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IntroductionHyperinflammatory responses substantially contribute to morbidity and mortality in severe COVID-19 and share features with secondary hemophagocytic lymphohistiocytosis and macrophage activation syndrome. The Hyperinflammation in COVID-19 (HIC) criteria allow early diagnosis and may provide a framework for dynamic treatment monitoring.MethodsWe retrospectively analyzed 218 hospitalized patients with hyperinflammation (HIC ≥35) who received anakinra at a tertiary referral center. The daily anakinra dose (100–800 mg/day, administered intravenously or subcutaneously) was adjusted according to clinical and laboratory parameters. The primary outcome was in-hospital mortality. Secondary outcomes included time to ≥50% CRP reduction, ICU admission, mechanical ventilation, and dynamic changes in ΔHIC and inflammatory biomarkers.ResultsOverall mortality was 12.8%. Survivors achieved earlier CRP reduction than non-survivors (3.1 vs. 4.7 days) and showed a progressive decline in HIC, whereas non-survivors had persistently elevated or rising scores. Divergence in ΔHIC and other parameters, including neutrophil count, D-dimer, LDH, procalcitonin, and creatine kinase, emerged within 3–4 days. ROC analysis demonstrated that HIC on the day of anakinra initiation and at the final assessment discriminated survivors from non-survivors (AUC 0.75, p < 0.001; cut-offs 70.8 and 66.5, with high sensitivity but moderate specificity), whereas baseline and first-response-day HIC had limited predictive value (AUC approximately 0.50–0.55) .DiscussionThese findings support the HIC score as both a diagnostic and dynamic monitoring tool during IL-1 blockade. Initiating anakinra when HIC is ≥35 but <70, and reassessing treatment response after 3–4 days using ΔHIC together with CRP kinetics, may help optimize outcomes.

COVID-19 is a contagious viral disease caused by SARS-CoV-2 that led to an ongoing pandemic with massive global health and socioeconomic consequences. The disease is characterized primarily, but not exclusively, by respiratory clinical manifestations ranging from mild common cold symptoms, including cough and fever, to severe respiratory distress and multi-organ failure. Macrophages, a heterogeneous group of yolk-sac derived, tissue-resident mononuclear phagocytes of complex ontogeny present in all mammalian organs, play critical roles in developmental, homeostatic and host defense processes with tissue-dependent plasticity. In case of infection, they are responsible for early pathogen recognition, initiation and resolution of inflammation, as well as repair of tissue damage. Monocytes, bone-marrow derived blood-resident phagocytes, are recruited under pathological conditions such as viral infections to the affected tissue to defend the organism against invading pathogens and to aid in efficient resolution of inflammation. Given their pivotal function in host defense and the potential danger posed by their dysregulated hyperinflammation, understanding monocyte and macrophage phenotypes in COVID-19 is key for tackling the disease’s pathological mechanisms. Here, we outline current knowledge on monocytes and macrophages in homeostasis and viral infections and summarize concepts and key findings on their role in COVID-19. While monocytes in the blood of patients with moderate COVID-19 present with an inflammatory, interferon-stimulated gene (ISG)-driven phenotype, cellular dysfunction epitomized by loss of HLA-DR expression and induction of S100 alarmin expression is their dominant feature in severe disease. Pulmonary macrophages in COVID-19 derived from infiltrating inflammatory monocytes are in a hyperactivated state resulting in a detrimental loop of pro-inflammatory cytokine release and recruitment of cytotoxic effector cells thereby exacerbating tissue damage at the site of infection.

[This corrects the article DOI: 10.3389/fimmu.2024.1448201.].

[This corrects the article DOI: 10.3389/fimmu.2023.1127358.].

The coronavirus disease-19 (COVID-19) elicited by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused devastating health, economic and social impact worldwide. Its clinical spectrum ranges from asymptomatic to respiratory failure and multi-organ failure or death. The pathogenesis of SARS-CoV-2 infection is attributed to a complex interplay between virus and host immune response. It involves activation of multiple inflammatory pathways leading to hyperinflammation and cytokine storm, resulting in tissue damage, acute respiratory distress syndrome (ARDS) and multi-organ failure. Accumulating evidence has raised concern over the long-term health effects of COVID-19. Importantly, the neuroinvasive potential of SARS-CoV-2 may have devastating consequences in the brain. This review provides a conceptual framework on how the virus tricks the host immune system to induce infection and cause severe disease. We also explore the key differences between mild and severe COVID-19 and its short- and long-term effects, particularly on the human brain.

Oxidative stress is a pivotal point in the pathophysiology of COVID-19 and presumably also in Long-COVID. Inflammation and oxidative stress are mutually reinforcing each other, thus contributing to the systemic hyperinflammatory state and coagulopathy which are cardinal pathological mechanisms of severe stages. COVID-19 patients, like other critically ill patients e.g. with pneumonia, very often show severe deficiency of the antioxidant vitamin C. So far, it has not been investigated how long this deficiency lasts or whether patients with long COVID symptoms also suffer from deficiencies. A vitamin C deficit has serious pathological consequences because vitamin C is one of the most effective antioxidants, but also co-factor of many enzymatic processes that affect the immune and nervous system, blood circulation and energy metabolism. Because of its anti-oxidative, anti-inflammatory, endothelial-restoring, and immunomodulatory effects the supportive intravenous (iv) use of supraphysiological doses has been investigated so far in 12 controlled or observational studies with altogether 1578 inpatients with COVID-19. In these studies an improved oxygenation, a decrease in inflammatory markers and a faster recovery were observed. In addition, early treatment with iv high dose vitamin C seems to reduce the risks of severe courses of the disease such as pneumonia and also mortality. Persistent inflammation, thrombosis and a dysregulated immune response (auto-immune phenomena and/or persistent viral load) seem to be major contributors to Long-COVID. Oxidative stress and inflammation are involved in the development and progression of fatigue and neuro-psychiatric symptoms in various diseases by disrupting tissue (e.g. autoantibodies), blood flow (e.g. immune thrombosis) and neurotransmitter metabolism (e.g. excitotoxicity). In oncological diseases, other viral infections and autoimmune diseases, which are often associated with fatigue, cognitive disorders, pain and depression similar to Long-COVID, iv high dose vitamin C was shown to significantly relieve these symptoms. Supportive iv vitamin C in acute COVID-19 might therefore reduce the risk of severe courses and also the development of Long-COVID.

IntroductionThe outbreak of coronavirus disease 2019 (COVID-19) has become one of the most serious pandemics of the recent times. Since this pandemic began, there have been numerous reports about the COVID-19 involvement of the nervous system. There have been reports of both direct and indirect involvement of the central and peripheral nervous system by the virus.ObjectiveTo review the neuropsychiatric manifestations along with corresponding pathophysiologic mechanisms of nervous system involvement by the COVID-19.BackgroundSince the beginning of the disease in humans in the later part of 2019, the coronavirus disease 2019 (COVID-19) pandemic has rapidly spread across the world with over 2,719,000 reported cases in over 200 countries [World Health Organization. Coronavirus disease 2019 (COVID-19) situation report-96.,]. While patients typically present with fever, shortness of breath, sore throat, and cough, neurologic manifestations have been reported, as well. These include the ones with both direct and indirect involvement of the nervous system. The reported manifestations include anosmia, ageusia, central respiratory failure, stroke, acute inflammatory demyelinating polyneuropathy (AIDP), acute necrotizing hemorrhagic encephalopathy, toxic–metabolic encephalopathy, headache, myalgia, myelitis, ataxia, and various neuropsychiatric manifestations. These data were derived from the published clinical data in various journals and case reports.ConclusionThe neurological manifestations of the COVID-19 are varied and the data about this continue to evolve as the pandemic continues to progress.

Decades of sepsis research into a specific immune system-targeting adjunctive therapy have not resulted in the discovery of an effective compound. Apart from antibiotics, source control, resuscitation and organ support, not a single adjunctive treatment is used in current clinical practice. The inability to determine the prevailing immunological phenotype of patients and the related large heterogeneity of study populations are regarded by many as the most important factors behind the disappointing results of past clinical trials. While the therapeutic focus has long been on immunosuppressive strategies, increased appreciation of the importance of sepsis-induced immunoparalysis in causing morbidity and mortality in sepsis patients has resulted in a paradigm shift in the sepsis research field towards strategies aimed at enhancing the immune response. However, similar to immunosuppressive therapies, precision medicine is imperative for future trials with immunostimulatory compounds to succeed. As such, identifying those patients with a severely suppressed or hyperactive immune system who will most likely benefit from either immunostimulatory or immunosuppressive therapy, and accurate monitoring of both the immune and treatment response is crucial. This review provides an overview of the challenges lying ahead on the path towards precision immunotherapy for patients suffering from sepsis.

Coronavirus disease 2019 (COVID‐19), triggered by the betacoronavirus SARS‐CoV‐2, has become one of the worst pandemics of our time that has already caused more than 250,000 deaths (JHU data‐05/06/2020, https://coronavirus.jhu.edu/ ). Effective therapeutic approaches are urgently needed to reduce the spread of the virus and its death toll. Here, we assess the possibility of using interferon‐lambda (IFNλ), a third type of interferon sharing low homology with type I IFNs and IL‐10, for treating COVID‐19 patients. We discuss the unique role of IFNλ in fine‐tuning antiviral immunity in the respiratory tract to achieve optimal protection and minimal host damage and review early evidence that SARS‐CoV‐2 may impair IFNλ induction, leading to a delayed type I IFN‐dominated response that triggers hyperinflammation and severe disease. We also consider the potential windows of opportunity for therapeutic intervention with IFNλ and potential safety considerations. We conclude that IFNλ constitutes a promising therapeutic agent for reducing viral presence and hyperinflammation in a single shot to prevent the devastating consequences of COVID‐19 such as pneumonia and acute respiratory distress syndrome (ARDS). Graphical Abstract Can we treat COVID‐19 with IFNλ? E. Andreakos and S. Tsiodras discuss how SARS‐CoV‐2 may impair IFNλ induction, leading to a delayed type I IFN‐dominated response that triggers hyperinflammation and severe disease.

COVID-19 has proven to be a disease that affects not only the respiratory tract but also leads to a state of generalized systemic hyperinflammation and overall immune dysregulation. An important role in its pathogenesis is the disturbance of many cytokines – a condition which, in its most pronounced form, is also called a „cytokine storm“.To evaluate the serum cytokine levels during COVID-19 infection as potential biomarkers for the severity and course of infection.By design, the study is a retrospective cross-sectional, in which the serum concentrations of 10 pro- and anti-inflammatory cytokines (IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNF-α, and GM-CSF) were investigated in 36 individuals (divided into 3 groups by severity – with a mild form of the infection/presymptomatic, moderately severe and severe/critical) within two periods – before and after the second week from the onset of symptoms of the disease.In the period up to the 2nd week, the serum concentrations of IFN-γ (p = 0.029), IL-1β (p = 0.017), and IL-5 (p = 0.014) showed a statistically significant correlation with the disease severity, however in the later stage of the disease the cytokine levels did not show any clinical value.Cytokine testing could be used to predict the severity of COVID-19 infection which could support individual therapeutic decisions. Analysis of a larger group of patients is needed to unfold the full potential of such testing.