key: cord-0806819-tm1udp27
authors: Della-Torre, Emanuel; Lanzillotta, Marco; Strollo, Marta; Ramirez, Giuseppe Alvise; Dagna, Lorenzo; Tresoldi, Moreno
title: Serum IgG4 level predicts COVID-19 related mortality
date: 2021-09-24
journal: Eur J Intern Med
DOI: 10.1016/j.ejim.2021.09.012
sha: 41151931a366e9f0d175e8e3e3068c8f0435c297
doc_id: 806819
cord_uid: tm1udp27

nan

Coronavirus-19 disease (COVID-19) outcomes [1] [2] [3] [4] . Specifically, a poor COVID-19 outcome reportedly depends on an imbalanced humoral response whereby impaired viral neutralization translates into excessive systemic inflammation [2] . Severe COVID-19, for instance, has been associated with higher serum concentration of pro-inflammatory spike-specific IgG3 and afucosylated IgG1 antibodies capable of triggering exaggerated macrophage activation [2] [3] [4] .

Similarly, anti type I interferon (IFN) autoantibodies have been demonstrated in critical COVID-19 patients, phenocopying inborn errors of type I IFN immunity and leading to impaired innate and intrinsic antiviral immune responses [1] . On the other hand, anti-spike monoclonal neutralizing antibodies of IgG1 subclass from the plasma of convalescent COVID-19 patients have been shown to prevent life-threatening disease and are currently under evaluation in clinical trials [5] .

In view of their different inflammatory properties, we aimed to assess a possible association between IgG subclasses and COVID-19 related mortality. One hundred twenty-eight consecutive patients (41 females, 31.3 %) referred to the Emergency Department of San Raffaele Hospital (Milan, Italy) for COVID-19 between June and December 2020 were included and prospectively followed-up with daily data collection into an electronic case report form (COVID-BioB Study, Ethical Committee approval no. 34/int/2020, ClinicalTrials.gov NCT04318366) ( Table 1 ). All patients tested positive for SARS-CoV-2 nasopharyngeal swab and were treated with local standard of care (6 mg/day intravenous dexamethasone for 10 days and 4000 units/day subcutaneous enoxaparin) in addition to antibiotic and antipyretic therapy. IgG subclasses were measured before the institution of glucocorticoid treatment.

At baseline, IgG1, IgG2, IgG3, IgG4 subclasses were elevated in 8 (6%), 6 (5%), 6 (5%), and 13 (10%) patients, respectively. Thirty patients (23%) died at 30-days follow-up. As shown in Table   1 and Figure 1A , age, C-reactive protein (CRP), interleukin (IL)-6 serum IgG4 level, IgG4/IgG ratio, and IgG4/IgG1 ratio were significantly higher in non-survivors, while the PaO2/FiO2 ratio was significantly lower in survivors. Receiving operating curves (ROC) curves of statistically significant variables were created to predict mortality at 30 days. The AUC for age, serum IgG4, (Table 1) . Specifically, a concentration of serum IgG4 > 700 mg/dl and an IgG4/IgG1 ratio > 0.05 were associated with a significantly increased mortality at 30-days ( Figure 1B) . Of note, a significantly positive correlation was found between serum IgG4 and IL-6 level, an established predictor of COVID-19 related mortality ( Figure 1C ) [8] [9] [10] .

In this prospective study we found that serum IgG4 level predicts a poor COVID-19 outcome. Abbreviations: erythrocyte sedimentation rate (ESR); C-reactive protein (CRP); interleukin-6 (IL-6); Odds ratio (OR).

Autoantibodies against type I IFNs in patients with lifethreatening COVID-19

Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure

Proinflammatory IgG Fc structures in patients with severe COVID-19

Serological analysis reveals an imbalanced IgG subclass composition associated with COVID-19 disease severity

Neutralizing monoclonal antibodies for treatment of COVID-19

Rapid Generation of Neutralizing Antibody Responses in COVID-19 Patients

Adult-onset immunodeficiency in Thailand and Taiwan

Respiratory Impairment Predicts Response to IL-1 and IL-6 Blockade in COVID-19 Patients With Severe Pneumonia and Hyper-Inflammation

Interleukin-6 blockade with sarilumab in severe COVID-19 pneumonia with systemic hyperinflammation: an open-label cohort study

The authors agree to share the data generated by the present research and to make them openly and publicly available upon publication.

The authors have not received any financial support or other benefits from commercial sources for the work reported in the manuscript, or any other financial interests that could create a potential conflict of interest or the appearance of a conflict of interest with regard to the work.