The complement cascade as a target against SARS-CoV-2-induced pneumonia

Dear Sir,

Fox, et al. [1] reported on the relevant cardiopulmonary findings in a series of autopsies of patients deceased from SARS-CoV-2 infection. In particular, regarding the histologic examination of the lungs, they observed bilateral diffuse alveolar damage with a lymphocytic infiltrate, thickened alveolar capillaries, fibrin thrombi within the capillaries and small vessels, and entrapment of neutrophils, without any significant neutrophilic, infiltrate within airways or the interstitium.

These findings resemble in part those reported by the Pathology Council of the International Society for Heart and Lung Transplantation (ISHLT) for the diagnosis of cellular-mediated rejection of lung transplant biopsies [2]. According to ISHLT, high-grade cellular-mediated rejection shows diffuse perivascular, interstitial, and air space infiltrates of mononuclear cells, alveolar pneumocyte damage and endothelialitis, with morphologic evidence of organizing pneumonia, fibrin deposition, or hyaline membranes.

By contrast, the observations reported by Fox, et al. [1] appear in part different from those that, according to the ISHLT, should indicate immunostaining of lung allograft biopsy specimen for complement 4d (C4d) for the diagnosis of antibody-mediated rejection: neutrophilic capillaritis with dense neutrophilic septal infiltrates and fibrin with or without plateletfibrin thrombi in the microvasculature [2]. Interestingly, even though the role of C4d deposition in the diagnosis of antibody-mediated rejection in lung allografts is still unclear [2], it has been observed that the lung histology in three of five children, after allogenic hematopoietic stem-cell transplant with pulmonary arterial hypertension, showed global thrombotic microangiopathy in the pulmonary arterioles [3].

The efficacy of eculizumab, a humanized monoclonal antibody against the complement component C5, in several patients with transplantation-associated thrombotic microangiopathy supports the importance of complement-mediated mechanisms for this clinical entity [4]. The excess in complement activation produces a systemic proinflammatory response to SARS-CoV infection [5] and is associated with significant thrombophilia, with endothelial cell integrity disruption, contributing to thrombotic occlusions in the micro- and even macro-vasculature. Thus, this aberrant complement cascade must be regarded as a crucial therapeutic target in facing SARS-CoV-2-induced pneumonia, as also reported on the activity of an anti-C5a monoclonal antibody in two critical COVID-19 patients [6].

However, it should be considered that different Human Leukocyte Antigen (HLA) molecules are involved in presenting peptides derived from pathogens to T-lymphocytes. It has been reported [7] that triggering an immune reaction and contemporarily being an HLA-DQA1 carrier may induce the production of anti-drug antibodies against anti-TNF drugs, which could represent a tool in the management of COVID-19, thus resulting in their failure against SARS-CoV-2-induced complications.

1. Fox SE, Akmatbekov A, Harbert JL, Li G, Brown JQ, Vander Heide RS. Pulmonary and Cardiac Pathology in Covid-19: The First Autopsy Series from New Orleans. MedRxiv Preprint. doi: https://doi.org/10.1101/2020.04.06.20050575
2. Roden AC, Aisner DL, Allen TC, Aubry MC, Barrios RJ, Beasley MB, Cagle PT, Capelozzi VL, Dacic S, Ge Y, Hariri LP, Lantuejoul S, Miller RA, Mino-Kenudson M, Moreira AL, Raparia K, Rekhtman N, Sholl L, Smith ML, Tsao MS, Vivero M, Yatabe Y, Yi ES. Diagnosis of Acute Cellular Rejection and Antibody-Mediated Rejection on Lung Transplant Biopsies: A Perspective From Members of the Pulmonary Pathology Society. Arch Pathol Lab Med. 2017 Mar;141(3):437-444. doi: 10.5858/arpa.2016-0459-SA. Epub 2016 Nov 7. PMID: 27819763.
3. Jodele S, Hirsch R, Laskin B, Davies S, Witte D, Chima R. Pulmonary arterial hypertension in pediatric patients with hematopoietic stem cell transplant-associated thrombotic microangiopathy. Biol Blood Marrow Transplant. 2013 Feb;19(2):202-7. doi: 10.1016/j.bbmt.2012.08.022. Epub 2012 Sep 6. PMID: 22960385.
4. Jodele S, Dandoy CE, Lane A, Laskin BL, Teusink-Cross A, Myers KC, Wallace G, Nelson A, Bleesing J, Chima RS, Hirsch R, Ryan TD, Benoit S, Mizuno K, Warren M, Davies SM. Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab. Blood. 2020 Mar 26;135(13):1049-1057. doi: 10.1182/blood.2019004218. PMID: 31932840; PMCID: PMC7099329.
5. Gralinski LE, Sheahan TP, Morrison TE, Menachery VD, Jensen K, Leist SR, Whitmore A, Heise MT, Baric RS. Complement Activation Contributes to Severe Acute Respiratory Syndrome Coronavirus Pathogenesis. mBio. 2018 Oct 9;9(5):e01753-18. doi: 10.1128/mBio.01753-18. PMID: 30301856; PMCID: PMC6178621.
6. Gao T, Hu M, Zhang X, Li H, Zhu L, Liu H, Dong Q, Zhang Z, Wang Z, Hu Y, Fu Y, Jin Y, Li K, Zhao S, Xiao Y, Luo S, Li L, Zhao L, Liu J, Zhao H, Liu Y, Yang W, Peng J, Chen X, Li P, Liu Y, Xie Y, Song J, Zhang L, Ma Q, Bian X, Chen W, Liu X, Mao Q, Cao C. Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2- mediated complement over-activation. MedRxiv Preprint. 2020. doi: https://doi.org/10.1101/2020.03.29.20041962.
7. Raslan MA, Alshahawey M, Shehata EM, Sabri NA. Does human leukocyte antigen gene polymorphism affects management of COVID-19 Patients? A review article. Scientific J Genet Gene Ther. 2020; 6(1): 001-003. DOI: http://dx.doi.org/10.17352/sjggt.000018