key: cord-1015394-5nz0pes5
authors: Wilfong, Erin M; Matthay, Michael A
title: Intravenous immunoglobulin therapy for COVID-19 ARDS
date: 2021-11-11
journal: Lancet Respir Med
DOI: 10.1016/s2213-2600(21)00450-1
sha: bd554e3d995153ab5c867e575fe9af02b9c8af88
doc_id: 1015394
cord_uid: 5nz0pes5

nan

To date, the SARS-CoV-2 virus and COVID-19 has killed more than 4 million individuals worldwide. Morbidity and mortality arise from direct viral-induced injury to multiple organ systems, a dysregulated systemic immune response, and thrombosis. 1 Pharmacological immunomodulation has decreased mortality in severe COVID-19. Dexamethasone was the first drug to significantly reduce the risk of death in patients hospitalised with COVID-19 requiring supplemental oxygen. 2 Since then, IL-6 antagonists 3 and the Janus kinase inhibitor, baracitinib, 4 have been shown to reduce COVID-19-related mortality. 5 In the Lancet Respiratory Medicine, Aurélien Mazeraud and colleagues 6 report the results of a multicentre, double-blind, placebo-controlled, phase 3 trial of 146 patients with moderate-to-severe COVID-19associated acute respiratory distress syndrome (ARDS) who received either intravenous immunoglobulin (IVIG; 69 [47%] patients) or placebo (77 [53%] patients). 6 IVIG is an attractive adjuvant for the management of severe COVID-19-associated ARDS because of its ability to simultaneously modulate multiple immune compartments. IVIG can neutralise autoantibodies, inhibit activation of the complement cascade, impair the costimulatory and antigen presenting capabilities of dendritic cells, inhibit T helper 17 cell proliferation, and expand regulatory T cell populations. 7 Because dendritic cell, B cell, and T cell dysregulation is associated with severe COVID-19, 8 the multimodal effects of IVIG make it a good therapeutic candidate for patients hospitalised with COVID-19.

The patients included in the study reflected the wider population of critically ill patients with COVID-19-associated ARDS. 103 (71%) patients were male, and 87 (60%) patients were 65 years old or older. The mean body-mass index in both groups was more than 30 kg/m². Patients were intubated at a median of 8 days after symptom onset, randomly assigned within 72 h of initiating invasive mechanical ventilation, and met the moderate-to-severe hypoxaemia categories of the Berlin definition of ARDS. The exclusion criteria were acute renal failure, pregnancy, allergy to IVIG, or immunoglobulin A deficiency. 121 (83%) patients received antibiotics, and 104 (71%) patients received corticosteroids, which is expected given the enrolment period. Baseline demographics, severity of illness, and indices of respiratory failure were similar between the placebo group and the IVIG group. Neither the primary outcome of ventilator-free days over 28 days nor 90-day mortality were different between the two groups. Of note, the number of deaths in the placebo group at day 28 (20 [26%] patients) was much lower than the predicted 28-day mortality rate of 50%, but the observed mortality was similar to the 29% mortality reported in the dexamethasone group of the RECOVERY trial. 2 Numerically, both 28-day mortality and median time to extubation both favoured the placebo group, although the confidence intervals were wide.

There was a trend towards increased serious adverse events in the IVIG group, but the difference was not significant. Three-times as many patients in the IVIG group (ten [15%] patients) compared with the placebo (three [4%] patients) developed deep venous thrombosis or pulmonary embolism. IVIG is associated with an increased risk of thromboembolism, potentially due to infusion-related transient hyper viscosity syndrome. Reduction of infusion rates, coadministration of hydration, and therapeutic enoxaparin can ameliorate these risks. 9 This trial infused IVIG slowly over 8 h, but therapeutic anticoagulation and hydration were not part of the trial protocol, which was reasonable in this patient population. However, the hypercoagulable state of COVID-19 probably increased the risk of IVIG associated thrombosis. Additionally, IVIG induced immune haemolytic anaemia was reported in two (3%) patients. Although the risk of thrombosis and haemolytic anaemia were not statistically significant, their presence raises the question of harm without a perceived potential benefit.

Patients in the IVIG group had increased IL-13 concentration at day 7 and an increased proportion of CD4 T regulatory and memory cells at day 28, but interpretation of these findings is challenging. IL-13 has been reported to both improve lung injury 10 and worsen pulmonary fibrosis. 11 Most deaths in the trial occurred before day 28; as a result, interpretation of the CD4 T regulatory and memory cell findings is limited by survivor bias.

The question of whether a subgroup of patients with severe COVID-19 might benefit from IVIG remains. Mazeraud that IVIG might prevent progression of severe COVID-19 to ARDS or be beneficial in the recovery phase, but replacement doses of IVIG might benefit patients with hypogammaglobulinaemia due to either a primary immunodeficiency or secondary hypogammaglobulinaemia due to B cell depleting drugs, such as rituximab. Hypogammaglobulinaemia is associated with an increased risk of encapsulated bacterial organisms, and hypogammaglobulinaemic patients with septic shock are at increased risk of death. 12 Although plausible that replacement doses of IVIG could benefit critically ill patients with hypogammaglobulinaemia, additional studies are required.

In conclusion, IVIG did not significantly improve outcomes in moderate-to-severe COVID-19-associated ARDS and was associated with an increase in thromboembolic adverse events. Future work might identify subgroups of patients with acute COVID-19 who would benefit from IVIG, but the current evidence does not support use of IVIG in COVID-19-associated ARDS. EMW reports support from the National Institutes of Health (NIH); and reports research funding and consulting fees from Boehringer-Ingelheim, outside of the submitted work. MAM reports funding from the NIH, outside the submitted work; and consulting fees from Citrus Pharmaceuticals, outside the submitted work.

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