Immunopathology Of COVID-19 Research Articles

Defining the scourge of COVID-19 hyperinflammatory syndrome.

Defining the scourge of COVID-19 hyperinflammatory syndrome.

Increased Serum Levels of sCD14 and sCD163 Indicate a Preponderant Role for Monocytes in COVID-19 Immunopathology.

BackgroundEmerging evidence indicates a potential role for monocytes in COVID-19 immunopathology. We investigated two soluble markers of monocyte activation, sCD14 and sCD163, in COVID-19 patients, with the aim of characterizing their potential role in monocyte-macrophage disease immunopathology. To the best of our knowledge, this is the first study of its kind.MethodsFifty-nine SARS-Cov-2 positive hospitalized patients, classified according to ICU or non-ICU admission requirement, were prospectively recruited and analyzed by ELISA for levels of sCD14 and sCD163, along with other laboratory parameters, and compared to a healthy control group.ResultssCD14 and sCD163 levels were significantly higher among COVID-19 patients, independently of ICU admission requirement, compared to the control group. We found a significant correlation between sCD14 levels and other inflammatory markers, particularly Interleukin-6, in the non-ICU patients group. sCD163 showed a moderate positive correlation with the time lapsed from admission to sampling, independently of severity group. Treatment with corticoids showed an interference with sCD14 levels, whereas hydroxychloroquine and tocilizumab did not.ConclusionsMonocyte-macrophage activation markers are increased and correlate with other inflammatory markers in SARS-Cov-2 infection, in association to hospital admission. These data suggest a preponderant role for monocyte-macrophage activation in the development of immunopathology of COVID-19 patients.

Immunomodulatory drug therapy for the disease caused by SARS-CoV-2 infection (COVID-19)

This systematic review focuses on the state-of-the-art pharmacotherapy of immune disorders in the novel coronavirus infection (COVID-19), leading to a cytokine storm and uncontrolled inflammatory response that causes severe tissue damage and multiple organ failure. A lot of theoretical, experimental and clinical data support the need for immunomodulatory (immunosuppressive) therapy for this disease. It should be emphasized that all immunomodulatory drugs for COVID-19 are prescribed off label, and the evidence base of the results of randomized trials is just being accumulated. We review the immunomodulatory therapy for COVID-19 with the following agents: glucocorticoids, hydroxychloroquine and chloro-quine, type 1 interferons, interleukin-6 antagonists (tocilizumab, sarilumab, olokizumab), interleukin-1 p inhibitor canakinumab, tumour necrosis factor inhibitors (infliximab), Janus kinase (JAK) inhibitors (tofacitinib, baricitinib, ruxolitinib), as well as drugs with other mechanisms of action (abatacept, nivolumab, tacrolimus, sirolimus, fingolimod, melphalan, cyclosporine, methotrexate). At the moment, the most reasonable is the use of interleukin-6 receptor inhibitors, intermediate and high dose glucocorticoids, and JAK inhibitors. Based on the latest data from clinical studies, especially the "Solidarity” trial, the use of hydroxychloroquine and chloroquine seems to have insufficient evidence. There are significant pathophysiological overlaps in the development of immunopathology in COVID-19 and in rheumatic diseases, and the strategy of early aggressive immunosuppressive therapy proposed by a number of researchers almost completely coincides with the current strategies for rheumatoid arthritis.

Complement C3 vs C5 inhibition in severe COVID-19: Early clinical findings reveal differential biological efficacy

Growing clinical evidence has implicated complement as a pivotal driver of COVID-19 immunopathology. Deregulated complement activation may fuel cytokine-driven hyper-inflammation, thrombotic microangiopathy and NET-driven immunothrombosis, thereby leading to multi-organ failure. Complement therapeutics have gained traction as candidate drugs for countering the detrimental consequences of SARS-CoV-2 infection. Whether blockade of terminal complement effectors (C5, C5a, or C5aR1) may elicit similar outcomes to upstream intervention at the level of C3 remains debated. Here we compare the efficacy of the C5-targeting monoclonal antibody eculizumab with that of the compstatin-based C3-targeted drug candidate AMY-101 in small independent cohorts of severe COVID-19 patients. Our exploratory study indicates that therapeutic complement inhibition abrogates COVID-19 hyper-inflammation. Both C3 and C5 inhibitors elicit a robust anti-inflammatory response, reflected by a steep decline in C-reactive protein and IL-6 levels, marked lung function improvement, and resolution of SARS-CoV-2-associated acute respiratory distress syndrome (ARDS). C3 inhibition afforded broader therapeutic control in COVID-19 patients by attenuating both C3a and sC5b-9 generation and preventing FB consumption. This broader inhibitory profile was associated with a more robust decline of neutrophil counts, attenuated neutrophil extracellular trap (NET) release, faster serum LDH decline, and more prominent lymphocyte recovery. These early clinical results offer important insights into the differential mechanistic basis and underlying biology of C3 and C5 inhibition in COVID-19 and point to a broader pathogenic involvement of C3-mediated pathways in thromboinflammation. They also support the evaluation of these complement-targeting agents as COVID-19 therapeutics in large prospective trials.

LBA81 Keeping exhausted T-cells in check in COVID-19

Clinical data suggest an aggravated COVID-19 disease course in cancer patients treated with immune checkpoint inhibitors (ICI). European guidelines advise to defer ICI therapy until complete resolution of COVID-19. However, mechanistic insight into how ICI impacts COVID-19 immunopathology is absent. We performed single-cell RNA- and T-Cell Receptor-sequencing (TCR-seq) on bronchoalveolar lavage fluid of COVID-19 pneumonia (n=19) and non-COVID pneumonia (n=10), and co-analyzed CD8+ T-cells with publicly available tumor-infiltrating T-cell data of treatment-naïve and ICI-treated patients (Sade-Feldman, Cell, 2018; Lambrechts, Nat Med, 2018). Cell lineages were determined by trajectory inference (Slingshot, Monocle v2) and stratified per condition. Pathogen- or tumor-directed T-cells were defined based on clonal selection (Zhang, Nature, 2018). To identify ICI responsive cells, we calculated a score derived from a validated gene set denoting ICI reactivity (Okamura, J. Autoimmun, 2019). We identified 3 CD8+ T-cell lineages, with ‘Naïve’ T-cells transitioning into ‘Effector Memory’ cells and then branching into either ‘Recently Activated Effector Memory (TEMRA)’, ‘Exhausted (TEX)’ or ‘Resident Memory (TRM)’ T-cells. In COVID-19, clonal expansion indicating a SARS-CoV-2 antigen-specific T-cell response, was mainly observed in the highly cytotoxic ‘TEMRA’ lineage. In contrast, tumor-specific T-cells were found in the ‘TEX’ lineage. Of importance, the ICI responsiveness score was significantly higher in the non-pathogen-directed ‘TRM’ and ‘TEX’ cells in COVID-19. In cancer, ‘TEX’ cells were shown to be ICI responsive as expected.Table:Demographics and characteristics of study cohortCOVID-19 pneumonia (n=19)Non-COVID pneumonia (n=10)Age (y)60 [55.5-69]69.5 [62.75-75.25]Men14 (74)5 (50)Women5 (26)5 (50)Time from illness onset to sampling (d)19 [16-25]15 [9-19]SARS-CoV-2 PCR positive6 (32)a0 (0)Other viral PCR positive4 (21)b1 (10)cBacterial culture positive3 (16)2 (20)PJP PCR positive0 (0)4 (40)Respiratory support19 (100)7 (70)Oxygen via nasal cannula0 (0)4 (40)Non-invasive ventilation0 (0)1 (10)Invasive ventilation15 (79)2 (20)Extracorporeal membrane oxygenation4 (21)0 (0)Antiviral therapy (<7d)13 (68)d0 (0)Antibiotics (<7d)19 (100)8 (80)Immunomodulatory therapy (<7d)5 (26)e0 (0) Open table in a new tab We are the first to provide a mechanistic rationale for an aggravated COVID-19 disease course in ICI-treated patients. Whereas ICI reactivates tumor-directed ‘exhausted’ T-cells in cancer, it preferentially potentiates non-pathogen-directed T-cells in COVID-19, thereby contributing to lung damage without boosting the antiviral immune response.

Iran-Cohort Study of COVID-19 Immunology and Immunopathology

Iran-Cohort Study of COVID-19 Immunology and Immunopathology

Immunological and Neurological Manifestations of COVID-19: An Intimate Relationship

Background: COVID-19 has superseded all medical scientific challenges in 2020. It presented with a range of respiratory involvement from the mild upper respiratory tract to severe pneumonia with ARDS. A percentage of these patients manifested variable neurological presentations expanding the challenges of patients’ assessment, care, and management.&#x0D; Objective: To discuss the neurological manifestations and the possible immunopathology of COVID-19.&#x0D; Methods: A literature search was performed in the PubMed database for the relevant articles published in English language between April 9th , 2020 and June 1, 2020. Few papers were extracted from Google Scholar and pre-print material as well. The keywords used to perform search included “COVID-19,” “SARS Cov2,” “neurological manifestations,” and “immunology and pathology of COVID-19”. However, animal studies were excluded in the neurological manifestations, and the final number of literature search outcome was 27 articles.&#x0D; Results: The immunopathology involves angiotensin-converting enzyme (ACE) receptor 2 and spike protein S1. COVID-19 has a tremendous affinity to the ACE2 receptor. The status of secondary hemophagocytic lymphohistiocytosis (sHLH) and the cytokine storm lead to different organ damage and the corresponding clinical manifestations. The documented neurological manifestations mainly include acute ischemic stroke, hemorrhagic stroke, temporal lobe, thalamic encephalitis, and one case of Guillain-Barre Syndrome, in addition to agitation, headache, and seizures.&#x0D; Conclusion: Although the intimate relationship between the neurons and the immune activation is the basic concept of COVID-19 immunopathology, the definite routes of entry to the neuronal cells are yet to be disclosed. Acute stroke, myositis, headache, and meningoencephalitis are the most common types of complications of COVID-19 so far.

Antecedent immunosuppressive therapy for immune-mediated inflammatory diseases in the setting of a COVID-19 outbreak

BackgroundFinite clinical data and understanding of COVID-19 immunopathology has led to limited, opinion-based recommendations for the management of patients with immune-mediated inflammatory disease (IMID) receiving immunosuppressive (IS) therapeutics.ObjectiveTo determine if IS therapeutic type affects COVID-19 risk among patients with IMID.MethodsWe conducted a retrospective cohort analysis of Henry Ford Health System patients tested for COVID-19 between February 1 and April 18, 2020, treated with IS medication for IMID. Therapeutic class of IS medication, comorbidities, and demographic factors were combined into multivariate models to determine predictors of COVID-19 infection, admission, ventilation, and mortality.ResultsOf 213 patients with IMID, 36.2% tested positive for COVID-19, and they had no greater odds of being hospitalized or requiring ventilation relative to the general population. No IS therapeutic worsened the course of disease after multivariate correction, although multidrug regimens and biologics predicted an increased and decreased rate of hospitalization, respectively, with the latter driven by tumor necrosis factor α inhibitors.LimitationsA single-center study somewhat limits the generalization to community-based settings. Only patients tested for COVID-19 were analyzed.ConclusionIS therapies for IMIDs are not associated with a significantly greater risk of SARS-CoV-2 or severe sequelae when controlling for other factors, and tumor necrosis factor α inhibitors may decrease the odds of severe infection.

BTK/ITK dual inhibitors: Modulating immunopathology and lymphopenia for COVID-19 therapy.

Bruton's tyrosine kinase (BTK) signaling is involved in innate immune responses and regulates the production of proinflammatory cytokines that can contribute to COVID‐19 immunopathology. Clinical trials with BTK inhibitors in COVID‐19 treatment have been proposed, and previous studies have attempted to investigate the therapeutic effects of ibrutinib and underlying mechanisms in treating viral pneumonia. These attempts, however, did not consider potential off target effect of BTK inhibitors on T cell differentiation, function, and survival, which may be beneficial in treatment for COVID‐19. Here, we summarize the current knowledge of BTK/IL‐2‐inducible T‐cell kinase (ITK) signaling in immunopathology and lymphopenia and discuss the potential of BTK/ITK dual inhibitors such as ibrutinib in modulating immunopathology and lymphopenia, for COVID‐19 therapy.

Immunopathology of SARS-CoV-2 Infection: Immune Cells and Mediators, Prognostic Factors, and Immune-Therapeutic Implications.

The present is a comprehensive review of the immunopathology of Covid-19. The immune reaction to SARS-CoV-2 infection is characterized by differentiation and proliferation of a variety of immune cells with immune mediator production and release, and activation of other pathogen resistance mechanisms. We fully address the humoral and cellular immune changes induced by the virus, with particular emphasis on the role of the “cytokine storm” in the evolution of the disease. Moreover, we also propose some immune alterations (i.e., inflammatory parameters, cytokines, leukocytes and lymphocyte subpopulations) as prognostic markers of the disease. Furthermore, we discuss how immune modifying drugs, such as tocilizumab, chloroquine, glucocorticoids and immunoglobulins, and blood purification therapy, can constitute a fundamental moment in the therapy of the infection. Finally, we made a critical analysis of a number of substances, not yet utilized, but potentially useful in SARS-CoV-2 patients, such as IFN lambda, TNF blockers, ulinastatin, siponimod, tacrolimus, mesenchymal stem cells, inhibitors of mononuclear macrophage recruitment, IL-1 family antagonists, JAK-2 or STAT-3 inhibitors.

Current Concepts on Immunopathology of COVID-19 and Emerging Therapies

Context: This scoping review tries to synthesize early findings on the immunopathogenicity of SARS-CoV-2 to assess the emerging therapies and vaccines by evaluating their impact based on the mechanism of pathogenicity. Methods: The three databases of PubMed, Scopus, and Google Scholar were searched from January 1, 2020, to March 15, 2020. To extract the results from the studies, the content, thematic analysis method was used. In this method, the topics studied were coded in the articles, and then major topics related to the articles were determined. After identifying major issues, the contents of the articles were reviewed. Results: A total of 2,250 articles were retrieved after deleting duplications, and after reviewing the thematic relevance, 45 of them were selected for the final analysis. Topics studied in the articles were classified into four main areas, including “virus entry inhibition and immune response”, “vaccine and treatment targets”, “genome structure similarity to other coronaviruses,” and “pathogensis”. Conclusions: Results of this review showed that we have a long way to develop an effective and safe vaccine due to the structural and behavioral complexities of this virus. In the meantime, the scientific community should use results of megatrials, but until their accomplishing them, we have to use results of systematic reviews of randomized controlled trials.

Immunopathology of COVID-19 caused by SARS-CoV-2: A brief review

Immunopathology of COVID-19 caused by SARS-CoV-2: A brief review

Novel paediatric presentation of COVID-19 with ARDS and cytokine storm syndrome without respiratory symptoms.

Novel paediatric presentation of COVID-19 with ARDS and cytokine storm syndrome without respiratory symptoms.

Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions.

The coronavirus disease-19 pandemic (COVID-19), which appeared in China in December 2019 and rapidly spread throughout the world, has forced clinicians and scientists to take up extraordinary challenges. This unprecedented situation led to the inception of numerous fundamental research protocols and many clinical trials. It quickly became apparent that although COVID-19, in the vast majority of cases, was a benign disease, it could also develop a severe form with sometimes fatal outcomes. Cytokines are central to the pathophysiology of COVID-19; while some of them are beneficial (type-I interferon, interleukin-7), others appear detrimental (interleukin-1β, -6, and TNF-α) particularly in the context of the so-called cytokine storm. Yet another characteristic of the disease has emerged: concomitant immunodeficiency, notably involving impaired type-I interferon response, and lymphopenia. This review provides an overview of current knowledge on COVID-19 immunopathology. We discuss the defective type-I IFN response, the theoretical role of IL-7 to restore lymphocyte repertoire, as well as we mention the two patterns observed in severe COVID-19 (i.e. interleukin-1β-driven macrophage activation syndrome vs. interleukin-6-driven immune dysregulation). Next, reviewing current evidence drawn from clinical trials, we examine a number of cytokine and anti-cytokine therapies, including interleukin-1, -6, and TNF inhibitors, as well as less targeted therapies, such as corticosteroids, chloroquine, or JAK inhibitors.

CORONAVIRUS DISEASE 2019 (COVID-19): A RHEUMATOLOGIST’S THOUGHTS

In December 2019, an outbreak of a novel infection under the working name 2019-nCoV was registered in Wuhan (the Hubei Province located in China's central region), which has quickly spread throughout almost the entire world and become pandemic. The World Health Organization (WHO) proposed a new name coronavirus disease (COVID-19) for this disease, whereas the International Committee on Virus Taxonomy renamed 2019-nCov as SARS-Cov-2 (Severe Acute Respiratory Syndrome Coronavirus-2). The development of the COVID-19 pandemic is not only of great social importance, but also draws the attention of a medical community to the fundamentally new clinical and fundamental problems of the immunopathology of human diseases that are yet to be formulated. The unique experience gained in rheumatology from studies of the pathogenetic mechanisms and pharmacotherapy of immune-mediated inflammatory rheumatic diseases (IMIRDs) can be of great importance for deciphering the nature of the pathological processes that underlie the severe, potentially fatal complications of COVID-19, and may assist in improving their therapy. As for prospects in patients with IMIRDs, although the development of COVID-19 in the presence of IMIRDs has not yet fortunately been described, infection with SARS-CoV-2, like other viruses, can be assumed to cause an exacerbation of the pathological process, whereas severe immune system pathology and comorbidities can worsen the course of infection. Since, according to the current concepts, it is the «hyperimmune» response, and not just the effect only of the virus itself, that underlies lung damage and deaths from COVID-19, special attention is drawn to the effects of antirheumatic therapy that includes glucocorticoids, disease-modifying anti-rheumatic drugs (DMARDs), biological agents, and targeted DMARDs, which can have a multidirectional effect on the course of COVID-19. There are significant theoretical prerequisites for the repurposing of some drugs widely used in rheumatology for the treatment of COVID-19 and its complications. Consideration is given to the prospects of studying the immunopathology of COVID-19 and to the theoretical justifications for the use of antimalarial 4-aminoquinolines, anti-cytokine monoclonal antibodies (mAbs), and Janus kinase inhibitors for the prevention of complications and for the treatment of COVID-19.

Immunophenotyping for Risk Stratification of Patients with COVID-19

Treating COVID-19 remains challenging, in part due to limited understanding of severe immunopathology. We performed a holistic and unbiased analysis of 17 immune cell types using flow cytometry immunophenotyping in 802 blood samples from 513 COVID-19 patients obtained at presentation and follow-up, 44 cases with other infection and 36 healthy donors. After adjusting to the corresponding age-range, we found that most COVID-19 patients showed normal patterns of immune response to infection. However, 14% displayed an immune signature at presentation with skewing of all cell types except neutrophils and plasmablasts, which was significantly associated with severe outcome. Divergent immune trajectories were observed in 8 cell types of cases with favorable vs fatal outcome. B-cells had the strongest impact in patients’ survival and, together with non-classical monocytes, had independent prognostic value regardless of age and comorbidities. Collectively, these results shed light into the immunopathology of COVID-19 and provide new tools for risk-stratification.Funding: This study was supported by the Centro de Investigación Biomédica en Red – Área de Oncología - del Instituto de Salud Carlos III (CIBERONC; CB16/12/00369), Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS No. PI17/01243), Fondo Europeo de Desarrollo Regional (FEDER) and Asociación Española Contra el Cáncer (FCAECC, Predoctoral Grant Junta Provincial Navarra). This study was supported internationally by the Cancer Research UK, FCAECC and AIRC under the Accelerator Award Programme, and the European Research Council (ERC) 2015 Starting Grant (MYELOMANEXT). Conflict of Interest: The authors declare no competing conflict of interest.Ethical Approval: The Clinica Universidad de Navarra Ethics Committee approved the protocol and informed consent forms, required prior to patient enrollment. The study was conducted per the ethical principles of the Declaration of Helsinki.