Immune Phenotyping Based on the Neutrophil-to-Lymphocyte Ratio and IgG Level Predicts Disease Severity and Outcome for Patients With COVID-19

Abstract

Introduction: A recently emerging respiratory disease named coronavirus disease 2019 (COVID-19) has quickly spread across the world. This disease is initiated by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and uncontrolled cytokine storm, but it remains unknown as to whether a robust antibody response is related to clinical deterioration and poor outcome in COVID-19 patients. Methods: Anti-SARS-CoV-2 IgG and IgM antibodies were determined by chemiluminescence analysis (CLIA) in COVID-19 patients at a single center in Wuhan. Median IgG and IgM levels in acute and convalescent-phase sera (within 35 days) for all included patients were calculated and compared between severe and non-severe patients. Immune response phenotyping based on the late IgG levels and neutrophil-to-lymphocyte ratio (NLR) was characterized to stratified patients into different disease severities and outcomes. Results: A total of 222 patients were included in this study. IgG was first detected on day 4 of illness, and its peak levels occurred in the fourth week. Severe cases were more frequently found in patients with high IgG levels, compared to those with low IgG levels (51.8 vs. 32.3%; p = 0.008). Severity rates for patients with NLR^hiIgG^hi, NLR^hiIgG^lo, NLR^loIgG^hi, and NLR^loIgG^lo phenotype were 72.3, 48.5, 33.3, and 15.6%, respectively (p < 0.0001). Furthermore, severe patients with NLR^hiIgG^hi, NLR^hiIgG^lo had higher inflammatory cytokines levels including IL-2, IL-6 and IL-10, and decreased CD4+ T cell count compared to those with NLR^loIgG^lo phenotype (p < 0.05). Recovery rates for severe patients with NLR^hiIgG^hi, NLR^hiIgG^lo, NLR^loIgG^hi, and NLR^loIgG^lo phenotype were 58.8% (20/34), 68.8% (11/16), 80.0% (4/5), and 100% (12/12), respectively (p = 0.0592). Dead cases only occurred in NLR^hiIgG^hi and NLR^hiIgG^lo phenotypes. Conclusions: COVID-19 severity is associated with increased IgG response, and an immune response phenotyping based on the late IgG response and NLR could act as a simple complementary tool to discriminate between severe and non-severe COVID-19 patients, and further predict their clinical outcome.

Keywords: COVID-19; IgG; clinical outcome; disease severity; neutrophil-to-lymphocyte ratio.

Figure 1

Median anti-SARS-CoV-2 IgG and IgM levels in patients with severe or non-severe illness within 35 days after symptom onset. (A) Median IgG and IgM levels in all patients. (B) Comparing median IgG levels between severe and non-severe patients. (C) Comparing median IgM levels between severe and non-severe patients. (D) Comparing the frequency of severity and non-severity between patients with low IgM levels (<34.1 AU/mL) or high IgM levels (≥3.04 AU/mL). (E) Comparing the frequency of severity and non-severity between patients with low IgG levels (<116.9 AU/mL) or high IgG levels (≥116.9 AU/mL). CLIA, chemiluminescence analysis.

Figure 2

Immune response phenotyping with diverse disease severity according to NLR and IgG levels. Analyzing the frequencies of severe illness (A), severe to mild (B), or severe to death (C) in patients with four individual immune response phenotyping based on low or high IgG and IgM levels.

Figure 3

Immune response phenotyping with different immunological mechanisms associated with organ damage, and potential therapeutic strategies against severe COVID-19.