “usual” pre-COVID ARDS.

Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, Huang H, Zhang L, Zhou X, Du C, Zhang Y, Song J, Wang S, Chao Y, Yang Z, Xu J, Zhou X, Chen D, Xiong W, Xu L, Zhou F, Jiang J, Bai C, Zheng J, Song Y. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med; 2020.

Puah SH. COVID-19 global perspectives. ATS/APSR Joint Webinar. Definition Task Force ARDS, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012;307: 2526–33.

Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA; 2020.

Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet; 2020.

Huang C, Wang Y, Li X, et al. Clinical features of patients with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506.

Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med; 2020.


Robba C, Battaglini, Ball L, Patroniti Loconte M Brunetti I, et al. Distinct phenotypes require distinct respiratory management strategies in sever COVID19. Respiratory Physiology & Neurobiology; 2020.

Gattinoni L, Chiumello D, Rossi S. COVID-19 pneumonia: ARDS or not? Crit Care. 2020;24:154.

Xiaowei Li, Shemin Lu. Molecular immune pathogenesis and diagnosis of COVID-19 Journal of pharmaceutical analysis. 2020; 10(2):102-108.

CHani MP. Revel diagnostic and inter-ventional imaging. 2020;101(5):263-268.

Shi H, Han X, Jiang N. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: A descriptive study. Lancet Infect Dis. 2020;20:425–434.

Wei-Jie Guan, et al. Clinical characteristics of Corona virus disease in China N Engl J Med; 2020.

Xu Zhe, Lei Shi, Yijin Wang, Jiyuan Zhang, Lei Huang, Chao Zhang, Shuhong Liu, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. The Lancet Respiratory Medicine. 2020;8(4):420-422.

Joshua M. Thurman, Michael Holers V. The central role of the alternative complement pathway in human disease. J Immunol. 2006;176.

Nilsson B, Nilsson Ekdahl K. The tick-over theory revisited: is C3 a contact-activated protein? Immunobiology. 2012;217(11): 1106‐1110.

Macref MC, Tschopp J. Assembly of macromolecular pores by immune defense systems. Curr. Opin. Cell Biol. 1991;3(4): 710–716.

Conrad DH, Carlo JR, Ruddy S. Interaction of beta1H globulin with cell-bound C3b: Quantitative analysis of binding and influence of alternative pathway components on binding. The Journal of Experimental Medicine. 1978; 147(6):1792–1805.

Weiler JM, Daha MR, Austen KF, Fearon DT. Control of the amplification convertase of complement by the plasma protein beta1H". Proceedings of the National Academy of Sciences of the United States of America. 1976;73(9):3268–72.

Pangburn MK, Schreiber RD, Müller-Eberhard HJ. Human complement C3b inactivator: Isolation, characterization, and demonstration of an absolute requirement for the serum protein beta1H for cleavage of C3b and C4b in solution. The Journal of Experimental Medicine. 1977;146(1):257–70.

McRae JL, Duthy TG, Griggs KM, Ormsby RJ, Cowan PJ, Cromer BA, McKinstry WJ, Parker MW, Murphy BF, Gordon DL. Human factor H-related protein 5 has cofactor activity, inhibits C3 convertase activity, binds heparin and C-reactive protein, and associates with lipoprotein. Journal of Immunology. 2005;174(10): 6250–6.

Butthep P, Bunyaratvej A, Bhamarapravati N. Dengue virus and endothelial cell: A related phenomenon to thrombocytopenia and granulo cytopenia in dengue hemorrhagic fever. Southeast Asian J. Trop. Med. Public Health. 1993;24(Suppl. 1):246–249.

Avirutnan P, Fuchs A, Hauhart RE, Somnuke P, Youn S, Diamond MS, Atkinson JP. Antagonism of the complement component C4 by flavivirus nonstructural protein NS1. J. Exp. Med. 2010;207:793–806.

Saifuddin M, Parker CJ, Peeples ME, Gorny MK, Zolla-Pazner S, Ghassemi M, Rooney IA, Atkinson JP, Spear GT. Role of virion-associated glycosylphosphatidy-linositol-linked proteins CD55 and CD59 in complement resistance of cell line-derived and primary isolates of HIV-1. J. Exp. Med. 1995;182:501–509.

Spear GT, Lurain NS, Parker CJ, Ghassemi M, Payne GH, Saifuddin M. Host cell-derived complement control proteins CD55 and CD59 are incorporated into the virions of two unrelated enveloped viruses. Human T cell leukemia/lymphoma virus type I (HTLV-I) and human cytome-galovirus (HCMV) J. Immunol. 1995;155: 4376–4381.

Datta PK, Rappaport J. HIV and complement: Hijacking an immune defense. Biomed. Pharmacother. 2006;60: 561–568.

Butthep P, Bunyaratvej A, Bhamarapravati N. Dengue virus and endothelial cell: A related phenomenon to thrombocytopenia and granulocytopenia in dengue hemorrhagic fever. Southeast Asian J. Trop. Med. Public Health. 1993;24(Suppl. 1).

Van Dam-Mieras MC, Muller AD, van Hinsbergh VW, Mullers WJ, Bomans PH, Bruggeman CA. The procoagulant response of cytomegalovirus infected endothelial cells. Thromb. Haemost. 1992;68:364–370.

[PubMed] [Google Scholar]

Renne T. The procoagulant and proinflammatory plasma contact system. Semin. Immunopathol. 2012;34:31–41.

Alexander H. Sprague, Raouf A. Khalil. Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol. 2009;78(6):539–552.

Marlies Van de, Wouwer Désiré Colle, Edward M. Conway arteriosclerosis, thrombosis and vascular biology. 2004; 24:1374–138.

Muzio M, Stockwell BR, Stennicke HR, Salvesen GS, Dixit VM. An induced proximity model for caspase-8 activation. J Biol Chem. 1998;273(5):2926–2930.

Yoshizumi M, Perrella MA, Burnett JC, Jr, Lee ME. Tumor necrosis factor down regulates an endothelial nitric oxide synthase mRNA by shortening its half-life. Circ Res. 1993;73(1):205–209.

Alma C, Meacci E, Perrotta C, Bruni P, Clementi E. Endothelial nitric oxide synthase activation by tumor necrosis factor alpha through neutral sphingo-myelinase 2, sphingosine kinase 1 and sphingosine 1 phosphate receptors: A novel pathway relevant to the patho-physiology of endothelium. Arterioscler ThrombVasc Biol. 2006;26(1):99–105.

Luscher TM, Steffel J. Sweet and sour unraveling diabetic vascular disease. Circ Res. 2007;102:9–1136. Liu J, et al. C5aR, TNF-alpha, and FGL2 contribute to coagulation and complement activation in virus-induced fulminant hepatitis. J Hepatol. 2015;62:354–362.

DOI: 10.1016/j.

Yamagishi S, et al. Decreased high-density lipoprotein cholesterol level is an independent correlate of circulating tumor necrosis factor-alpha in a general population. Clinical Cardiology. 2009;32: E29–32.

DOI: 10.1002/clc.20517

Yang G, Shao GF. Elevated serum IL-11, TNF alpha, and VEGF expressions contribute to the pathophysiology of hypertensive intracerebral hemorrhage (HICH) Neurol Sci. 2016;37:1253–1259.

Zhang H, et al. Role of TNF-alpha in vascular dysfunction. Clin Sci (Lond) 2009; 116:219–230.

Pober JS. Effects of tumour necrosis factor and related cytokines on vascular endothelial cells. Ciba Found Symp. 1987; 131:170–184.

Zelová H, Hošek J. TNF-alpha signalling and inflammation: interactions between old acquaintances. Inflamm Res. 2013;62: 641–651. Nikoletopoulou V, Markaki M, Palikaras K, Tavernarakis N. Crosstalk between apoptosis, necrosis and autophagy. Biochim Biophys Acta. 2013; 1833:3448–3459.

Pignatelli P, et al. Tumor necrosis factor-alpha as trigger of platelet activation in patients with heart failure. Blood. 2005; 106:1992–1994.

DOI: 10.1182/blood-2005-03-1247

Pignatelli P, et al. Tumour necrosis factor alpha upregulates platelet CD40L in patients with heart failure. Cardiovasc Res. 2008;78:515–522.

Lapin ZJ, Hoppener C, Gelbard HA, Novotny L. Near-field quantification of complement receptor 1 (CR1/CD35) protein clustering in human erythrocytes. J Neuroimmune Pharmacol. 2012;7:539–543.

Pascual M, Schifferli JA. The binding of immune complexes by the erythrocyte complement receptor 1 (CR1) Immuno-pharmacology. 1992;24:101–106.

Meulenbroek EM, Wouters D, Zeerleder S. Methods for quantitative detection of antibody-induced complement activation on red blood cells. J Vis Exp. 2014; e51161.

Patzelt J, Verschoor A, Langer HF. Platelets and the complement cascade in atherosclerosis. Front Physiol. 2015;6:49.

DOI: 10.3389/fphys.2015.00049

Hamad OA, et al. Complement activation triggered by chondroitin sulfate released by thrombin receptor-activated platelets. J Thromb Haemost. 2008;6:1413–1421.

Martel C, et al. Requirements for membrane attack complex formation and anaphylatoxins binding to collagen-activated platelets. PLoS One. 2011;6: e18812.

DOI: 10.1371/journal.pone.

Del Conde I, Cruz MA, Zhang H, Lopez JA, Afshar-Kharghan V. Platelet activation leads to activation and propagation of the complement system. J Exp Med. 2005; 201:871–879.

DOI: 10.1084/jem.20041497

Verschoor A, et al. A platelet-mediated system for shuttling blood-borne bacteria to CD8alpha+ dendritic cells depends on glycoprotein GPIb and complement C3. Nat Immunol. 2011;12:1194–1201.

Marlies Van de Wouwer Désiré Collen and Edward M. Conway Thrombomodulin-Protein C-EPCR SystemIntegrated to Regulate Coagulation and Inflammation. Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1374–13838.

Stearns-Kurosawa DJ, Kurosawa S, Mollica JS, Ferrell GL, Esmon CT. The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. Proc Natl Acad Sci USA. 1996; 93:10212–10216.

Ali Ganji, et al. Increased Expression of CD8 Marker on T-cells in COVID-19 Patients.Blood Cells Mol Dis. 2020; 83:102437.

Zheng et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cellular & Molecular immunology; 2020.