Autoantibodies neutralizing antiinflammatory mediators in the context of SARS-CoV-2 infection and COVID-19

Breakdown of peripheral immune tolerance can be triggered by environmental factors or excessive inflammation. These can induce atypically posttranslational modified isoforms of self-proteins, which—in context of permissive HLA-alleles—can trigger autoimmune phenomena including the formation of autoantibodies. Various self-reactive antibody responses have been reported in context of the hyperinflammation associated with SARS-CoV-2 infection. Here we describe unique autoantibodies targeting the antiinflammatory mediators progranulin and the interleukin one receptor antagonist (IL-1-Ra), both arising frequently in the course of critical COVID-19 in adults or exclusively (anti-IL-1Ra-Ab) in multisystem inflammatory syndrome in children (MIS-C). These antibodies are triggered by hyperphosphorylated, transiently occurring isoforms of PGRN and of IL-1-Ra. Anti-PGRN- and anti-IL1-Ra-autoantibodies deplete their endogenous antigens from patients' plasma and impair their antiinflammatory bioactivity. Collectively, these antibodies can contribute to imbalanced inflammatory signaling in context of SARS-CoV-2 infection-associated hyperinflammation and potentially exacerbate disease. © 2023 Elsevier Inc. All rights reserved.

Investigation of the potential of leukoreduction filters in the creation of anti-inflammatory compound.

BACKGROUND: Some viruses such as SARS, SARS-CoV-2, and MERS cause an imbalance in immune responses and leads to an acute inflammatory reaction named cytokine storm. In this situation, an anti-inflammatory component can modulate the immune system and decrease mortality. The aim of this study was investigate the potential of leukoreduction filters (LRFs) in creating an anti-inflammatory compound. MATERIALS AND METHODS: In this experimental study, firstly optimal dose of the anti-inflammatory drug was obtained through LRFs treatment with 0.1 mg, 0.4 mg, 0.6 mg of Betamethasone. Then inflammatory and anti-inflammatory cytokine in gene and protein level was evaluated. In the next step, LRFs were categorized into treatment 1, treatment 2, control assay, and control groups and treated with the optimal dose of the drug. Finally, the obtained compound was investigated for the concentration of IL1, IL6, and TNF-α as inflammatory and IL4, IL1Ra, and IL10 as anti-inflammatory cytokines. RESULTS: The results of the current study showed that the concentration of 0.4 mg of Betamethasone lead to a significant increase of anti-inflammatory cytokine in gene and protein levels. The results also showed that the Betamethasone treated groups (treatment1) causes a significant increase in the secretion of anti-inflammatory cytokine compares to the control while inflammatory cytokine remained at the control level. CONCLUSION: The results showed that under influence of anti-inflammatory drug treatments the production and secretion of anti-inflammatory cytokines can be induced in LRFs.

Hyperinflammatory State and Low T1 Adaptive Immune Response in Severe and Critical Acute COVID-19 Patients.

Background: A better understanding of COVID-19 immunopathology is needed to identify the most vulnerable patients and improve treatment options. Objective: We aimed to identify immune system cell populations, cytokines, and inflammatory markers related to severity in COVID-19. Methods: 139 hospitalized patients with COVID-19-58 mild/moderate and 81 severe/critical-and 74 recovered patients were included in a prospective longitudinal study. Clinical data and blood samples were obtained on admission for laboratory markers, cytokines, and lymphocyte subsets study. In the recovered patients, lymphocyte subsets were analyzed 8-12 weeks after discharge. Results: A National Early Warning Score 2 >2 (OR:41.4; CI:10.38-167.0), ferritin >583 pg/mL (OR:16.3; CI: 3.88-69.9), neutrophil/lymphocyte ratio >3 (OR: 3.5; CI: 1.08-12.0), sIL-2rα (sCD25) >512 pg/mL (OR: 3.3; CI: 1.48-7.9), IL-1Ra >94 pg/mL (OR: 3.2; IC: 1.4-7.3), and IL-18 >125 pg/mL (OR: 2.4; CI: 1.1-5.0) were associated with severe/critical COVID-19 in the multivariate models used. Lower absolute values of CD3, CD4, CD8, and CD19 lymphocytes together with higher frequencies of NK cells, a CD4 and CD8 activated (CD38+HLA-DR+) memory T cell and effector memory CD45RA+ (EMRA) phenotype, and lower T regulatory cell frequencies were found in severe/critical patients relative to mild/moderate and recovered COVID-19 patients. A significant reduction in Th1, Tfh1, and Tc1 with higher Th2, Tfh2, Tc2, and plasma cell frequencies was found in the most severe cases. Conclusion: A characteristic hyperinflammatory state with significantly elevated neutrophil/lymphocyte ratio and ferritin, IL-1Ra, sIL-2rα, and IL-18 levels together with a "low T1 lymphocyte signature" was found in severe/critical COVID-19 patients.

COVID-19 Disease and Associated Thrombocytopenia: Pathogenesis and a Clue to the Etiology.

(1) Background: Hospital mortality in patients suffering from SARS-CoV-2 infection has been associated with thrombocytopenia. The present study was conducted to establish the correlation of thrombocytopenia and the severity of infection. The impact of IL-1Ra gene polymorphism on the incidence and severity of thrombocytopenia was also studied. (2) Methods: Various biochemical parameters measured in all the 1200 enrolled patients included full blood counts, renal and liver function tests, iron study, inflammatory markers, and coagulation assays. A further 70 patients each were selected from the severe thrombocytopenic and non-thrombocytopenic patient groups to study the IL-1Ra gene polymorphism by RCR. (3) Results: Out of 1200 patients, 436 (36.3%) had thrombocytopenia. Among these patients, 118 (27.1%), 75 (17.2%), and 42 (9.6%) had mild, moderate, severe, and very severe thrombocytopenia, respectively. Severe cases mostly resulted from peripheral consumption (73.5%), hemo-phagocytosis (15.4%), and bone marrow suppression (11.11%). A statistically significant correlation was found between the occurrence and severity of thrombocytopenia with perturbated levels of inflammatory markers and the presence of comorbidities. The IL-1Ra∗3 variant was found to be significantly associated with thrombocytopenia. The IL-1Ra∗2 variant was significantly seen among controls. (4) Conclusions: The present study revealed a significant correlation between thrombocytopenia and the severity of COVID-19 disease. Moreover, the IL-1Ra∗3 variant of IL-1Ra gene was associated with thrombocytopenia.

Anakinra reduces lung inflammation in experimental acute lung injury.

INTRODUCTION: Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury (ALI) resulting in life-threatening hypoxaemia. Although ARDS can be caused by a variety of pathogens or major trauma, it is best known as the major cause of mortality in COVID-19 patients. Since ARDS is often associated with dysregulated inflammatory immune responses, immunomodulatory approaches represent a possible treatment option. The objective of this study was to evaluate the therapeutic potential of interleukin (IL)-1 blockade using Anakinra in a mouse model of lipopolysaccharide (LPS)-induced ALI. METHODS: We evaluated the effects of a daily subcutaneous Anakinra treatment in a mouse model of LPS-induced ALI. We monitored body weight to assess the general health status of the mice. Two days after ALI induction, we evaluated the inflammatory cytokine MIP-2 as well as protein levels in bronchoalveolar lavage (BAL) fluids. Two and nine days after ALI induction, we evaluated infiltrating leukocytes in BAL fluid and lung tissue. RESULTS: Anakinra treatment reduced ALI-induced weight loss compared to nontreated groups. At Day 2, Anakinra treatment reduced levels of MIP-2 and protein in BAL fluids and reduced frequencies of NK cells and neutrophils in the lung tissue. Nine days after ALI induction, Anakinra treated mice displayed reduced levels of neutrophils and alveolar macrophages in BAL fluids. CONCLUSIONS: IL-1 blockade using Anakinra reduced classical hallmarks of inflammation in a mouse model of ALI. Our data support ongoing and future research on the evaluation of Anakinra as a potential treatment option in ARDS.

Evaluation of alpha defensin, IL-1 receptor antagonist, and IL-18 levels in COVID-19 patients with macrophage activation syndrome and acute respiratory distress syndrome.

BACKGROUND: Many laboratory parameters have been associated with morbidity and mortality in SARS-CoV-2 (COVID-19), which emerged in an animal market in Wuhan, China in December 2019 and has infected over 20 million people. This study investigated the relationship between serum interleukin (IL)-18, IL-1 receptor antagonist (IL-1Ra), and alpha defensin levels and the clinical course and prognosis of COVID-19. MATERIALS AND METHODS: This study included 100 patients who were admitted to the chest diseases department and intensive care unit of our hospital and diagnosed with COVID-19 by real-time polymerase chain reaction (PCR) of nasopharyngeal swab samples between March 24 and May 31, 2020. The control group consisted of 50 nonsymptomatic health workers with negative real-time PCR results in routine COVID-19 screening in our hospital. RESULTS: Serum alpha defensin, IL-1Ra, and IL-18 levels were significantly higher in patients who developed macrophage activation syndrome (MAS) and acute respiratory distress syndrome (ARDS) compared to patients who did not (p < .001 for all). Alpha defensin, IL-1Ra, and IL-18 levels were significantly higher in COVID-19 patients with and without MAS or ARDS when compared to the control group (p < .001 for all). When the 9 patients who died were compared with the 91 surviving patients, IL-1Ra and IL-18 levels were found to be significantly higher in the nonsurvivors (p < .001). CONCLUSION: Our findings of correlations between alpha defensin and levels of IL-1Ra and IL-18, which were previously shown to be useful in COVID-19 treatment and follow-up, indicates that it may also be promising in treatment.

Case Report: Case Series of Children With Multisystem Inflammatory Syndrome Following SARS-CoV-2 Infection in Switzerland.

Since the beginning of the severe SARS-CoV-2 pandemic, an increasing number of countries reported cases of a systemic hyperinflammatory condition defined as multi-system inflammatory syndrome in children (MIS-C). The clinical features of MIS-C can be an overlap of Kawasaki Disease (KD), Toxic Shock Syndrome (TSS), Macrophage Activation Syndrome (MAS), or have often an acute abdominal presentation. Intravenous immunoglobulin (IVIG) is recommended as first line therapy in KD. Recent evidence suggests intravenous immunoglobulins (IVIG) resistance in some cases of SARS-CoV-2 related MIS-C, thereby questioning the benefit of immunomodulators such as IL-1 or IL-6 blocking agents. We report on a cohort of 6 Swiss children with SARS-CoV2 related MIS-C presenting with clinical features compatible with Incomplete KD and Toxic Shock Syndrome associated to a cytokine storm. Serum cytokine profile investigations showed increased IL1RA levels (8 to 22-fold) in 5 of the 6 patients (one patient had not been tested), whereas, IL-6 serum levels were increased only in the 3 patients of the 6 who were tested. With exception of one patient who had only benefited by Anakinra, all patients received at least one dose of IVIG. One patient has only received Anakinra with favorable evolution, and three patients had also a steroid treatment. In addition to all this anti-inflammatory medication two patients have also received one dose of anti-IL6. In conclusion, our case series reports on clinical and laboratory findings of most of Swiss cases with MIS-C and suggests the use of Anakinra as an alternative to steroids in these children, most of whom presented with high IL-1RA levels.

Unique inflammatory profile is associated with higher SARS-CoV-2 acute respiratory distress syndrome (ARDS) mortality.

The COVID19 pandemic has caused more than a million of deaths worldwide, primarily due to complications from COVID19-associated acute respiratory distress syndrome (ARDS). Controversy surrounds the circulating cytokine/chemokine profile of COVID19-associated ARDS, with some groups suggesting that it is similar to patients without COVID19 ARDS and others observing substantial differences. Moreover, although a hyperinflammatory phenotype associates with higher mortality in non-COVID19 ARDS, there is little information on the inflammatory landscape's association with mortality in patients with COVID19 ARDS. Even though the circulating leukocytes' transcriptomic signature has been associated with distinct phenotypes and outcomes in critical illness including ARDS, it is unclear whether the mortality-associated inflammatory mediators from patients with COVID19 are transcriptionally regulated in the leukocyte compartment. Here, we conducted a prospective cohort study of 41 mechanically ventilated patients with COVID19 infection using highly calibrated methods to define the levels of plasma cytokines/chemokines and their gene expressions in circulating leukocytes. Plasma IL1RA and IL8 were found positively associated with mortality, whereas RANTES and EGF negatively associated with that outcome. However, the leukocyte gene expression of these proteins had no statistically significant correlation with mortality. These data suggest a unique inflammatory signature associated with severe COVID19.