Immunoglobulin deficiency as an indicator of disease severity in patients with COVID-19

Abstract

Despite the pandemic status of COVID-19, there is limited information about host risk factors and treatment beyond supportive care. Immunoglobulin G (IgG) could be a potential treatment target. Our aim was to determine the incidence of IgG deficiency and associated risk factors in a cohort of 62 critically ill patients with COVID-19 admitted to two German ICUs (72.6% male, median age: 61 yr). Thirteen (21.0%) of the patients displayed IgG deficiency (IgG < 7 g/L) at baseline (predominant for the IgG1, IgG2, and IgG4 subclasses). Patients who were IgG-deficient had worse measures of clinical disease severity than those with normal IgG levels (shorter duration from disease onset to ICU admission, lower ratio of [Formula: see text] to [Formula: see text], higher Sequential Organ Failure Assessment score, and higher levels of ferritin, neutrophil-to-lymphocyte ratio, and serum creatinine). Patients who were IgG-deficient were also more likely to have sustained lower levels of lymphocyte counts and higher levels of ferritin throughout the hospital stay. Furthermore, patients who were IgG-deficient compared with those with normal IgG levels displayed higher rates of acute kidney injury (76.9% vs. 26.5%; P = 0.001) and death (46.2% vs. 14.3%; P = 0.012), longer ICU [28 (6-48) vs. 12 (3-18) days; P = 0.012] and hospital length of stay [30 (22-50) vs. 18 (9-24) days; P = 0.004]. Univariable logistic regression showed increasing odds of 90-day overall mortality associated with IgG-deficiency (odds ratio 5.14, 95% confidence interval 1.3-19.9; P = 0.018). IgG deficiency might be common in patients with COVID-19 who are critically ill, and warrants investigation as both a marker of disease severity as well as a potential therapeutic target.

Keywords: cytokine release syndrome; immunodysregulation; respiratory failure; severe acute respiratory syndrome coronavirus 2.

Figure 1.

Comparison of total IgG and IgG subclass levels in patients with COVID-19 with reduced vs. normal IgG levels at baseline. Comparison of levels of total IgG (A) and IgG1-4 subclasses (B–E) between patients with COVID-19 with reduced (<7 g/L) and normal (>7 g/L) IgG levels at baseline. Boxes show medians and IQR; whiskers show the 1.5 IQR of the 25th quartile or 1.5 IQR of the 75th quartile; and dots show individual observations. Extreme values of IgG4 were clipped. COVID-19, coronavirus disease 2019; IgG, immunoglobulin G; IQR; interquartile range.

Figure 2.

Comparison of measures of clinical disease severity in patients with COVID-19 with reduced vs. normal IgG levels at baseline. Comparison of duration of onset of disease to ICU admission (A), $\text{P}{\text{a}}_{\text{O}}{}_{{}_2}$/${\text{FI}}_{{\text{O}}_2}$ (B), APACHE II (C), SOFA (D), neutrophil-to-lymphocyte ratio (E), ferritin (F), and serum creatinine (G) between patients with COVID-19 with reduced (<7 g/L) and normal (>7 g/L) IgG levels at baseline. Boxes show medians and IQR; whiskers show the 1.5 IQR of the 25th quartile or 1.5 IQR of the 75th quartile; and dots show individual observations. APACHE II, Acute Physiology and Chronic Health Evaluation II; COVID-19, coronavirus disease 2019; ${\text{FI}}_{{\text{O}}_2}$, fraction of inspired oxygen; ICU, intensive care unit; IgG, immunoglobulin G; IQR; interquartile range; $\text{P}{\text{a}}_{\text{O}}{}_{{}_2}$, partial pressure of arterial oxygen; SOFA, Sequential Organ Failure Assessment.

Figure 3.

Comparison of leukocyte and lymphocyte subclasses count in patients with COVID-19 with reduced vs. normal IgG levels at baseline. Comparison of levels of leucocyte count (A), lymphocyte count (B), and lymphocyte subset count (C–F) between patients with COVID-19 with reduced (<7 g/L) and normal (>7 g/L) IgG levels at baseline. Boxes show medians and IQR; whiskers show the 1.5 IQR of the 25th quartile or 1.5 IQR of the 75th quartile; and dots show individual observations. Extreme values of CD4⁺/CD8⁺ ratio were clipped. *The lymphocyte count of Patient 2 (see Supplemental Table S1), who received two cycles of intravenous rituximab for the treatment of chronic lymphocytic leukemia at 3 mo before admission, was excluded. †Lymphocyte subset count was performed in 21/62 (33.9%) patients. COVID-19, coronavirus disease 2019; IgG, immunoglobulin G; IQR; interquartile range.

Figure 4.

Time course of laboratory findings and clinical characteristics in patients with COVID-19 with reduced and normal IgG levels at baseline. *6/13 (46.2%) patients with IgG deficiency at baseline received IVIg on the day of admission, whereas four required additional IVIg during the ICU course due to a further drop in IgG levels. The levels of lymphocyte count (A), IgG (B), and ferritin (C) in patients with COVID-19 with IgG-deficiency (<7 g/L IgG; red line) and normal IgG levels (>7 g/L IgG; blue line) at baseline were analyzed at different time points after hospital admission. The upper dotted lines show the upper normal limit of each parameter, and the lower dotted lines show the lower normal limit of each parameter. The graphs show the predictions from the generalized linear models for both groups (lines) with their 95% confidence bands (colored areas). The P values show the empirical significance of a difference in time trends between groups (group × time interaction, likelihood ratio test). COVID-19, coronavirus disease 2019; ICU, intensive care unit; IgG, immunoglobulin G; IVIg, intravenous immunoglobulin.