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• Anakinra is an adjuvant treatment in severe COVID-19 by blocking IL-1. • We aimed to summarize the studies that evaluated its the safety and efficacy. • 23 studies and 3179 patients were incorporated in the study. • Anakinra had some promising results in COVID-19 by reducing mortality and need of invasive mechanical ventilation. • Anakinra may be effective in immunocompromised cases. The most important presentation of COVID-19 is hyper inflammatory condition and cytokine storm that occurs due to excessive increase of the inflammatory mediators specially, pro-inflammatory interleukins such as IL-1β, IL-6 and tumor necrosis factor-α which have an important role in the cytokine storm pathway. Up till now there is not a definitive treatment for COVID-19 disease, but according to the pathophysiology of the disease, Anakinra (Interleukin- 1 inhibitor) is an adjuvant treatment option in patients with severe COVID-19 by blocking the effect of IL-1. So, we aimed to summarize the studies that evaluated the safety and efficacy of Anakinra in patients diagnosed with COVID-19. We performed a search in PubMed, Cochrane Library, Scopus, and Web of Science (WOS) databases from inception till 7 Jan 2022. Additionally, we searched randomized and non-randomized clinical trials, cohort, case series, case control, case report more than 3 patients which contain confirmed cases of COVID-19 who received Anakinra (Interleukin- 1 inhibitor) for the management of hyper-inflammatory condition associated with COVID-19 disease. A meta-analysis was conducted using review manager 5.4. We included 44 articles in the systematic review. Ultimately, 23 studies were incorporated in the meta-analysis with a total number of 3179 patients. Our analysis showed statistically significant difference in the following outcomes: duration of ICU stays [MD = −0.65, 95% CI (−1.09, −0.03), p = 0.04], the number of patients who needed invasive mechanical ventilation [RR = 0.57, 95% CI (0.39, 0.84), p = 0.004], and number of deaths [RR = 0.80, 95% CI (0.66, 0.99), p = 0.04]. Our analysis showed no statistically significant difference in the following outcomes: length of hospital stays [MD = −0.16, 95% CI (−0.42, 0.11), p = 0.26], oxygen-free days [MD = −0.81, 95% CI (−3.81, 2.20), p = 0.60], and the number of patients who needed non-invasive mechanical ventilation [RR = 1.09, 95% CI (0.47, 2.52), p = 0.84]. Anakinra showed some promising results in important outcomes related to COVID-19 as it significantly reduced the rate of mortality and the need of invasive mechanical ventilation. It should be used in severe cases more than mild and moderate cases to avoid possible immunosuppression complications. Anakinra use is safe in cases of COVID-19 at dose less than 100 mg. Another important outcome was significant reduction is the D-dimer level. Anakinra may be effective in the treatment of specific immunocompromised cases, but it should be used cautiously. [ABSTRACT FROM AUTHOR]

• Meta-summary highlights potential conserved COVID-19 severity biomarkers. • FGG, SERPINA3, IL10, CRP and d -dimer are increased in three severe COVID-19 studies. • IGFBP3 is decreased in three severe COVID-19 studies. • IL6 is a master regulator of COVID-19 severity biomarkers. • Drugs that manipulate these proteins may modulate COVID-19 disease severity. With the rising demand for improved COVID-19 disease monitoring and prognostic markers, studies have aimed to identify biomarkers using a range of screening methods. However, the selection of biomarkers for validation from large datasets may result in potentially important biomarkers being overlooked when datasets are considered in isolation. Here, we have utilized a meta -summary approach to investigate COVID-19 biomarker datasets to identify conserved biomarkers of COVID-19 severity. This approach identified a panel of 17 proteins that showed a consistent direction of change across two or more datasets. Furthermore, bioinformatics analysis of these proteins highlighted a range of enriched biological processes that include inflammatory responses and compromised integrity of physiological systems including cardiovascular, neurological, and metabolic. A panel of upstream regulators of the COVID-19 severity biomarkers were identified, including chemical compounds currently under investigation for COVID-19 treatment. One of the upstream regulators, interleukin 6 (IL6), was identified as a "master regulator" of the severity biomarkers. COVID-19 disease severity is intensified due to the extreme viral immunological reaction that results in increased inflammatory biomarkers and cytokine storm. Since IL6 is the primary stimulator of cytokines, it could be used independently as a biomarker in determining COVID-19 disease progression, in addition to a potential therapeutic approach targeting IL6. The array of upstream regulators of the severity biomarkers identified here serve as attractive candidates for the development of new therapeutic approaches to treating COVID-19. In addition, the findings from this study highlight COVID-19 severity biomarkers which represent promising, robust biomarkers for future validation studies for their use in defining and monitoring disease severity and patient prognosis. [ABSTRACT FROM AUTHOR]

Compound 8a exhibited the promising activity against anti-SARS-CoV-2 via inhibiting host Cat B activity, and had the advantage of broad-spectrum anti-coronavirus and anti-cytokine activity in the treatment of COVID-19. [Display omitted] • 54 aloperine derivatives were evaluated for the anti-SARS-CoV-2 activities. • Compound 8a exhibited the most promising activity against authentic SARS-CoV-2. • Compound 8a showed broad-spectrum anti-coronavirus and anti-cytokine effects. • Compound 8a displayed a good PK and safety profile in vivo. • Compound 8a blocked viral entry at a late stage by inhibiting host Cat B activity. So far, there is still no specific drug against COVID-19. Taking compound 1 with anti-EBOV activity as the lead, fifty-four 12 N -substituted aloperine derivatives were synthesized and evaluated for the anti-SARS-CoV-2 activities using pseudotyped virus model. Among them, 8a exhibited the most potential effects against both pseudotyped and authentic SARS-CoV-2, as well as SARS-CoV and MERS-CoV, indicating a broad-spectrum anti-coronavirus profile. The mechanism study disclosed that 8a might block a late stage of viral entry, mainly via inhibiting host cathepsin B activity rather than directly targeting cathepsin B protein. Also, 8a could significantly reduce the release of multiple inflammatory cytokines in a time- and dose-dependent manner, such as IL-6, IL-1β, IL-8 and MCP-1, the major contributors to cytokine storm. Therefore, 8a is a promising agent with the advantages of broad-spectrum anti-coronavirus and anti-cytokine effects, thus worthy of further investigation. [ABSTRACT FROM AUTHOR]

• Myeloid cell hyperactivation is a key mechanism of COVID-19 pathogenesis. • Dysregulation occurs via direct innate sensing or stimulation of myeloid receptors by viral components. • Potential COVID-19 therapies should focus on correcting myeloid dysregulation, particularly at late stages of the disease. The dysregulation of myeloid cell responses is increasingly demonstrated to be a major mechanism of pathogenesis for COVID-19. The pathological cellular and cytokine signatures associated with this disease point to a critical role of a hyperactivated innate immune response in driving pathology. Unique immunopathological features of COVID-19 include myeloid-cell dominant inflammation and cytokine release syndrome (CRS) alongside lymphopenia and acute respiratory distress syndrome (ARDS), all of which correlate with severe disease. Studies suggest a range of causes mediating myeloid hyperactivation, such as aberrant innate sensing, asynchronized immune cellular responses, as well as direct viral protein/host interactions. These include the recent identification of new myeloid cell receptors that bind SARS-CoV-2, which drive myeloid cell hyperinflammatory responses independently of lung epithelial cell infection via the canonical receptor, angiotensin-converting enzyme 2 (ACE2). The spectrum and nature of myeloid cell dysregulation in COVID-19 also differs from, at least to some extent, what is observed in other infectious diseases involving myeloid cell activation. While much of the therapeutic effort has focused on preventative measures with vaccines or neutralizing antibodies that block viral infection, recent clinical trials have also targeted myeloid cells and the associated cytokines as a means to resolve CRS and severe disease, with promising but thus far modest effects. In this review, we critically examine potential mechanisms driving myeloid cell dysregulation, leading to immunopathology and severe disease, and discuss potential therapeutic strategies targeting myeloid cells as a new paradigm for COVID-19 treatment. [ABSTRACT FROM AUTHOR]

Hyper-inflammatory responses, lymphopenia, unbalanced immune responses, cytokine storm, large viral replication and massive cell death play fundamental roles in the pathogenesis of COVID-19. Extreme production of many kinds of pro-inflammatory cytokines and chemokines occur in severe COVID-19 that called cytokine storm. Signal transducer and activator of transcription-3 (STAT-3) present in the cytoplasm in an inactive form and can be stimulated by a vast range of cytokines, chemokines and growth factors. Thus, STAT-3 can participate in the induction of inflammatory responses during coronavirus infections. STAT-3 can also suppress anti-virus interferon response and induce unbalanced anti-virus adaptive immune response, through influencing Th17-, Th1-, Treg-, and B cell-mediated functions. Furthermore, STAT-3 can contribute to the M2 macrophage polarization, lung fibrosis and thrombosis. Moreover, STAT-3 may be directly targeted by some virus-derived protein and operate as a pro-viral or anti-viral element in a virus-specific process. Here, the possible contribution of STAT-3 to the pathogenesis of COVID-19 was explained, while providing potential approaches to target this transcription factor in an attempt for COVID-19 treatment. • STAT-3 can be activated by numerous cytokines during COVID-19. • STAT-3 is hyper-activated and can play a central role in COVID-19 pathogenesis. • Activated STAT-3 can promote hyper-inflammation, lung fibrosis and thrombosis. • Activated STAT-3 promotes lymphopenia and impairs anti-virus immune responses. • STAT3 may be a potential therapeutic target for the treatment of COVID-19. [ABSTRACT FROM AUTHOR]

• Severe COVID-19 is associated with increased plasma concentrations of IL-6. • Tocilizumab, an interleukin-6 inhibitor, might alleviate the cytokine storm. • Tocilizumab treated group has better clinical outcome, laboratory results, and swab conversion. • The benefit from tocilizumab is more significant in severe COVID-19 patients. • Therefore, tocilizumab might be one of the promising therapies for severe COVID-19. COVID-19 is a public health emergency of international concern with millions confirmed cases globally including in Indonesia with more than two hundred thousand confirmed cases to date COVID-19. (1) COVID-19 has wide clinical manifestation ranging from asymptomatic, acute respiratory illness, respiratory failure that necessitates mechanical ventilation and support in an ICU, to MODS. (2) Several comorbidities have been demonstrated to be associated with the development of severe outcomes from COVID-19 infection, such as hypertension, diabetes, cardiovascular disease, dyslipidemia, thyroid disease, and pulmonary disease. (3)–(5) Severe COVID-19 is associated with increased plasma concentrations of IL-6, resulting in cytokine storm. (6) Tocilizumab, an interleukin-6 inhibitor, might alleviates the cytokine storm, prevents significant lungs and organs damage, thus improving clinical outcomes. (7) Therefore, tocilizumab, might be one of the promising therapies for severe COVID-19. (8) However there were limited studies regarding the efficacy in COVID-19 patients, especially with control group. We would like to report our experience in using tocilizumab as treatment in severe COVID-19 patients in Indonesia, which is the first in Indonesia to the best of our knowledge. [ABSTRACT FROM AUTHOR]

• COVID-19 can have CNS and PNS neurological manifestations. • Headache and hyposmia are common neurological symptoms. • COVID-19 could trigger cytokine storm. • COVID-19 neurological sequalae may be due to viral neuroinvasion and cytokine storm. • Cytokine storm-targeting therapies may help manage COVID-19 neurological symptoms. The new coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can trigger a hyperinflammatory state characterized by elevated cytokine levels known as hypercytokinemia or cytokine storm, observed most often in severe patients. Though COVID-19 is known to be a primarily respiratory disease, neurological complications affecting both the central and peripheral nervous systems have also been reported. This review discusses potential routes of SARS-CoV-2 neuroinvasion and pathogenesis, summarizes reported neurological sequelae of COVID-19, and examines how aberrant cytokine levels may precipitate these complications. Clarification of the pathogenic mechanisms of SARS-CoV-2 is needed to encourage prompt diagnosis and optimized care. In particular, identifying the presence of cytokine storm in patients with neurological COVID-19 manifestations will facilitate avenues for treatment. Future investigations into aberrant cytokine levels in COVID-19 patients with neurological symptoms as well as the efficacy of cytokine storm-targeting treatments will be critical in elucidating the pathogenic mechanisms and effective treatments of COVID-19. [ABSTRACT FROM AUTHOR]

COVID-19, caused by SARS-CoV-2, emerged as the deadliest outbreak that has now become a serious health issue to mankind. Activation of inflammatory signaling pathways and cytokine storm are crucial factors that lead to acute respiratory distress syndrome (ARDS) in COVID-19 patients. Excessive secretion of pro-inflammatory cytokines and chemokines leads to the dysregulation of the innate immune system. The cytokine storm attracts many inflammatory cells that infiltrate into the lung tissues and ultimately cause immune damage. In addition to the dysregulation of the immune system, dysfunction of the renin-angiotensin system (RAS) due to the downregulation of ACE2 is also associated with the mortality of COVID-19 patients. Both the mechanisms are directly or indirectly associated with cytokine storm that promotes vascular hyperpermeability, vascular edema leading to hypercoagulation and hence multiorgan damage. As of now, there is no specific treatment available for COVID-19, but scientists have purposed several treatment options including cytokine inhibitors, JAK inhibitors, immunomodulators, plasma therapy, etc. In this article, we have provided the detailed mechanism of occurrence of SARS-CoV-2 induced inflammatory storm and its connection with the pre-existing inflammatory conditions. Possible treatment options to cope up with the severe clinical manifestations of COVID-19 are also discussed. Image 1 • COVID-19, caused by SARS-CoV-2, is an ongoing pandemic. • Various inflammatory pathways are activated in COVID-19. • Patients with pre-existing inflammatory conditions are more prone to infection. • Various strategies to counter these conditions have been discussed in detail. [ABSTRACT FROM AUTHOR]

The repositioning of therapeutic agents already approved by the regulatory agencies for the use of drugs is very interesting due to the immediacy of their use; similarly, the possibility of using molecules derived from foods, whether nutrients or not, is of great importance, also because of their immediate therapeutic applicability. Candidates for these natural therapies against COVID-19 should show certain effects, such as restoring mitochondrial function and cellular redox balance. This would allow reducing the susceptibility of risk groups and the cascade of events after SARS-CoV-2 infection, responsible for the clinical picture, triggered by the imbalance towards oxidation, inflammation, and cytokine storm. Possible strategies to follow through the use of substances of food origin would include: a) the promotion of mitophagy to remove dysfunctional mitochondria originating from free radicals, proton imbalance and virus evasion of the immune system; b) the administration of transition metals whose redox activity would lead to their own oxidation and the consequent generation of a reduced environment, which would normalize the oxidative state and the intracellular pH; c) the administration of molecules with demonstrated antioxidant capacity; d) the administration of compounds with anti-inflammatory and vasodilatory activity; e) the administration of immunomodulatory compounds. • Repositioning of drugs or the use of natural substances may be a good opportunity to fight against COVID-19. • Food-derived molecules should act on redox balance and mitochondrial function restoring to be effective against SARS-CoV-2. • Nutrients and non-nutrient compounds are of interest because the interaction with pathways affected by SARS-CoV-2. • Combinatory therapy between natural and non-natural drugs is of great interest. • It must be mandatory the promotion of clinical trials against COVID-19 in which food-derived molecules are included. [ABSTRACT FROM AUTHOR]

• Coronavirus disease 2019 is characterized by acute respiratory distress syndrome. • The mortality rate of SARS-CoV-2 infection is linked to cytokine storm. • Methotrexate, is well known for its ability to mitigate overactive immune system. • Methotrexate could be an effective drug candidate in treating COVID-19 patients. Coronavirus disease 2019 (COVID-19) is a global health emergency caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The rapid worldwide spread of SARS-CoV-2 infection has necessitated a global effort to identify effective therapeutic strategies in the absence of vaccine. Among the re-purposed drugs being tested currently, hydroxychloroquine (HCQ), without or with zinc ion (Zn++) and the antibiotic azithromycin (AZM), has been administered to prevent or treat patients with COVID-19. The outcome of multiple clinical studies on HCQ has been mixed. Zn++ interferes with viral replication by inhibiting replicative enzymes and its entry into cells may be facilitated by HCQ. Another immunomodulatory drug, methotrexate (MTX), is well known for its ability to mitigate overactive immune system by upregulating the anti-inflammatory protein, A20. However, its beneficial effect in treating COVID-19 has not drawn much attention. This review provides an overview of the virology of SARS-CoV-2 and an analysis of the mechanisms by which these anti-inflammatory agents may act in the treatment of COVID-19 patients. We propose a rationale for the combinatorial use of these re-purposed drugs that may help to combat this ongoing pandemic health emergency. [ABSTRACT FROM AUTHOR]

Respiratory virus infections are among the most prevalent diseases in humans and contribute to morbidity and mortality in all age groups. Moreover, since they can evolve fast and cross the species barrier, some of these viruses, such as influenza A and coronaviruses, have sometimes caused epidemics or pandemics and were associated with more serious clinical diseases and even mortality. The recently identified Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a Public Health Emergency of International concern and has been associated with rapidly progressive pneumonia. To ensure protection against emerging respiratory tract infections, the development of new strategies based on modulating the immune responses is essential. The use of probiotic components has substantially increased due to their effects on immune responses, in particular on those that occur in the upper/lower respiratory tract. Superinduction of inflammatory reaction, known as a cytokine storm, has been correlated directly with viral pneumonia and serious complications of respiratory infections. In this review, probiotics, as potential immunomodulatory agents, have been proposed to improve the host's response to respiratory viral infections. In addition, the effects of probiotics on different aspects of immune responses and their antiviral properties in both pre-clinical and clinical contexts have been described in detail. • Immunomodulatory effects of probiotics on different aspects of immune responses has been presented. • Antiviral properties effects of probiotics in both pre-clinical and clinical contexts have been described in detail. • Probiotics' mechanism of action on immunity in respiratory virus infections has been elucidated. [ABSTRACT FROM AUTHOR]