key: cord-0733328-f5v6sx79
authors: López-Medrano, Francisco; Aguado, José María
title: Intravenous immunoglobulins for the treatment of the hyper-inflammatory response in COVID-19. Another failure of immunomodulatory therapy?
date: 2021-07-26
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2021.07.012
sha: 2535645dbc227400121d9e0330ed26ee380545f2
doc_id: 733328
cord_uid: f5v6sx79

nan

It was in 1880 when diphtheria toxin was discovered and, shortly after, the treatment of this infectious diseases with the serum of convalescent patients was proposed for the first time (1) . Since then, a long chapter has been written in the History of Medicine about the use of serum o plasma containing immunoglobulins for the treatment, pre-emptive therapy or prophylaxis of infectious diseases. In the pandemic of influenza virus infection in 1918, called the Spanish flu, convalescent human serum was used for patients with pneumonia (2) . In Spain and in other European countries, "anti-pneumococcal" and "anti-streptococcal" serum was also used during this devastating pandemic of the 20 th century(3). Hyperimmune intravenous immunoglobulins (IVIG) have been used, with greater or lesser success, for the treatment or post-exposition prophylaxis of diphtheria, tetanus, botulism, rabies, hepatitis A and B virus, cytomegalovirus, dengue, varicella-zoster virus or Ebola virus infection (4) . The exact mechanism of action of the immunoglobulins when they are used for this latter purpose is not completely understood. The immunoglobulin G (IgG) presents two functional domains, known as F(ab)´2 fragment (dimeric antigenbinding fragment) and Fc fragment (crystallizable fragment). The first one is responsible for specific antigen binding and the second one for binding to the receptor and complement system. Several hypotheses have been proposed to explain their anti-inflammatory and immunomodulatory effects (5) . For example, IVIG include antigen-specific IgG targeting endogenous antigens (mediated by the F(ab)´2 fragment) as cytokines, chemokines or complement factors. High levels of Fc can saturate their receptors in endothelial cells, decreasing the activity of the innate immunity (macrophages, dendritric cells, natural killer cells and neutrophils) and decreasing the activation of the complement system.

Other mechanisms mediated by Fc fragment present the adaptive immunity as their target: some Fc receptors (mainly FcγRIIB) negatively regulate the inflammatory response. High-dose IVIG produce an upregulation in FcγRIIB that induces the apoptosis of B cells as well as the death of Th1, Th2 and Th17 cells (6) .

In this issue of Clinical Microbiology and Infection Liu J et al. (7) present the results of a multicenter retrospective study to evaluate the effect of IVIG, as immunomodulatory therapy, in patients admitted to the hospital due to severe pneumonia by SARS-CoV-2 (according to pre-specified criteria that included PaO2/FiO2 ≤ 300 mmHg). The investigators included 406 patients that had received IVIG according to a decision at the "discretion of the physician in charge of the patient". They compared them 1:1 to controls, matched by J o u r n a l P r e -p r o o f 6 confounding factors, which did not receive IVIG. The authors did not find a significant difference in 28-day mortality (that was established as the main outcome): average treatment effect was 0.008 (95% confidence interval -0.081 to 0.097; p=0.86). There were no differences between the two groups for most of the secondary outcomes.

There are some methodological issues of this article(7) that must be highlighted. First, the authors included patients with "lung imaging" lesions that has progressed "more than 50% within a period of 24-48 hours". In our opinion, We would also like to call attention to the fact that the median dose of IVIG that was used was 9.8 g/day for survivors and 10.42 g/day for non-survivors (7) . This J o u r n a l P r e -p r o o f doses seems to be much lower than those usually prescribed when an immunomodulatory effect of IVIG is searched. For example, in a recent study evaluating IVIG treatment for patients developing septic shock in the context of necrotizing fasciitis, the median dose was 1g/kg (this will mean a dose of 70 g/day for a standard weight of 70 kg) (8) . This difference in doses might justify the negative results obtained in the current study. In another study reporting negative results, developed in Japan, low-dose IVIG were used in sepsis (9) .

As previously specified, IVIG can be used for the treatment of infectious diseases in different ways and it is important not to confuse them. The authors of the present study propose using nonspecific IVIG based on their immunomodulatory effect. But they cite as previous relevant studies in the same line of research, three studies that used IVIG in a different way: in one of them IVIG were used for an autoimmune disease(10), in the second one the plasma with high-titer anti-influenza antibodies was used due to the supposed direct neutralizing properties of the specific immunoglobulins (11) but not based in their immunomodulatory properties. The third refers to a study based in the use of convalescent plasma for MERS-CoV pneumonia but, again, not based on the use of nonspecific IVIG(12) (the use of convalescent plasma has also been extensively studied in the context of COVID-19(13)).

The primary outcome for the study(7) was 28-day mortality, which is the standard for many trials and other comparative studies searching for therapeutic alternatives in COVID-19. In our opinion, many other determinants for mortality might be implicated when the outcome is set 4 weeks away from a punctual and short-in-time therapeutic decision as is IVIG treatment. May be, alternative outcomes such as 14-day mortality or improvement in respiratory and/or inflammatory parameters, might be more adequate for measuring the effect of this type of immunomodulatory treatments.

Previous experiences about the use of non-specific IVIG with an immunomodulatory purpose, in the context of severe COVID-19, have been published. Two comparative studies demonstrated a benefit of IVIG in terms of mortality rate (14, 15) . Both studies included less than 30 patients in the arm receiving IVIG. Another study demonstrated a benefit of IVIG in terms of clinical parameters (16) . A randomized controlled trial, also including a very limited number of patients, did not demonstrate a reduction in mortality rate (17) . The methodological limitations of all of them preclude the extraction of any definitive conclusion about the role of IVIG in the context of SARS-Cov-2 infection.

The treatment with immunoglobulins is not exempt from adverse events as serum-sickness reaction or thrombotic events (that were not specifically assessed in their study) as well as the potential transmission of some microorganisms(18). Maximum caution and quality controls should be applied for IVIG preparation(18).

We acknowledge the effort of Liu J et al. (7) to bring some light into a field with scarce scientific information available. Despite its negative results, their study must be considered as an exploratory approach for a complex clinical situation that paves the way for the development of prospective clinical trials to study the immunomodulatory effect of nonspecific IVIG in the context of the COVID-19 pandemic.

J o u r n a l P r e -p r o o f

Funding sources: This work was supported by Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (COV20/00181)co-financed by European Development Regional Fund "A way to achieve Europe". 

Ueber das Zustandekommen der Diphtherie-Immunität bei Thieren

THE USE OF CONVALESCENT HUMAN SERUM IN INFLUENZA PNEUMONIA-A PRELIMINARY REPORT

Polyclonal hyper immunoglobulin: A proven treatment and prophylaxis platform for passive immunization to address existing and emerging diseases

High-Dose Intravenous Immunoglobulins in the Treatment of Severe Acute Viral Pneumonia: The Known Mechanisms and Clinical Effects

Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor

Intravenous immunoglobulin treatment for patients with severe COVID-19: a retrospective multi

Impact of Intravenous Immunoglobulin on Survival in Necrotizing Fasciitis With Vasopressor-Dependent Shock: A Propensity Score-Matched Analysis From 130 US Hospitals

Intravenous immunoglobulin and mortality in pneumonia patients with septic shock: an observational nationwide study

Randomized Placebo-Controlled Trial of Intravenous Immunoglobulin in Autoimmune LGI1/CASPR2 Epilepsy

Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial

Feasibility of Using Convalescent Plasma Immunotherapy for MERS-CoV Infection, Saudi Arabia

Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review

High-Dose Intravenous Immunoglobulin in Severe Coronavirus Disease 2019: A Multicenter Retrospective Study in China

The use of intravenous immunoglobulin gamma for the treatment of severe coronavirus disease 2019: a randomized placebo-controlled doubleblind clinical trial

A Phase II Safety and Efficacy Study on Prognosis of Moderate Pneumonia in Coronavirus Disease 2019 Patients With Regular Intravenous Immunoglobulin Therapy

Evaluating the effects of Intravenous Immunoglobulin (IVIg) on the management of severe COVID-19 cases: A randomized controlled trial