P-selectin blockade in COVID-19-related ARDS

to the editor: Many patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop a syndrome that fulfills the Berlin definition for the acute respiratory distress syndrome (ARDS) characterized by very high mortality (14). The pathogenesis of ARDS is complex and partially dependent on the underlying mechanism; however, polymorphonuclear cell influx into the extravascular compartments of the lungs is considered a defining characteristic of the disease (13).

P-selectin (formerly PADGEM and GMP140) is an integral membrane protein that mediates the adhesion of activated platelets (8) and endothelial cells (5) to neutrophils and monocytes. Upon binding to the cognate ligand on leukocytes, P-selectin glycoprotein ligand (PSGL)-1, P-selectin mediates the initial rolling of leukocytes onto the inflamed endothelium, which represents the first step in leukocyte recruitment to sites of inflammation (4). P-selectin also activates monocytes to synthesize tissue factor, an essential cofactor in the initiation of the so-called extrinsic pathway of blood coagulation (3).

A possible role for P-selectin-mediated leukocyte recruitment into the lungs during ARDS has been investigated. Infusion of either a monoclonal antibody to P-selectin (9) or of Sialyl-Lewis-X, a component of PSGL-1 (10), dramatically reduced lung injury in a rat model of ARDS. In humans, soluble P-selectin is increased in ARDS patients compared with controls and in nonsurvivors compared with survivors (11). More recently, a genome-wide association study has recognized SELPLG, encoding PSGL-1, as a novel ARDS susceptibility gene. The authors also report data showing a significant attenuation of lung injury in Selplg^−/− mice exposed to LPS. These observations have prompted the authors to conclude that SELPLG and PSGL-1 are potentially novel therapeutic targets for reducing ARDS pathobiology (2). Although P-selectin expression is considered limited to platelets and endothelial cells (4), Yen et al. (12) surprisingly demonstrated the expression of P-selectin in pneumocytes in autopsy specimens of a patient who died from the 2002 coronavirus (SARS CoV) infection; they expanded on the observation showing that cells of the immortal alveolar epithelial line, A549, express P-selectin (both mRNA and protein) upon exposure to the SARS CoV. As leukocytes do not roll on epithelial cells, the biological relevance of this observation remains speculative and worthy of further investigation; however, the data are consistent with a potential pathogenetic role of P-selectin in this condition. The observation of a particularly high frequency of thrombotic events in coronavirus disease (COVID-19) patients (7) is also consistent with a P-selectin-mediated activation of intravascular coagulation.

The hypothesis that inhibition of leukocyte recruitment might be beneficial in ARDS is intriguing (13). It is clear, however, that ARDS is heterogeneous and that different causative agents are involved in its development. The COVID-19 pandemic has prompted numerous studies aimed at investigating potential therapeutic approaches. Owing to its sudden and unexpected outbreak and the ensuing need for a rapid response, drugs that are already approved for other indications appear particularly appealing. Crizanlizumab is a humanized monoclonal antibody to P-selectin recently approved for patients with sickle cell anemia. Its safety profile appears satisfactory (1). Crizanlizumab has been recently approved in the United States for this indication; European Medicines Agency (EMA) approval is pending. Based on the above considerations, there appears to be a strong rationale to test crizanlizumab in COVID-19-related ARDS. As is the case with any therapeutic strategy aimed at blunting the inflammatory response, the risk of impairing host defense must be balanced against the potential benefits. Data from clinical trials show no evidence of increased risk or severity of infection with crizanlizumab (6). In the specific setting of COVID-19, timing of drug administration will likely be critical; other anti-inflammatory agents including the anti-IL-6 receptor, tocilizumab, are currently being tested in this setting and will generate data that might prove instrumental in designing a clinical trial with crizanlizumab.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

T.N., D.N., and A.C. drafted manuscript; edited and revised manuscript; and approved final version of manuscript.