Brief Research Report: Virus-Specific Humoral Immunity at Admission Predicts the Development of Respiratory Failure in Unvaccinated SARS-CoV-2 Patients

Abstract

Introduction: There is robust evidence indicating that the SARS-CoV-2-specific humoral response is associated with protection against severe disease. However, relatively little data exist regarding how the humoral immune response at the time of hospital admission correlates with disease severity in unimmunized patients. Our goal was toidentify variables of the humoral response that could potentially serve as prognostic markers for COVID-19 progressionin unvaccinated SARS-CoV-2 patients.

Methods: A prospective cross-sectional study was carried out in a cohort of 160 unimmunized, adult COVID-19 patients from the Hospital Universitario 12Octubre. Participants were classified into four clinical groups based on disease severity: non-survivors with respiratory failure (RF), RF survivors, patients requiring oxygen therapy and those not receiving oxygen therapy. Serum samples were taken on admission and IgM, IgG, IgG subclass antibody titers were determined by ELISA, and neutralizing antibody titersusing a surrogate neutralization assay. The differences in the antibody titers between groups and the association between the clinical and analytical characteristics of the patients and the antibody titers were analyzed.

Results: Patients that developed RF and survived had IgM titers that were 2-fold higher than non-survivors (p = 0.001), higher levels of total IgG than those who developed RF and succumbed to infection (p< 0.001), and than patients who required oxygen therapy (p< 0.05), and had 5-fold higher IgG1 titers than RF non-survivors (p< 0.001) and those who needed oxygen therapy (p< 0.001), and 2-fold higher than patients that did not require oxygen therapy during admission (p< 0.05). In contrast, RF non-survivorshad the lowest neutralizing antibodylevels, which were significantly lower compared those with RF that survived (p = 0.03). A positive correlation was found between IgM, total IgG, IgG1 and IgG3 titers and neutralizing antibody titers in the total cohort (p ≤ 0.0036).

Conclusions: We demonstrate that patients with RF that survived infection had significantly higher IgM, IgG, IgG1 and neutralizing titers compared to patients with RF that succumb to infection, suggesting that using humoral response variables could be used as a prognostic marker for guiding the clinical management of unimmunized patients admitted to the hospital for SARS-CoV-2 infection.

Keywords: COVID disease severity; IgG; IgM 2; SARS-CoV-2; humoral response.

Figure 1

Analysis of antibody levels and neutralizing activity against SARS-CoV-2 S protein in serum samples from COVID-19 patients. Anti-S IgM, anti-S IgG (A) anti-S IgG1, anti-S IgG2, anti-S IgG3 and anti-S IgG4 (B) and neutralizing titers (C) are indicated for the total cohort of patients (grey circles, n = 160) and the different disease severity groups: RF non-survivors (pink circles, n = 40), RF survivors (green circles, n = 40), oxygen therapy (orange circles, n = 40) and non-oxygen therapy (blue circles, n = 40). Cutoff value to determine positive (above) and negative (below dashed line) samples is indicated. Black lines represent medians and interquartile range. Statistical significance was determined by the non-parametric Kruskall-Wallis and Dunn’s Multiple Comparison tests, where *p< 0.05 and **p< 0.001. RF indicates respiratory failure. Y axis is represented by logarithmic scale.

Figure 2

Antibody levels and neutralizing activity against SARS-CoV-2 by sample precocity in total cohort and by clinical group. Anti-S IgM, anti-S IgG and neutralizing titers were determined in early serum samples (ES, collected in the first nine days of symptoms) and in late serum samples (LS, collected from ten days of symptoms) for the total cohort (A–C) (light grey circles, n = 94 and dark grey squares, n = 66, respectively) and for the different disease severity groups (D–I) RF non-survivors (pink circles, ES: n = 24; pink squares, LS: n = 16), RF survivors (green circles, ES: n = 25; green squares, LS: n = 15), oxygen therapy (orange circles, ES: n = 24; orange squares, LS: n = 16) and non-oxygen therapy (blue circles, ES: n = 21; blue squares, LS: n = 19). Cutoff value to determine positive (above) and negative (below dashed line) samples is indicated and black lines represent medians and interquartile range. Statistical analysis were performed using Mann-Whitney U test and Kruskall-Wallis and Dunn’s Multiple Comparison tests. *p< 0.05 **p< 0.01 and ***p< 0.001. RF indicates respiratory failure. Y axis is represented by logarithmic scale.