Factors affecting disease severity of multisystem inflammatory syndrome in children

Purpose: Multisystem inflammatory syndrome that occurs after SARS-Cov-2 infection with fever, cardiogenic shock and hyperinflammation in children, can be life threatening. In this study, it was aimed to investigate the effects of the complaint and duration at diagnosis on the severity of multisystem inflammatory syndrome in children. Materials and methods: The medical records of 99 pediatric patients, who were diagnosed multisystem inflammatory syndrome between September 2020 and August 2021 according to Centers for Disease Control and Prevention, were evaluated retrospectively. Demographic features, initial findings, and admission time of patients were noted. Patients were categorized according to intensive care necessity. Results: The median age of the patients was 10 (2-18) and 62 (62.6%) of patients were male. The median duration before admission was 4 (1-10) days. All patients has fever, 81.8% had gastrointestinal and 75.8% had cardiovascular involvement at admission. The patients (56.6%) who were accepted as severe and moderate MIS-C required intensive care. Prolonged fever, delayed admission, cardiovascular involvement, high inflammatory markers, lymphopenia and thrombocytopenia were found to key parameters determining the need for intensive care. Conclusion: Multisystem inflammatory syndrome in children is a new disease characterized by fever, signs of inflammation and organ dysfunction associated with SARS-CoV-2 infection. Delayed admission, high cardiac and inflammatory markers at diagnosis increase the need for intensive care. © 2022, Pamukkale University. All rights reserved.

COVID-19 in the context of inborn errors of immunity, autoimmune diseases, and immune suppression

The COVID-19 pandemic reached five waves in three years, with over 6.5 million deaths across the globe. Knowing the differential susceptibility to the novel betacoronavirus has allowed us to better understand the pathophysiology and inflammatory complications and dissect the response against the virus. As in other viral infections, CD8+ T lymphocytes and NK cells stand out as key players, together with viral sensors, type 1 interferons, an exaggerated inflammatory response by NLRP3, and a storm that includes cytokines IL-6 and IL-8. Whole-exome sequencing has identified several genes with pathogenic germline variants in patients with severe COVID-19;said genes would account for around 5% of all severe cases. In addition, up to 20% of hospitalized adults harbor autoantibodies against type-I and III interferons. These findings translate into novel genetic etiologies, whereas autoantibodies explain the worse prognosis of the elderly, linked to the inflammaging phenomenon. In general, patients with known primary immune deficiencies who acquired COVID-19 fared well, with global survival rates over 80% and a predominance of mild courses. The exceptions were patients with severe-combined immune deficiency, and with the autoimmune polyglandular syndrome 1, the latter because they develop autoantibodies against interferon. Neither have there been reports of greater severity in patients with autoimmune or autoinflammatory disorders. However, those receiving immunosuppressant treatments usually have a more protracted course. Patients with NLRP3 or STAT1 gain of function might be especially susceptible to systemic inflammatory complications. In this review, we summarize the global experience in the caretaking of patients with immune alterations who were infected by SARS-CoV-2. © 2022 Instituto Nacional de Pediatria. All rights reserved.

Development of a novel score model to predict hyperinflammation in COVID-19 as a forecast of optimal steroid administration timing.

Objectives: This study aims to create and validate a useful score system predicting the hyper-inflammatory conditions of COVID-19, by comparing it with the modified H-score. Methods: A total of 98 patients with pneumonia (without oxygen therapy) who received initial administration of casirivimab/imdevimab or remdesivir were included in the study. The enrolled patients were divided into two groups: patients who required corticosteroid due to deterioration of pneumonia, assessed by chest X-ray or CT or respiratory failure, and those who did not, and clinical parameters were compared. Results: Significant differences were detected in respiratory rate, breaths/min, SpO2, body temperature, AST, LDH, ferritin, and IFN-λ3 between the two groups. Based on the data, we created a corticosteroid requirement score: (1) the duration of symptom onset to treatment initiation ≥ 7 d, (2) the respiratory rate ≥ 22 breaths/min, (3) the SpO2 ≤ 95%, (4) BT ≥ 38.5°C, (5) AST levels ≥ 40 U/L, (6) LDH levels ≥ 340 U/L, (7) ferritin levels ≥ 800 ng/mL, and (8) IFN-λ3 levels ≥ 20 pg/mL. These were set as parameters of the steroid predicting score. Results showed that the area under the curve (AUC) of the steroid predicting score (AUC: 0.792, 95%CI: 0.698-0.886) was significantly higher than that of the modified H-score (AUC: 0.633, 95%CI: 0.502-0.764). Conclusion: The steroid predicting score may be useful to predict the requirement of corticosteroid therapy in patients with COVID-19. The data may provide important information to facilitate a prospective study on a larger scale in this field.

Delineating the SARS-CoV-2 Induced Interplay between the Host Immune System and the DNA Damage Response Network.

COVID-19 is an infectious disease caused by the SARS-CoV-2 coronavirus and characterized by an extremely variable disease course, ranging from asymptomatic cases to severe illness. Although all individuals may be infected by SARS-CoV-2, some people, including those of older age and/or with certain health conditions, including cardiovascular disease, diabetes, cancer, and chronic respiratory disease, are at higher risk of getting seriously ill. For cancer patients, there are both direct consequences of the COVID-19 pandemic, including that they are more likely to be infected by SARS-CoV-2 and more prone to develop severe complications, as well as indirect effects, such as delayed cancer diagnosis or treatment and deferred tests. Accumulating data suggest that aberrant SARS-CoV-2 immune response can be attributed to impaired interferon signaling, hyper-inflammation, and delayed adaptive immune responses. Interestingly, the SARS-CoV-2-induced immunological abnormalities, DNA damage induction, generation of micronuclei, and the virus-induced telomere shortening can abnormally activate the DNA damage response (DDR) network that plays a critical role in genome diversity and stability. We present a review of the current literature regarding the molecular mechanisms that are implicated in the abnormal interplay of the immune system and the DDR network, possibly contributing to some of the COVID-19 complications.

Discovering the potential of natural remedies in the post COVID-19 complications based on in silico techniques

The first incidence of corona virus was reported in China in December of 2019, and the virus quickly spread over the world, eventually being designated a pandemic in March of 2020. It has had a disastrous impact on the global healthcare system. Virus has claimed the lives of 5,298,933 people through December 2021. As a result of the pandemic, there was a boost of research into diagnostic and therapeutic methods to infection. Gradually, the world has discovered new vaccine candidates and medicinal repurposing strategies that have a significant influence on mortality, by which there has been a drop-in death rates over the world since July, 2021. Many patients, particularly those who have been hospitalized due to a viral infection, experience complications beyond discharge that have a significant influence on their lives. Post COVID-19 complications are problems that last longer than 3-4 weeks following a viral infection. There is currently no specific treatment accessible for post COVID-19 problems because whatever medications are available or repurposed are limited to disease prophylaxis and therapeutics. As a result, we're looking for a remedy employing natural substances using the In-Silico technique (molecular docking) and recent research from reputable journals. Allicin, Berberine, Epigallocatechin, Rosmarinic acid and Withaferin-A were docked against ACE (PDB ID: 1O8A), IL-6 (PDB ID: 1ALU), NADPH Oxidase (PDB ID: 2CDU) and TNF-alpha (PDB ID: 2AZ5) using Autodock.

Vinpocetine is the forthcoming adjuvant agent in the management of COVID-19.

Vinpocetine (VPN) is an alkaloid derivative of vincamine inhibits phosphodiesterase type 1 that increase cyclic guanosine monophosphate and cyclic adenosine monophosphate. VPN have anti-inflammatory and antioxidant effects with suppression release of pro-inflammatory cytokines. Moreover, VPN mitigates oxidative stress (OS) and inflammatory reactions through inhibition of mitogen-activated protein kinase (MAPK) signaling pathway. Therefore, VPN may decrease hyper-inflammation-induced acute lung injury in COVID-19 through modulation of NF-κB pathway. Taken together, VPN has pulmonary and extra-pulmonary protective effects against COVID-19 through mitigation of OS and hyperinflammation. In conclusion, VPN has noteworthy anti-inflammatory and anti-oxidant effects through inhibition of NF-κB/MAPK signaling pathway so, it may reduce SARS-CoV-2-induced hyper inflammatory and OS.

Continuous Renal Replacement Therapy With oXiris Filter May Not be an Effective Resolution to Alleviate Cytokine Release Syndrome in Non-AKI Patients With Severe and Critical COVID-19.

In this study, we aimed to determine whether continuous renal replacement therapy (CRRT) with oXiris filter may alleviate cytokine release syndrome (CRS) in non-AKI patients with severe and critical coronavirus disease 2019 (COVID-19). A total of 17 non-AKI patients with severe and critical COVID-19 treated between February 14 and March 26, 2020 were included and randomly divided into intervention group and control group according to the random number table. Patients in the intervention group immediately received CRRT with oXiris filter plus conventional treatment, while those in the control group only received conventional treatment. Demographic data were collected and collated at admission. During ICU hospitalization, the concentrations of circulating cytokines and inflammatory chemokines, including IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ, were quantitatively measured daily to reflect the degree of CRS induced by SARS-CoV-2 infection. Clinical data, including the severity of COVID-19 white blood cell count (WBC), neutrophil proportion (NEUT%), lymphocyte count (LYMPH), lymphocyte percentage (LYM%), platelet (PLT), C-reaction protein (CRP), high sensitivity C-reactive protein (hs-CRP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), albumin (ALB), serum creatinine (SCr), D-Dimer, fibrinogen (FIB), IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, number of hospital days and sequential organ failure assessment (SOFA) score were obtained and collated from medical records, and then compared between the two groups. Age, and SCr significantly differed between the two groups. Besides the IL-2 concentration that was significantly lower on day 2 than that on day 1 in the intervention group, and the IL-6 concentrations that were significantly higher on day 1, and day 2 in the intervention group compared to the control group, similar to the IL-10 concentration on day 5, there were no significant differences between the two groups. To sum up, CRRT with oXiris filter may not effectively alleviate CRS in non-AKI patients with severe and critical COVID-19. Thus, its application in these patients should be considered with caution to avoid increasing the unnecessary burden on society and individuals and making the already overwhelmed medical system even more strained (IRB number: IRB-AF/SC-04).

The Rheumatologist's Role in the Battle Against COVID-19: Insights from the Front Line and Challenges for the Future.

As the worldwide burden of COVID-19 increases exponentially, healthcare systems are plagued by unprecedented pressure. In this setting, many rheumatologists across the globe have been recruited to support the front line, facing several unexpected challenges, but also providing valuable skills in combating COVID-19. At the same time, the rheumatic disease patient population may be especially vulnerable to such a rapidly contagious infectious disease and thus needs care and support that has to be provided quickly and efficiently. Clear advice on viral spread mitigation, precise guidelines on immunosuppressive treatment use and alternative methods of providing care, such as telemedicine, are a few of the rheumatologists' new challenges in caring for their patients in the COVID-19 era. Finally, among other specialties, rheumatologists hold a unique place in the fight against the hyper-inflammatory state caused by severe SARS-CoV-2 infection, leading to increased morbidity and mortality. Given their vast experience in the use of biologic and targeted therapies, rheumatologists should lead the way in developing reliable scientific evidence for the optimal treatment of severe COVID-19.

Updated Management Protocol for Multisystem Inflammatory Syndrome in Children (MIS-C).

The multisystem inflammatory syndrome in children (MIS-C) is a post-viral immunological or hyper-inflammatory complication of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection commonly seen in older children, who commonly present with fever, multi-systemic involvement including myocardial dysfunction and shock, and hyper-inflammation. The treatment of MIS-C is adapted from the treatment of other immunological or hyper-inflammatory conditions and these treatment protocols are not uniform across the globe, and more so, in India. We propose a uniform management protocol for MIS-C based on our experience of treating MIS-C cases, available evidence till now, and recent guidelines. The aims are to identify children with MIS-C with high sensitivity, recognize other infections or inflammatory processes, stratify treatment based on severity, and manage hyper-inflammatory syndrome.

Attenuating the Effects of Novel COVID-19 (SARS-CoV-2) Infection-Induced Cytokine Storm and the Implications.

The COVID-19 pandemic constitutes an arduous global health challenge, and the increasing number of fatalities calls for the speedy pursuit of a remedy. This review emphasizes the changing aspects of the COVID-19 disease, featuring the cytokine storm's pathological processes. Furthermore, we briefly reviewed potential therapeutic agents that may modulate and alleviate cytokine storms. The literature exploration was made using PubMed, Embase, MEDLINE, Google scholar, and China National Knowledge Infrastructure databases to retrieve the most recent literature on the etiology, diagnostic markers, and the possible prophylactic and therapeutic options for the management of cytokine storm in patients hospitalized with COVID-19 disease. The causative agent, severe acute respiratory coronavirus-2 (SARS-CoV-2), continually threatens the efficiency of the immune system of the infected individuals. As the first responder, the innate immune system provides primary protection against COVID-19, affecting the disease's progression, clinical outcome, and prognosis. Evidence suggests that the fatalities associated with COVID-19 are primarily due to hyper-inflammation and an aberrant immune function. Accordingly, the magnitude of the release of pro-inflammatory cytokines such as interleukin (IL)-1, (IL-6), and tumor necrosis alpha (TNF-α) significantly differentiate between mild and severe cases of COVID-19. The early prediction of a cytokine storm is made possible by several serum chemistry and hematological markers. The prompt use of these markers for diagnosis and the aggressive prevention and management of a cytokine release syndrome is critical in determining the level of morbidity and fatality associated with COVID-19. The prophylaxis and the rapid treatment of cytokine storm by clinicians will significantly enhance the fight against the dreaded COVID-19 disease.

Demystifying Excess Immune Response in COVID-19 to Reposition an Orphan Drug for Down-Regulation of NF-κB: A Systematic Review.

The immunological findings from autopsies, biopsies, and various studies in COVID-19 patients show that the major cause of morbidity and mortality in COVID-19 is excess immune response resulting in hyper-inflammation. With the objective to review various mechanisms of excess immune response in adult COVID-19 patients, Pubmed was searched for free full articles not related to therapeutics or co-morbid sub-groups, published in English until 27.10.2020, irrespective of type of article, country, or region. Joanna Briggs Institute's design-specific checklists were used to assess the risk of bias. Out of 122 records screened for eligibility, 42 articles were included in the final review. The review found that eventually, most mechanisms result in cytokine excess and up-regulation of Nuclear Factor-κB (NF-κB) signaling as a common pathway of excess immune response. Molecules blocking NF-κB or targeting downstream effectors like Tumour Necrosis Factor α (TNFα) are either undergoing clinical trials or lack specificity and cause unwanted side effects. Neutralization of upstream histamine by histamine-conjugated normal human immunoglobulin has been demonstrated to inhibit the nuclear translocation of NF-κB, thereby preventing the release of pro-inflammatory cytokines Interleukin (IL) 1ß, TNF-α, and IL-6 and IL-10 in a safer manner. The authors recommend repositioning it in COVID-19.

Use of Baricitinib in Patients With Moderate to Severe Coronavirus Disease 2019.

Hyperinflammation is associated with increased mortality in coronavirus disease 2019 (COVID-19). In this retrospective, uncontrolled patient cohort with moderate -severe COVID-19, treatment with baricitinib plus hydroxychloroquine was associated with recovery in 11 of 15 patients. Baricitinib for the treatment of COVID-19 should be further investigated in randomized, controlled clinical trials.

COVID-19: Rational discovery of the therapeutic potential of Melatonin as a SARS-CoV-2 main Protease Inhibitor.

The SARS-CoV-2 spread quickly across the globe. The World Health Organization (WHO) on March 11 declared COVID-19 a pandemic. The mortality rate, hospital disorders and incalculable economic and social damages, besides the unproven efficacy of the treatments evaluated against COVID-19, raised the need for immediate control of this disease. Therefore, the current study employed in silico tools to rationally identify new possible SARS-CoV-2 main protease (Mpro) inhibitors. That is an enzyme conserved among the coronavirus species; hence, the identification of an Mpro inhibitor is to make it a broad-spectrum drug. Molecular docking studies described the binding sites and the interaction energies of 74 Mpro-ligand complexes deposited in the Protein Data Bank (PDB). A structural similarity screening was carried out in order to identify possible Mpro ligands that show additional pharmacological properties against COVID-19. We identified 59 hit compounds and among them, melatonin stood out due to its prominent immunomodulatory and anti-inflammatory activities; it can reduce oxidative stress, defence cell mobility and efficiently combat the cytokine storm and sepsis. In addition, melatonin is an inhibitor of calmodulin, an essential intracellular component to maintain angiotensin-converting enzyme 2 (ACE-2) on the cell surface. Interestingly, one of the most promising hits in our docking study was melatonin. It revealed better interaction energy with Mpro compared to ligands in complexes from PDB. Consequently, melatonin can have response potential in early stages for its possible effects on ACE-2 and Mpro, although it is also promising in more severe stages of the disease for its action against hyper-inflammation. These results definitely do not confirm antiviral activity, but can rather be used as a basis for further preclinical and clinical trials.

Severe COVID-19, Another Piece in the Puzzle of the Hyperferritinemic Syndrome. An Immunomodulatory Perspective to Alleviate the Storm.

The coronavirus disease 2019 (COVID-19), an acute respiratory disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has been declared as a worldwide public health emergency. Interestingly, severe COVID-19 is characterized by fever, hyperferritinemia, and a hyper-inflammatory process with a massive release of pro-inflammatory cytokines, which may be responsible for the high rate of mortality. These findings may advocate for a similarity between severe COVID-19 and some challenging rheumatic diseases, such as adult onset Still's disease, secondary hemophagocytic lymphohistiocytosis, and catastrophic anti-phospholipid syndrome, which have been included in the "hyperferritinemic syndrome" category. Furthermore, as performed in these hyper-inflammatory states, severe COVID-19 may benefit from immunomodulatory therapies.

Mitochondria and microbiota dysfunction in COVID-19 pathogenesis.

The COVID-19 pandemic caused by the coronavirus (SARS-CoV-2) has taken the world by surprise into a major crisis of overwhelming morbidity and mortality. This highly infectious disease is associated with respiratory failure unusual in other coronavirus infections. Mounting evidence link the accelerated progression of the disease in COVID-19 patients to the hyper-inflammatory state termed as the "cytokine storm" involving major systemic perturbations. These include iron dysregulation manifested as hyperferritinemia associated with disease severity. Iron dysregulation induces reactive oxygen species (ROS) production and promotes oxidative stress. The mitochondria are the hub of cellular oxidative homeostasis. In addition, the mitochondria may circulate "cell-free" in non-nucleated platelets, in extracellular vesicles and mitochondrial DNA is found in the extracellular space. The heightened inflammatory/oxidative state may lead to mitochondrial dysfunction leading to platelet damage and apoptosis. The interaction of dysfunctional platelets with coagulation cascades aggravates clotting events and thrombus formation. Furthermore, mitochondrial oxidative stress may contribute to microbiota dysbiosis, altering coagulation pathways and fueling the inflammatory/oxidative response leading to the vicious cycle of events. Here, we discuss various cellular and systemic incidents caused by SARS-CoV-2 that may critically impact intra and extracellular mitochondrial function, and contribute to the progression and severity of the disease. It is crucial to understand how these key modulators impact COVID-19 pathogenesis in the quest to identify novel therapeutic targets that may reduce fatal outcomes of the disease.