Early changes in immune cell subsets with corticosteroids in patients with solid tumors: implications for COVID-19 management

Abstract

BackgroundThe risk–benefit calculation for corticosteroid administration in the management of COVID-19 is complex and urgently requires data to inform the decision. The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation associated with poor prognosis in both COVID-19 and cancer. Investigating NLR as an inflammatory marker and lymphocyte levels as a critical component of antiviral immunity may inform the dilemma of reducing toxic hyperinflammation while still maintaining effective antiviral responses.MethodsWe performed a retrospective analysis of NLR, absolute neutrophil counts (ANCs) and absolute lymphocyte counts (ALCs) in patients with cancer enrolled in immunotherapy trials who received moderate-dose to high-dose corticosteroids. We compared paired presteroid and available poststeroid initiation values daily during week 1 and again on day 14 using the Wilcoxon signed-rank test. Associated immune subsets by flow cytometry were included where available.ResultsPatients (n=48) with a variety of solid tumors received prednisone, methylprednisolone, or dexamethasone alone or in combination in doses ranging from 20 to 190 mg/24 hours (prednisone equivalent). The median NLR prior to steroid administration was elevated at 5.0 (range: 0.9–61.2). The corresponding median ANC was 5.1 K/µL (range: 2.03–22.31 K/µL) and ALC was 1.03 K/µL (0.15–2.57 K/µL). One day after steroid administration, there was a significant transient drop in median ALC to 0.54 K/µL (p=0.0243), driving an increase in NLR (median 10.8, p=0.0306). Relative lymphopenia persisted through day 14 but was no longer statistically significant. ANC increased steadily over time, becoming significant at day 4 (median: 7.31 K/µL, p=0.0171) and remaining significantly elevated through day 14. NLR was consistently elevated after steroid initiation, significantly at days 1, 7 (median: 8.2, p=0.0272), and 14 (median: 15.0, p=0.0018). Flow cytometry data from 11 patients showed significant decreases in activated CD4 cells and effector memory CD8 cells.ConclusionsThe early drop in ALC with persistent lymphopenia as well as the prolonged ANC elevation seen in response to corticosteroid administration are similar to trends associated with increased mortality in several coronavirus studies to include the current SARS-CoV-2 pandemic. The affected subsets are essential for effective antiviral immunity. This may have implications for glucocorticoid therapy for COVID-19.

Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19

“…Noteworthy, there is evidence that the use of corticosteroids is associated with a delayed viral clearance in patients COVID-19 ( 40 ). In addition, treatment with glucocorticoids in patients with COVID-19 has been reported to induce an early drop in absolute lymphocyte counts, with prolonged lymphopenia, along with a significant steady increase in the absolute neutrophil count, altogether driving significant increases in the neutrophil-lymphocyte ratio for at least 2 wk ( 41 ). Absolute neutrophil count elevation seen in response to corticosteroid administration is similar to trends associated with increased mortality in several coronavirus studies to include the current SARS-CoV-2 pandemic ( 41 ).…”

Clinical Presentations and Outcomes of Coronavirus Disease 2019 in Patients With Solid Tumors

“…However, a study showed a positive correlation between recent cytotoxic therapy and the mortality rate in COVID-19 patients. It also presented a higher risk in patients who received cytotoxic treatment within two weeks, but if the time was more than three weeks, the risk was lower [ 17 ]. From the results of our study, we can conclude that during cytotoxic treatment, a pandemic patient who can move to alternative treatment should be shifted to safer therapies, and a patient who has no alternative treatment option should continue with cytotoxic treatment with the utmost care and strong protective measures against COVID-19.…”

COVID-19–Associated Bone Marrow Necrosis—A Case Report

“…4 A host of studies scrutinizing the use of steroids in viral respiratory diseases showed expected complications of avascular necrosis and diabetes, increased mortality, and secondary infections in influenza and reduced clearance of viral particles in SARS and Middle East respiratory syndrome (MERS) coronavirus outbreaks. 5 Patients plagued with the severe form of COVID-19 disease often find themselves faced with such challenges as coagulopathies and DIC. Infection-induced endothelial dysfunction causes an excess of procoagulant thrombin with concomitant shutting down of the fibrinolytic cascade resulting in a hypercoagulable state which can spur thrombosis by increasing blood viscosity and coupled with hypoxia can activate the hypoxia-induced transcription factor-dependent signaling.…”

“… 4 A host of studies scrutinizing the use of steroids in viral respiratory diseases showed expected complications of avascular necrosis and diabetes, increased mortality, and secondary infections in influenza and reduced clearance of viral particles in SARS and Middle East respiratory syndrome (MERS) coronavirus outbreaks. 5 …”