Intravenous Immunoglobulin Plus Methylprednisolone Mitigate Respiratory Morbidity in Coronavirus Disease 2019

Abstract

Dysregulated neutrophil and platelet interactions mediate immunothrombosis and cause lung injury in coronavirus disease 2019. IV immunoglobulin modulates neutrophil activation through FcγRIII binding. We hypothesized that early therapy with IV immunoglobulin would abrogate immunothrombosis and improve oxygenation and reduce progression to mechanical ventilation in coronavirus disease 2019 pneumonia.

Design: Prospective randomized open label.

Setting: Inpatient hospital.

Patients and intervention: Hypoxic subjects with coronavirus disease 2019 pneumonia were randomized 1:1 to receive standard of care plus IV immunoglobulin 0.5 g/kg/d with methylprednisolone 40 mg 30 minutes before infusion for 3 days versus standard of care alone.

Main results: Sixteen subjects received IV immunoglobulin and 17 standard of care. Median ages were 51 and 58 years for standard of care and IV immunoglobulin, respectively. Acute Physiology and Chronic Health Evaluation II and Charlson comorbidity scores were similar for IV immunoglobulin and standard of care. Seven standard of care versus two IV immunoglobulin subjects required mechanical ventilation (p = 0.12, Fisher exact test). Among subjects with A-a gradient of greater than 200 mm Hg at enrollment, the IV immunoglobulin group showed: 1) a lower rate of progression to requiring mechanical ventilation (2/14 vs 7/12, p = 0.038 Fisher exact test), 2) shorter median hospital length of stay (11 vs 19 d, p = 0.01 Mann Whitney U test), 3) shorter median ICU stay (2.5 vs 12.5 d, p = 0.006 Mann Whitey U test), and 4) greater improvement in Pao₂/Fio₂ at 7 days (median [range] change from time of enrollment +131 [+35 to +330] vs +44·5 [-115 to +157], p = 0.01, Mann Whitney U test) than standard of care. Pao₂/Fio₂ improvement at day 7 was significantly less for the standard of care patients who received glucocorticoid therapy than those in the IV immunoglobulin arm (p = 0.0057, Mann Whiney U test).

Conclusions: This pilot study showed that IV immunoglobulin significantly improved hypoxia and reduced hospital length of stay and progression to mechanical ventilation in coronavirus disease 2019 patients with A-a gradient greater than 200 mm Hg. A phase 3 multicenter randomized double-blinded clinical trial is under way to validate these findings.

Keywords: coronavirus disease 2019; immunothrombosis; intravenous immunoglobulin; pneumonia.

Figure 1.

Distribution of (A) Charlson comorbidity index and (B) Acute Physiology and Chronic Health Evaluation II scores of enrolled study subjects in both treatment arms, showing even distribution of chronic illness and acute severity of illness. Horizontal bars denote median values. Red points indicate patients who ultimately required a need for mechanical ventilation. IVIG = IV immunoglobulin, SOC = standard of care.

Figure 2.

A, Rates of mechanical ventilation in study subjects stratified by alveolar-arterial (A-a) gradient. Among patients with A-a gradient > 200 mm Hg, receipt of IV immunoglobulin (IVIG) reduced rates of mechanical ventilation (*p = 0.038, Fisher exact test). B, Total length of hospital stay (d) among patients in standard of care (SOC) vs IVIG with A-a gradient > 200 mm Hg. Median stay (horizontal bar) SOC 19 d vs IVIG 11 d, p = 0.01 Mann Whitney U test. C, Length of ICU stay (d) among patients in SOC vs IVIG with A-a gradient > 200 mm Hg. Median (horizontal bar) stay SOC 12.5 d vs IVIG 2.5 d, p = 0.006 Mann Whitney U test.

Figure 3.

Individual patient progress of Pao₂/Fio₂ at day of enrollment (day 0) and 7 d later in control standard of care (SOC) group (A) and IV immunoglobulin (IVIG) group (B). Patients who were discharged and the one patient that died before day 7 had values placed from the last available day. C, The absolute differences for each group. Red data points denote patients who did not receive any glucocorticoid therapy. Differences in 7-d Pao₂/Fio₂ showed greater improvement oxygenation in IVIG-treated patients when compared with the entire SOC cohort (p = 0·057, Mann Whitney U test) but became significant after considering only those patients with alveolar-arterial gradient at enrollment of > 200 (p = 0.01, Mann Whitney U test) and when comparing IVIG vs only SOC patients who received glucocorticoid therapy (p = 0.025, Mann Whitney U test).