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SARS-CoV-2 infection has claimed just over 1.1 million lives in the US since 2020. Globally, the SARS-CoV-2 respiratory infection spread to 771 million people and caused mortality in 6.9 million individuals to date. Much of the early literature showed that SARS-CoV-2 immunity was defective in the early stages of the pandemic, leading to heightened and, sometimes, chronic inflammatory responses in the lungs. This lung-associated 'cytokine storm' or 'cytokine release syndrome' led to the need for oxygen supplementation, respiratory distress syndrome, and mechanical ventilation in a relatively high number of people. In this study, we evaluated circulating PBMC from non-hospitalized, male and female, COVID-19+ individuals over the course of infection, from the day of diagnosis (day 0) to one-week post diagnosis (day 7), and finally 4 weeks after diagnosis (day 28). In our early studies, we included hospitalized and critically care patient PBMC; however, most of these individuals were lymphopenic, which limited our assessments of their immune integrity. We chose a panel of 30 interferon-stimulated genes (ISG) to evaluate by PCR and completed flow analysis for immune populations present in those PBMC. Lastly, we assessed immune activation by stimulating PBMC with common TLR ligands. We identified changes in innate cells, primarily the innate lymphoid cells (ILC, NK cells) and adaptive immune cells (CD4+ and CD8+ T cells) over this time course of infection. We found that the TLR-7 agonist, Resiquimod, and the TLR-4 ligand, LPS, induced significantly better IFN α and IFN γ responses in the later phase (day 28) of SARS-CoV-2 infection in those non-hospitalized COVID-19+ individuals as compared to early infection (day 0 and day 7). We concluded that TLR-7 and TLR-4 agonists may be effective adjuvants in COVID-19 vaccines for mounting immunity that is long-lasting against SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Background COVID-19 disease causes complications that are classified according to likelihood to high such as venous thromboembolism, acute kidney injury, and postintensive care syndrome. Other complications are low in likelihood such as cytokine release syndrome, pancreatic injury, gastrointestinal complications, and pregnancy-related complications. Mortality and morbidity are really high when it is combined with surgical intervention especially under general anesthesia. Objectives To evaluate the incidence of COVID-19 in general surgery emergency and complications associated in different types of management. Patient and method This is a retrospective study from June 2020 to January 2021 including all COVID-19 positive cases admitted in general surgery department during previously mentioned period. Before September 2020, screening for COVID was based on swab for only clinically suspected COVID-positive patients. Starting from September 2020, routine swab to all admitted patients was done. All data collected about included cases in study underwent statistical analysis to get results. Results In this study, incidence of COVID-19 is 1.35%, mortality incidence is 26.4% (about 92.9% of mortality cases underwent surgery) and morbidity incidence is 30.2%. About 74% (73.6%) of positive cases improved and discharged. Management of cases is according to guidelines of management to each disease and decision of ER consultant. About 77.4% of cases are managed surgically; about 70.7% of cases operated upon underwent exploration. However, 60.4% of cases are admitted with sepsis and septic shock. Asymptomatic cases for COVID during admission are 26.4%. Conclusion Incidence of COVID-19 in acute general surgery emergency in Kasr Al-Ainy is not that high. However, cases operated upon in the era of COVID are associated with high incidence of mortality. Cases are presented to our institute late, which might be an effect of lock down. [ABSTRACT FROM AUTHOR]

Background: Human coronaviruses can be divided based on their pathogenicity. The types with high pathogenicity including SARS-CoV, MERS-CoV, and the current novel SARS-CoV2. SARS COV2 has led to possibly the worst pandemic of this century in the form of Coronavirus disease 2019 (COVID-19). Initially recognized as a respiratory system disease, COVID-19 has been found to interact with functions of other organ systems like cardiovascular, GIT, CNS Peripheral nervous system, during the course of the disease and postcovid syndromic manifestations including Endocrinal and psychological. The acute manifestations primarily lung will be involved that leads to ARDS, in severe disease all the organs will be effected that may lead to multiorgan dysfunction (MODS), and death. AIM: Evaluation of various endocrinal manifestations secondary to endocrinal gland dysfunction, in COVID 19 peak of the pandemic causing morbidity and mortality. In this COVID 19 pandemic everywhere the mortality was very high, the researchers and all over the globe thought that this is not only viral invasion or host's immune mediated of it's not due to viral virulence and postulated the actual pathogenesis of the disease and its manifestations causing morbidity and mortality. Some patients with coronavirus disease 2019 (COVID-19) develop a life-threatening hyper-inflammatory state that is commonly referred to as cytokine storm. This is the prime cause of all the syndromes presenting in this SARS COV2. The mortality has been increasing and new biochemical parameters are increasing in moderate to severe disease. [ABSTRACT FROM AUTHOR]

Introduction: COVID-19 has been declared a pandemic by the WHO. Most mortality cases were linked to the presence of cytokine storms induced by the virus. Platelet parameters and IL-6 may provide significant results in the disease severity and input in a COVID-19 patient's management. This study aimed to determine the usefulness of platelet parameters and IL-6 with disease severity and outcomes amongst COVID-19 patients admitted to Hospital Kuala Lumpur (HKL). Methods: A retrospective study utilising clinical data of confirmed COVID-19 cases. Demographic data, platelet parameters on admission, serum IL-6 level, and treatment outcomes were retrieved and analysed. Results: 283 patients' data were analysed. The mean age of patients was 54.10 ±14.9 years old. Sixty percent of the patients were with comorbidities and (n=65, 23%) of them had succumbed to the disease. Males and females were equally affected and (n=139, 49.1%) were Malays. Ethnicity was an independent predictor for COVID-19 severity. A significant association was found between platelet count, MPV, and IL-6 with COVID-19 severity and outcomes. PDW was not associated with disease outcomes (p=0.236). Comorbidity and platelet count were independent predictors of COVID-19 death. A multivariate analysis of patients' platelet count, MPV, and IL-6 level using binary logistic analysis showed that platelet count of the non-survivor group significantly decreased by 0.004, compared to the survivor group. Conclusion: Combining a readily available routine blood investigation of low platelet count, raised MPV, and IL-6 level signifies an increased risk of COVID-19 severity, and thus, warrants close clinical attention in reducing mortality. [ABSTRACT FROM AUTHOR]

Depression is among the psychiatric sequelae of COVID-19, affecting more than 20% of the convalescents. Its underlying pathophysiology remains unclear. Interleukin 6 (IL-6), a pro-inflammatory cytokine, plays a critical role in the COVID-19-associated cytokine storm, has been implicated in depressive disorders, and may thus be involved in post-COVID-19 depression. PubMed, Scopus, Embase, and Web of Science were systematically searched for relevant studies assessing peripheral IL-6 levels in convalescents who developed depression after COVID-19 vs. convalescents who did not. Five studies were included in our systematic review, and four entered the meta-analysis. The meta-analysis revealed that post-COVID people with de novo depression did not have statistically significant differences in IL-6 levels compared to those without depression (standardised mean difference (SMD) = 0.09, 95% confidence interval (CI) = −0.35, 0.54, p-value = 0.68). Although convalescents with depression did not have significantly higher IL-6 levels than convalescents without depression, the results should be interpreted considering the limited sample size and the low power of the included studies. [ABSTRACT FROM AUTHOR]

Paraguay is currently facing a new outbreak of Chikungunya virus. This report summarizes two severe cases of Chikungunya (CHIKV) infection, confirmed by real-time reverse transcription polymerase chain reaction. We present the cases of patients with acute CHIKV infection and multisystem involvement, with fever, rash, abdominal pain, vomiting, myocarditis, and coronary artery anomalies, very similar to the cases described in MIS-C related to SARS-CoV-2 during the COVID-19 Pandemic. Both patients received IVIG and methylprednisolone, with good clinical response. In this setting of cytokine storm in Chikungunya, can we call it "Multisystem inflammatory syndrome associated with Chikungunya"?. [ABSTRACT FROM AUTHOR]

Background: COVID-19 pandemic has caused more than 6 million deaths worldwide. Co-morbid conditions such as Type 2 Diabetes (T2D) have increased mortality in COVID-19. With limited translatability of in vitro and small animal models to human disease, human organ-on-a-chip models are an attractive platform to model in vivo disease conditions and test potential therapeutics. Methods: T2D or non-diabetic patient-derived macrophages and human liver sinusoidal endothelial cells were seeded, along with normal hepatocytes and stellate cells in the liver-on-a-chip (LAMPS – liver acinus micro physiological system), perfused with media mimicking non-diabetic fasting or T2D (high levels of glucose, fatty acids, insulin, glucagon) states. The macrophages and endothelial cells were transduced to overexpress the SARS-CoV2-S (spike) protein with appropriate controls before their incorporation into LAMPS. Cytokine concentrations in the efflux served as a read-out of the effects of S-protein expression in the different experimental conditions (non-diabetic-LAMPS, T2D-LAMPS), including incubation with tocilizumab, an FDA-approved drug for severe COVID-19. Findings: S-protein expression in the non-diabetic LAMPS led to increased cytokines, but in the T2D-LAMPS, this was significantly amplified both in the number and magnitude of key pro-inflammatory cytokines (IL6, CCL3, IL1β, IL2, TNFα, etc.) involved in cytokine storm syndrome (CSS), mimicking severe COVID-19 infection in T2D patients. Compared to vehicle control, tocilizumab (IL6-receptor antagonist) decreased the pro-inflammatory cytokine secretion in T2D-COVID-19-LAMPS but not in non-diabetic-COVID-19-LAMPS. Interpretation: macrophages and endothelial cells play a synergistic role in the pathophysiology of the hyper-inflammatory response seen with COVID-19 and T2D. The effect of Tocilizumab was consistent with large clinical trials that demonstrated Tocilizumab's efficacy only in critically ill patients with severe disease, providing confirmatory evidence that the T2D-COVID-19-LAMPS is a robust platform to model human in vivo pathophysiology of COVID-19 in T2D and for screening potential therapeutics. [ABSTRACT FROM AUTHOR]

The first cases of COVID-19 were identified in China in 2019, and the disease subsequently spread rapidly around the world, leading it to be declared a pandemic. The disease affects the lungs through the upper and lower respiratory tracts, and with the development of pneumonia, a clinical picture leading to respiratory failure referred to as cytokine storm occurs as a result of excessive cytokine production associated with an excessive inflammatory immune response. The increase in inflammatory markers is related to acute respiratory distress syndrome, disseminated intravascular coagulation and hypercoagulation. We present here an explanation of cytokine storm and the associated immune damage mechanisms. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the current pandemic coronavirus disease 2019 (COVID-19). Dysregulated and excessive production of cytokines and chemokines, known as cytokine storm, is frequently seen in patients with severe COVID-19 disease and it can provoke a severe systematic inflammation in the patients. The IL-1R/TLRs/IRAKs signaling network is a key pathway in immune cells that plays a central role in regulating innate immunity and inflammatory responses via stimulating the expression and production of various proinflammatory molecules including cytokines. Modulation of IRAKs activity has been proposed to be a promising strategy in the treatment of inflammatory disorders. In this review, we highlight the biochemical properties of IRAKs and their role in regulating inflammatory molecular signaling pathways and discuss the potential targeting of IRAKs to suppress the SARS-CoV-2-induced cytokine storm in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Introduction: COVID-19 (coronavirus disease 2019) was first identified in China in December 2019 and is rapidly spreading worldwide as a pandemic. Since COVID-19 causes mild to severe acute respiratory syndrome, most studies in this context have focused on pathogenesis primarily in the respiratory system. However, evidence shows that the central nervous system (CNS) may also be affected by COVID-19. Since COVID-19 is spreading, it is necessary to study its possible cognitive effects on COVID-19 patients and their recovery. Methods: The articles used in this study were searched by keywords, such as cytokine storm and COVID-19, COVID-19 and executive dysfunction, cognitive disorder, and COVID-19, central nervous system (CNS) and COVID-19, coronavirus, neuroinvasion in Science Direct, Scopus, PubMed, Embase, and Web of Science databases based on preferred reporting items for systematic reviews and meta-analysis (PRISMA) checklist. The study evaluates all observational studies published between December 2019 and April 2021 in peer-reviewed journals, including cross-sectional, cohort, case-control studies, case reports, and case series. The search result was 106 articles, of which 73 articles related to COVID-19, the stages of infection by this virus, its effect on the nervous system and neurological symptoms, the cytokine storm caused by this infection, and the possible cognitive consequences caused by this virus in patients, has been reviewed. Other articles were not checked due to their limited relevance to the topic under discussion. Results: Studies showed that neurons may be directly affected by severe acute respiratory syndrome coronavirus (SARS-CoV)-1 and SARS-CoV-2. Furthermore, various studies indicated that systemic inflammation (so-called “cytokine storm”) is also responsible for brain damage induced by infection with SARS-CoV-1 and SARS-CoV-2. In such a way that these patients showed elevated levels of interleukin (IL-), 6, 8, and 10 and of tumor necrosis factor- alpha (TNF-α) in their blood. Conclusion: Various cognitive defects have been observed following an increased level of cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6, 8. Therefore, due to the increased level of these pro-inflammatory factors in the brains of these patients, cognitive deficits can be expected, which need further investigation. [ABSTRACT FROM AUTHOR]

The cytokine storm in SARS-CoV-2 infection contributes to the onset of inflammation and target-organ damage. The endothelium is a key player in COVID-19 pathophysiology and it is an important target for cytokines. Considering that cytokines trigger oxidative stress and negatively impact endothelial cell function, we sought to determine whether serum from individuals with severe COVID-19 decreases endothelial cells' main antioxidant defense, i.e., the antioxidant transcriptional factor Nrf2. Human umbilical vein endothelial cells (HUVECs) were incubated with serum from patients with severe COVID-19 at different time points and the effects on redox balance and Nrf2 activity were determined. Serum from individuals with COVID-19 increased oxidant species, as indicated by higher DHE (dihydroethydine) oxidation, increased protein carbonylation, and induced mitochondrial reactive oxygen species (ROS) generation and dysfunction. Serum from patients with COVID-19, but not serum from healthy individuals, induced cell death and diminished nitric oxide (NO) bioavailability. In parallel, Nrf2 nuclear accumulation and the expression of Nrf2-targeted genes were decreased in endothelial cells exposed to serum from individuals with COVID-19. In addition, these cells exhibited higher expression of Bach-1, a negative regulator of Nrf2 that competes for DNA binding. All events were prevented by tocilizumab, an IL-6 receptor blocker, indicating that IL-6 is key to the impairment of endothelial antioxidant defense. In conclusion, endothelial dysfunction related to SARS-CoV-2 infection is linked to decreased endothelial antioxidant defense via IL-6-dependent mechanisms. Pharmacological activation of Nrf2 may decrease endothelial cell damage in individuals with severe COVID-19. NEW & NOTEWORTHY We demonstrate that endothelial cell dysfunction in SARS-CoV-2-infected individuals is linked to decreased activity of the major antioxidant system regulator, the Nrf2 transcription factor. We provide evidence that this phenomenon relies on IL-6, an important cytokine involved in the pathophysiology of COVID-19. Our data support the view that Nrf2 activation is a potential therapeutical strategy to prevent oxidative stress and vascular inflammation in severe cases of COVID-19. [ABSTRACT FROM AUTHOR]

Different strategies have been proposed to treat cytokine storm syndrome (CSS), the final deadly complication of COVID-19. One approach is to target CSS by blocking the interleukin-6 (IL-6) pathway. A promising group of medications blocking the IL-6 pathway is α-blockers, such as prazosin. First, we hypothesized that Panax ginseng, commonly known as ginseng, can be an effective therapeutic agent in preventing CSS due to its blocking activity on alpha-1 adrenergic receptors (α1-AR). Furthermore, we suggested that herbs with 5α-reductase inhibitory effects, such as Saw palmetto, Nettle root, soya, black pepper, and green tea, can have debilitating impacts on pulmonary function since they can lead to impairment of the lung's ability to regenerate. Thus, we encourage the prospective studies to explore the potential effect of herbal medications, with possible beneficial effects for benign prostatic hyperplasia, during the COVID-19 pandemic since they are commonly consumed. [ABSTRACT FROM AUTHOR]

The ongoing pandemic of COVID‐19 is intrinsically a systemic inflammatory disorder; hence, those patients suffering an underlying chronic inflammatory disease such as diabetes mellitus are at high risk of severe complications. Preventing or suppressing the inflammatory responses are of importance in diabetic patients. Sodium‐glucose cotransporters‐2 inhibitors (SGLT2i) are a newly introduced anti‐diabetic drugs that have hypoglycemic effects through the urinary excretion of glucose. They also have an anti‐inflammatory potential in diabetes patients, in addition to improving glycemic control, and while there is no direct data available in diabetic patients with COVID‐19 disease, there is evidence that suggests that SGLT2i can reduce systemic inflammation and diminish the cytokine storm effect via several cellular mechanisms. In the current review, our aim was to classify and describe the molecular and cellular pathways by which SGLT2i have anti‐inflammatory effects in diabetic patients with COVID‐19 disease. [ABSTRACT FROM AUTHOR]

Several studies have suggested that "cytokine storms" are significant causes of the severity of COVID-19. Controlling and inhibiting the cytokine storm in COVID-19 could prevent the spread of COVID-19 and saves patient lives. Soybean (Glycine max L.) is known to have various biological activities. This study aims to examine bioactive compounds in SSE and the effect of SSE on the ARDS rats model. A total of 25 Sprague Dawley Lipopolysaccharide-induced rats were used. Determination of serum IL-1β, IL-12, and lung TNF-α levels was performed by ELISA method. NF-κB and IFN-γ expression were determined by the qRTPCR method. IL-6 expressions were analyzed by immunohistochemistry assay. The bleeding, inflammation, and alveolus collapse score were analyzed using the HE staining method. The results showed that SSE could decrease the level of IL-1β, IL-12, TNF-α, IL-6, NF-kB, and IFN-γ and improve the bleeding, inflammation, and alveolus score in the lung. SSE could decrease the proinflammatory cytokines and improve lung condition in ARDS rats model. [ABSTRACT FROM AUTHOR]

The coronavirus disease (COVID)-19 pandemic led to a new challenge in the field of effective treatment methods for this disease. Antiviral and immunomodulatory agents were suggested as potential therapeutic methods in this field. Since the most severe clinical symptoms associated with COVID-19 disease appear to be acute respiratory syndrome, azithromycin has been proposed as a potentially effective drug in this context. We have updated the evidence and selected all relevant items to understand the mechanism of role of azithromycin, clinical efficacy, and their side effects in coronavirus disease-19 treatment on July 20th and updated on March 20th, 2020. A literature search of electronic databases including the Web of Science, PubMed, and Google Scholar was conducted by searching keywords such as "Azithromycin", "COVID-19", and "Combination therapy". The ultimate goal of this review was identifying eligible studies about the pharmacological activities, safety, and effectiveness of azithromycin in treating COVID-19 patients. Immunomodulatory properties of azithromycin include the ability to reduce cytokine production, maintain epithelial cell integrity, or prevent lung fibrosis. The use of azithromycin in some studies was associated with a decrease in mortality and need for ventilation in patients. These properties can be useful during the period of COVID-19 infection, especially in patients with underlying diseases. However, the evidence for the use of azithromycin is still scarce and the quality of the studies is low. In some retrospective studies, azithromycin was mainly evaluated in combination with hydroxychloroquine, which showed no particular advantage. The results of this review showed that azithromycin has appropriate and well-known safety characteristics in the treatment of patients with COVID-19. However, the most appropriate dosage in different stages of the disease and the effect of its combination with other drugs are important questions that should be considered in future clinical trials. [ABSTRACT FROM AUTHOR]

Since ancient times, spices such as black pepper, cinnamon, ginger, turmeric, garlic, black cumin, clove, ocimum, saffron, and nutmeg constitute an important part of foods and beverages in India. Besides, adding aroma and flavour to the food, they are also known for multiple medicinal benefits. During the COVID-19 pandemic, an interesting pattern of disease prevalence and severity was observed especially in the countries where spices are consumed regularly. It has attracted researchers worldwide to explore the therapeutic potential of spices in COVID-19 management. Various in silico studies have reported good binding affinities of spices and derived components towards structural druggable targets of SARS-CoV2. There are several compelling pieces of evidence for the role of spices in the attenuation of inflammatory cytokine storm which is the crux in the pathogenesis of COVID-19. Therefore, this review is written to provide deep insights into the role of food spices and their underlying mechanism in targeting SARS-CoV2. Based on experimentally verified data from different in-vitro, in-vivo, in-silico, and clinical studies, the information presented will certainly help in the development of promising drug therapeutics or preventive strategies to deal with SARS-CoV2. Further studies geared towards the development of drugs based on spices and derived compounds are suggested. [ABSTRACT FROM AUTHOR]

COVID-19 may cause the release of systemic inflammatory cytokines resulting in severe inflammation. PARP-1 has been identified as a nuclear enzyme that is activated by DNA strand breaks. It has been suggested that PARP-1 has a role in the cytokine storm shown as a cause of mortality in COVID-19, and its inhibition may adversely affect the replication of SARS -CoV-2. We aimed to investigate the relationship between PARP-1 gene polymorphisms and the clinical severity of COVID-19. rs8679 TT genotype was found to increase with the COVID-19 disease severity. The 3′UTR polymorphism rs8679 may cause PARP-1 activity as a result of viral replication increase by changing the binding site of antiviral or anti-inflammatory miRNAs. PARP-1 may affect the severity of COVID-19 by cytokine release and maybe a possible treatment target. • COVID-19 disease causes the release of systemic inflammatory cytokines resulting in severe inflammation in the lung. • Although PARP-1 has been associated with the COVID-19's complications, this relationship has not been investigated before. • miRNA binding site polymorphism rs8679 may be altering the binding site of antiviral or antiinflammatory miRNAs. The effect of these miRNAs on viral replication may result in PARP-1 activity. • The effect of these miRNAs on viral replication may result in PARP-1 activity. • NFK-B/NLRP3 inflammasome pathways activated by PARP-1 may increase the severity of COVID-19 by triggering cytokine release. • rs8679 polymorphism is a possible prognostic marker for clinical severity of COVID-19. • PARP-1/NLRP3 inflammasome pathway may be a possible treatment target. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) and schizophrenia have a genetic basis, but environmental factors also play a significant role in their etiopathogenesis. One of them may be an infectious disease in the mother during pregnancy. This is indicated mainly by the epidemiological studies, in which a prenatal infection has been shown to increase under certain circumstances the risk of ASD and schizophrenia in the offspring. Animal experiments indicate that the immune response of the mother plays a key role here, especially in the form of a cytokine storm. However, the resulting effect of the prenatal infection depends on several risk and protective factors on the side of the mother and the fetus, as well as on the characteristics of the infections. In case of COVID-19, due to the shortness of time, such studies are absent, however, due to its infectious nature, and predominantly its high prevalence rates, it is reasonable to consider this disease as a potential risk. The objective of our paper was to summarize results of epidemiological and animal studies in respect to other infections and, based on that, to analyse whether COVID-19 during pregnancy represents a risk for the development of ASD or schizophrenia in the offspring. [ABSTRACT FROM AUTHOR]

Hyperinflammation characterized by elevated proinflammatory cytokines known as 'cytokine storms' is the major cause of high severity and mortality seen in COVID‐19 patients. The pathology behind the cytokine storms is currently unknown. Increased HMGB1 levels in serum/plasma of COVID‐19 patients were reported by many studies, which positively correlated with the level of proinflammatory cytokines. Dead cells following SARS‐CoV‐2 infection might release a large amount of HMGB1 and RNA of SARS‐CoV‐2 into extracellular space. HMGB1 is a well‐known inflammatory mediator. Additionally, extracellular HMGB1 might interact with SARS‐CoV‐2 RNA because of its high capability to bind with a wide variety of molecules including nucleic acids and could trigger massive proinflammatory immune responses. This review aimed to critically explore the many possible pathways by which HMGB1‐SARS‐CoV‐2 RNA complexes mediate proinflammatory responses in COVID‐19. The contribution of these pathways to impair host immune responses against SARS‐CoV‐2 infection leading to a cytokine storm was also evaluated. Moreover, since blocking the HMGB1‐SARS‐CoV‐2 RNA interaction might have therapeutic value, some of the HMGB1 antagonists have been reviewed. The HMGB1‐ SARS‐CoV‐2 RNA complexes might trigger endocytosis via RAGE which is linked to lysosomal rupture, PRRs activation, and pyroptotic death. High levels of the proinflammatory cytokines produced might suppress many immune cells leading to uncontrolled viral infection and cell damage with more HMGB1 released. Altogether these mechanisms might initiate a proinflammatory cycle leading to a cytokine storm. HMGB1 antagonists could be considered to give benefit in alleviating cytokine storms and serve as a potential candidate for COVID‐19 therapy. [ABSTRACT FROM AUTHOR]

Severe respiratory involvement that follows a process of immune dysregulation and intense cytokine production remains to be the most dreaded complication of Coronavirus Disease-2019 (COVID-19) infection. The aim of this study was to analyze T lymphocyte subsets and natural killer (NK) lymphocytes in moderate and severe cases of COVID-19 infection and assess their significance in disease severity and prognosis. Twenty moderate cases and 20 severe cases of COVID-19 were studied and compared regarding blood picture, biochemical markers, T lymphocyte population subsets, and NK lymphocytes, which were determined by flow cytometric analysis. On analyzing the flow cytometric data of T lymphocyte cells and their subsets and NK cells in two groups of COVID-19 infection (one group moderate and the other severe cases), some immature NK lymphocyte relative and absolute counts were higher in the severe patients with worse outcome and death, while some mature NK lymphocyte relative and absolute counts were depressed in both groups. Also, interleukin (IL)-6 was significantly higher in severe cases when compared to moderate cases, and there was a positive significant correlation between immature NK lymphocyte relative and absolute counts and IL-6. There was no statistically significant difference between T lymphocyte subsets (T helper and T cytotoxic) with disease severity or outcome. Some immature NK lymphocyte subsets contribute to the widespread inflammatory response that complicates severe cases of COVID-19; therapeutic approaches directed to enhancing NK maturation or drugs that block NK cell inhibitory receptors have a potential role in controlling COVID-19 induced cytokine storm. [ABSTRACT FROM AUTHOR]

In December 2019, a new infectious complication called CoronaVirus Infectious Disease-19, briefly COVID-19, caused by SARS-COV-2, is identified in Wuhan, China. It spread all over the world and became a pandemic. In many individuals who had suffered SARS-COV-2 infection, cytokine storm starts through cytokine overproduction and leads to Acute Respiratory Syndrome (ARS), organ failure, and death. According to the obtained evidence, Vitamin D (VitD) enhances the ACE2/Ang(1–7)/MasR pathway activity, and it also reduces cytokine storms and the ARS risk. Therefore, VitD intake may be beneficial for patients with SARS-COV-2 infection exposed to cytokine storm but do not suffer hypotension. In the present review, we have explained the effects of VitD on the renin-angiotensin system (RAS) function and angiotensin-converting enzyme2 (ACE2) expression. Furthermore, we have reviewed the biochemical and immunological effects of VitD on immune function in the underlying diseases and its role in the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Although the exact mechanism of the pathogenesis of coronavirus SARS-CoV-2 (COVID-19) is not fully understood, oxidative stress and the release of pro-inflammatory cytokines have been highlighted as playing a vital role in the pathogenesis of the disease. In this sense, alternative treatments are needed to reduce the level of inflammation caused by COVID-19. Therefore, this study aimed to investigate the potential effect of red photobiomodulation (PBM) as an attractive therapy to downregulate the cytokine storm caused by COVID-19 in a zebrafish model. RT-qPCR analyses and protein–protein interaction prediction among SARS-CoV-2 and Danio rerio proteins showed that recombinant Spike protein (rSpike) was responsible for generating systemic inflammatory processes with significantly increased levels of pro-inflammatory (il1b, il6, tnfa, and nfkbiab), oxidative stress (romo1) and energy metabolism (slc2a1a and coa1) mRNA markers, with a pattern similar to those observed in COVID-19 cases in humans. On the other hand, PBM treatment was able to decrease the mRNA levels of these pro-inflammatory and oxidative stress markers compared with rSpike in various tissues, promoting an anti-inflammatory response. Conversely, PBM promotes cellular and tissue repair of injured tissues and significantly increases the survival rate of rSpike-inoculated individuals. Additionally, metabolomics analysis showed that the most-impacted metabolic pathways between PBM and the rSpike treated groups were related to steroid metabolism, immune system, and lipid metabolism. Together, our findings suggest that the inflammatory process is an incisive feature of COVID-19 and red PBM can be used as a novel therapeutic agent for COVID-19 by regulating the inflammatory response. Nevertheless, the need for more clinical trials remains, and there is a significant gap to overcome before clinical trials can commence. [ABSTRACT FROM AUTHOR]

The oral cavity is a unique environment that consists of teeth surrounded by periodontal tissues, oral mucosae with minor salivary glands, and terminal parts of major salivary glands that open into the oral cavity. The cavity is constantly exposed to viral and microbial pathogens. Recent studies indicate that components of the plasminogen (Plg)/plasmin (Pm) system are expressed in tissues of the oral cavity, such as the salivary gland, and contribute to microbial infection and inflammation, such as periodontitis. The Plg/Pm system fulfills two major functions: (a) the destruction of fibrin deposits in the bloodstream or damaged tissues, a process called fibrinolysis, and (b) non-fibrinolytic actions that include the proteolytic modulation of proteins. One can observe both functions during inflammation. The virus that causes the coronavirus disease 2019 (COVID-19) exploits the fibrinolytic and non-fibrinolytic functions of the Plg/Pm system in the oral cavity. During COVID-19, well-established coagulopathy with the development of microthrombi requires constant activation of the fibrinolytic function. Furthermore, viral entry is modulated by receptors such as TMPRSS2, which is necessary in the oral cavity, leading to a derailed immune response that peaks in cytokine storm syndrome. This paper outlines the significance of the Plg/Pm system for infectious and inflammatory diseases that start in the oral cavity. [ABSTRACT FROM AUTHOR]

Background: Pulmonary hypoperfusion is common in children with congenital heart diseases (CHDs) or pulmonary hypertension (PH) and causes adult pulmonary dysplasia. Systematic reviews have shown that some children with CHDs or PH have mitigated clinical outcomes with COVID-19. Understanding the effects of pulmonary hypoperfusion on postnatal alveolar development may aid in the development of methods to improve the pulmonary function of children with CHDs or PH and improve their care during the COVID-19 pandemic, which is characterized by cytokine storm and persistent inflammation. Methods and results: We created a neonatal pulmonary hypoperfusion model through pulmonary artery banding (PAB) surgery at postnatal day 1 (P1). Alveolar dysplasia was confirmed by gross and histological examination at P21. Transcriptomic analysis of pulmonary tissues at P7(alveolar stage 2) and P14(alveolar stage 4) revealed that the postnatal alveolar development track had been changed due to pulmonary hypoperfusion. Under the condition of pulmonary hypoperfusion, the cell–cell communication and axon guidance, which both determine the final number of alveoli, were lost; instead, there was hyperactive cell cycle activity. The transcriptomic results were further confirmed by the examination of axon guidance and cell cycle markers. Because axon guidance controls inflammation and immune cell activation, the loss of axon guidance may explain the lack of severe COVID-19 cases among children with CHDs or PH accompanied by pulmonary hypoperfusion. Conclusions: This study suggested that promoting cell–cell communication or supplementation with guidance molecules may treat pulmonary hypoperfusion–induced alveolar dysplasia, and that COVID-19 is less likely to cause a cytokine storm in children with CHD or PH accompanied by pulmonary hypoperfusion. [ABSTRACT FROM AUTHOR]

Infection with the SARS-CoV-2 virus results in manifestation of several clinical observations from asymptomatic to multi-organ failure. Biochemically, the serious effects are due to what is described as cytokine storm. The initial infection region for COVID-19 is the nasopharyngeal/oropharyngeal region which is the site where samples are taken to examine the presence of virus. We have now carried out detailed proteomic analysis of the nasopharyngeal/oropharyngeal swab samples collected from normal individuals and those tested positive for SARS-CoV-2, in India, during the early days of the pandemic in 2020, by RTPCR, involving high throughput quantitative proteomics analysis. Several proteins like annexins, cytokines and histones were found differentially regulated in the host human cells following SARS-CoV-2 infection. Genes for these proteins were also observed to be differentially regulated when their expression was analyzed. Majority of the cytokine proteins were found to be up regulated in the infected individuals. Cell to Cell signaling interaction, Immune cell trafficking and inflammatory response pathways were found associated with the differentially regulated proteins based on network pathway analysis. [ABSTRACT FROM AUTHOR]

Objective The suppressor of cytokine signaling-1 (SOCS-1) gene is an essential physiological regulator of cytokine signaling. Tumor necrosis factor-α (TNF-α) is an important component of the immunological response. Herein, we aimed to investigate the effects of SOCS-1 (-1478 CA > Del) and TNF-α (-308) polymorphisms on disease susceptibility and prognosis in pediatric patients with coronavirus disease 2019 (COVID-19). Methods One-hundred fifty COVID-19 patients in the COVID-19 emergency department between September 2020 and April 2021 and 80 healthy volunteers (control group) without any additional disease were included. Baseline gene polymorphisms were compared between the patient and healthy control groups. Afterward, the gene polymorphism distribution was examined by forming two separate clinical patients' subgroups. Results While CA/CA and CA/Del gene variants of SOCS-1 were higher in the patient group, Del/Del genotype was more common in the control group (p < 0.05). The GG genotype of the TNF-α was significantly more common in the severe subgroup (p = 0.044). The GA genotype of TNF-α was associated with the risk of hospitalization (2.83-fold), while the GG genotype was found to be protective in terms of hospitalization (2.95-fold). Conclusions This study will be a guide in terms of the presence of high cytokine release genotypes and COVID-19-related cytokine release syndromes. [ABSTRACT FROM AUTHOR]

Purpose: The emergence of the COVID-19 pandemic has led to the search for potential therapeutic responses for various aspects of this disease. Fruits of Pterodon emarginatus Vogel (Fabaceae), sucupira, have been used in Brazilian traditional medicine because of their antiinflammatory properties, which have been proven in vivo, in vitro, and in silico. Therefore, the aim of this work is to evaluate P. emarginatus oleoresin and isolated diterpenes by in vitro antiinflammatory models. Methods: In this study, the mechanisms underlying the anti-inflammatory activity of P. emarginatus oleoresin and vouacapanes 6α,19β-diacetoxy-7β,14β-dihydroxyvouacapan (V1), 6α-acetoxy-7β,14β-dihydroxyvouacapan (V2), and methyl 6α-acetoxy-7β-hydroxyvouacapan-17β-oate (V3) were investigated in HaCaT cells. Results: Oleoresin, V2, and V3 inhibited phospholipase A2 (30.78%, 24.96%, and 77.64%, respectively). Both vouacapanes also inhibited the expression of COX-2 (28.3% and 33.17%, respectively). The production of interleukin 6 (IL-6) was inhibited by oleoresin by 35.47%. However, oleoresin did not interfere with Nrf-2 expression or IL-8 production. Conclusion: The results support the ethnomedicinal use of P. emarginatus oleoresin as an anti-inflammatory herbal medicine, and also highlight P. emarginatus oleoresin and isolated vouacapanes as an attractive therapeutic approach for COVID-19 through the reduction or chronological control of the inflammatory mediators IL-6, cyclooxygenase-2 (COX-2), phospholipase A2, and INF-y (indirectly) during the SARS-CoV-2 infection process. [ABSTRACT FROM AUTHOR]

Recently, the world has been dealing with a destructive global pandemic Coronavirus disease 2019 (COVID-19) infection, since 2020; there were millions of infections and hundreds of thousands of deaths worldwide. With sequencing generations of the virus, around 60% are expected to become infected during the pandemic. Unfortunately, no drug or vaccine has been approved because no real evidence from clinical trials in treatment was reached. According to current thinking, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mortality is caused by a cytokine storm syndrome in patients with hyper-inflammatory conditions, resulting in acute respiratory distress and finally death. In this review, we discuss the various types of natural immune-modulatory agents and their role in the management of SARS-CoV-2, and cytokine storm syndrome. For example, Polyphenols as natural products can block the binding of SARS-CoV-2 spike protein to host cell receptor ACE2, stop viral entry into the host cell and block viral RNA replication. Also, saikosaponins (A, B2, C, and D), triterpene glycosides, which are isolated from medicinal plants exert antiviral action against HCoV-22E9, and Houttuynia cordata water extract has antiviral effects on SARS-CoV. Moreover, eucalyptus oil has promising potential for COVID-19 prevention and treatment. There is an urgent need for research to improve the function of the human immune system all over the world. As a result, actions for better understanding and improving the human immune system are critical steps toward mitigating risks and negative outcomes. These approaches will be strongly recommended for future emerging viruses and pathogens. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has persisted for almost three years. However, the mechanisms linked to the SARS-CoV-2 effect on tissues and disease severity have not been fully elucidated. Since the onset of the pandemic, a plethora of high-throughput data related to the host transcriptional response to SARS-CoV-2 infections has been generated. To this end, the aim of this study was to assess the effect of SARS-CoV-2 infections on circulating and organ tissue immune responses. We profited from the publicly accessible gene expression data of the blood and soft tissues by employing an integrated computational methodology, including bioinformatics, machine learning, and natural language processing in the relevant transcriptomics data. COVID-19 pathophysiology and severity have mainly been associated with macrophage-elicited responses and a characteristic "cytokine storm". Our counterintuitive findings suggested that the COVID-19 pathogenesis could also be mediated through neutrophil abundance and an exacerbated suppression of the immune system, leading eventually to uncontrolled viral dissemination and host cytotoxicity. The findings of this study elucidated new physiological functions of neutrophils, as well as tentative pathways to be explored in asymptomatic-, ethnicity- and locality-, or staging-associated studies. [ABSTRACT FROM AUTHOR]

Vasoactive peptides play an important role in a wide range of physiological and pathological conditions. Due to its known functions, the calcitonin gene-related peptide (CGRP) has been suggested as a possible modulator of the hyperimmune response in COVID-19 and thus, blocking its action may lessen the pulmonary effects of COVID-19. To compare the circulating levels of CGRPα and CGRPβ in healthy controls compared to hospitalized COVID-19 patients. The study also analyzed how different comorbidities and treatments may affect these concentrations in cases of COVID-19 infection with pulmonary involvement Serum samples were collected from the antecubital vein of 51 control subjects (mean age = 55 ± 14 years; range = 26–77; 56.9% female) and 52 patients hospitalized with COVID-19 infection (mean age = 55 ± 13; range = 23–77; 55.8% female) from December 2020 to May 2021. Enzyme-linked immunosorbent assays (ELISAs) were used for CGRPα (Abbexa, UK) and CGRPβ (CUSABIO, China) measurements. Comorbidities, symptoms, and treatments of infection were listed. The results showed that the serum levels of both isoforms of CGRP were significantly higher in patients with COVID-19 (α: 57.9 ± 35.8 pg/mL; β: 6.1 ± 2.6 pg/mL) compared to controls (α: 41.8 ± 25.4 pg/mL; β: 4.5 ± 2.4 pg/mL) (p <0.01). Also, the presence of arterial hypertension (HT), obesity, or corticosteroid treatment significantly alter the serum concentration of CGRPα in the subgroups compared to controls. The elevated serum CGRP levels found in our COVID-19 group compared to controls may suggest that CGRP plays a role in the pathophysiology of the disease, more specifically, in the cytokine storm and in the pulmonary involvement. Future studies should focus on the source of this CGRP elevation. [ABSTRACT FROM AUTHOR]

Introduction. COVID-19, an epidemic of coronavirus infection, has become a major global threat. The coronavirus mainly targets the human respiratory system, followed by cytokine storm, and altered immune responses associated with disease progression and adverse outcomes. Sumac and pomegranate juice are rich in bioactive compounds, which potentially have antiviral activities. This study is aimed at investigating the effect of a diet based on the use of sumac and pomegranate juice on the treatment of outpatients with COVID-19. Methods. In this study, 182 outpatients with COVID-19 were randomly divided into two groups receiving a diet containing pomegranate juice and sumac along with standard treatment and the control group (group 2) receiving standard treatment. Results. Consumption of a diet containing pomegranate juice and sumac in outpatients with COVID-19, who were receiving standard-of-care treatment, led to a significant decrease in fever, chills, cough, weakness, smell and taste disorders, shortness of breath, diarrhea, nausea and vomiting, and abdominal pain compared with outpatients with COVID-19 who received only standard treatment. Conclusion. Clinical trials of outpatients have limitations such as patients' resilience to post-COVID-19 follow-up. However, the use of pomegranate juice and sumac can be efficacious in reducing COVID-19 symptoms. This trial is registered with IRCT20190406043175N3. [ABSTRACT FROM AUTHOR]

Viral infections are a continuing global burden on the human population, underscored by the ramifications of the COVID-19 pandemic. Current treatment options and supportive therapies for many viral infections are relatively limited, indicating a need for alternative therapeutic approaches. Virus-induced damage occurs through direct infection of host cells and inflammation-related changes. Severe cases of certain viral infections, including COVID-19, can lead to a hyperinflammatory response termed cytokine storm, resulting in extensive endothelial damage, thrombosis, respiratory failure, and death. Therapies targeting these complications are crucial in addition to antiviral therapies. Nitric oxide and hydrogen sulfide are two endogenous gasotransmitters that have emerged as key signaling molecules with a broad range of antiviral actions in addition to having anti-inflammatory properties and protective functions in the vasculature and respiratory system. The enhancement of endogenous nitric oxide and hydrogen sulfide levels thus holds promise for managing both early-stage and later-stage viral infections, including SARS-CoV-2. Using SARS-CoV-2 as a model for similar viral infections, here we explore the current evidence regarding nitric oxide and hydrogen sulfide's use to limit viral infection, resolve inflammation, and reduce vascular and pulmonary damage. [Display omitted] • COVID-19 leads to hyperinflammation and endothelial dysfunction, resulting in pulmonary and vascular complications. • NOand H 2 S are endogenous gasotransmitters with antiviral, anti-inflammatory, and anti-thrombotic activity. • Modulation of NO and H 2 S levels may be protective against pulmonary and vascular complications in viral infections. • Further investigation into efficacy, dosage, delivery methods, and timing of therapy is necessary. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has had a deep impact on people worldwide since late 2019 when SARS-CoV-2 was first identified in Wuhan, China. In addition to its effect on public health, it has affected humans in various aspects of life, including social, economic, cultural, and political. It is also true that researchers have made vigorous efforts to overcome COVID-19 throughout the world, but they still have a long way to go. Accordingly, innumerable therapeutics and vaccine candidates have been studied for their efficacies and have been tried clinically in a very short span of time. For example, the versatility of extracellular vesicles, which are membrane-bound particles released from all types of cells, have recently been highlighted in terms of their effectiveness, biocompatibility, and safety in the fight against COVID-19. Thus, here, we tried to explain the use of extracellular vesicles as therapeutics and for the development of vaccines against COVID-19. Along with the mechanisms and a comprehensive background of their application in trapping the coronavirus or controlling the cytokine storm, we also discuss the obstacles to the clinical use of extracellular vesicles and how these could be resolved in the future. [ABSTRACT FROM AUTHOR]

The pandemic of coronavirus disease 2019 (COVID-19), for which there does not appear to be an approved cure, the primary treatment options consist of non-pharmacological preventive measures and supportive treatment that are aimed at halting the progression of the disease. Nuclear factor kappa B (NFκB) presents a promising therapeutic opportunity to mitigate COVID-19-induced cytokine storm and reduce the risk of severe morbidity and mortality resulting from the disease. However, the effective clinical application of NFκB modulators in COVID-19 is hampered by a number of factors that must be taken into consideration. This paper therefore explored the modulation of the NFB pathway as a potential strategy to mitigate the severe morbidity and mortality caused by COVID-19. The paper also discusses the factors that form the barrier, and it offers potential solutions to the various limitations that may impede the clinical use of NFκB modulators against COVID-19. This paper revealed and identified three key potential solutions for the future clinical use of NFκB modulators against COVID-19. These solutions are pulmonary tissue-specific NFκB blockade, agents that target common regulatory proteins of both canonical and non-canonical NFκB pathways, and monitoring clinical indicators of hyper inflammation and cytokine storm in COVID-19 prior to using NFκB modulators. [ABSTRACT FROM AUTHOR]

Background: To date, Coronavirus disease 2019 (COVID-19) remains a global health concern, with fatalities mostly in older age groups with underlying medical conditions, while children are less likely to manifest severe symptoms. Case Reports: We describe the clinical cases of 2 brothers admitted to our Children's Hospital for persistent fever and cough during the COVID-19 pandemic. Case 1. A 1.5-year-old boy had fever, expiratory dyspnea, desaturation, oxygen saturation 94-96% with O2, and bilateral hissing and crackling rales. His interleukin-6 level in the acute phase of the disease was 100.41 and at the resolution it was 46.2 pg/ml. Treatment with amoxicillin plus clavulanic acid, methylprednisolone, and O2 allowed progressive improvement of clinical conditions and laboratory data. Case 2. A 3-month-old toddler was admitted to our hospital for fever, cough, and tachypnea, which started 2 days before hospitalization. He had fever, cough, conjunctivitis, mucous rhinorrhea, and 99% oxygen saturation on room air. Thorax auscultation showed whistles and buzzes. He had a positive molecular test result from a COVID-19 swab. Interleukin-6 levels during all the phases of the disease were <6.25 pg/ml. The chest X-ray was normal. Treatment with azithromycin and methylprednisolone was followed by progressive improvement of clinical conditions. Conclusions: These cases support the strong correlation between interleukin-6 levels and severe clinical manifestations such as COVID-19 pneumonia, and this marker predicts a more severe clinical outcome in children. Testing serum levels of interleukin-6 in children with COVID-19 could be useful to better understand the outcome of lung damage. [ABSTRACT FROM AUTHOR]

Introduction: The preferred treatment for COVID-19 cases is Convalescent Plasma. In COVID-19 patients, cytokine storms are caused by high levels of cytokines including: Inflammatory cytokines such as (IL-10, IL-12, IL-27, IL-21, TNF-α and IFN-γ, IL-2, and IL-6), are triggered by T cell responses. The goal of this research is to determine Does administration of convalescent plasma affect the TNF-α and IFN-γ cases of COVID-19 sufferers. Materials and methods: The experimental research method uses (a post-test only control group design). The study material in the form of serum from the blood of COVID-19 patients as many as 38 samples selected randomly with details of COVID-19 patients as many as 19 samples were not given convalescent plasma treatment and 19 samples of COVID-19 patients receiving convalescent plasma therapy. Results: This study showed that there was no effect on TNF-α levels before and after convalescent plasma administration (P> 0.05), while IFN-γ levels showed an effect between before and after convalescent plasma administration (P< 0.05). Conclusion: Although in this study there were differences in the results of statistical analysis of TNF-α and IFN-γ levels in convalescent plasma treatment of COVID-19 patients, this study proved to be able to improve the clinical condition of COVID-19 cases. [ABSTRACT FROM AUTHOR]

Cytokine storm is a condition in which the immune system produces an excessive number of inflammatory signals, which can result in organ failure and death. It is also known as cytokine release syndrome, CRS, or simply cytokine storm, and it has received a lot of attention recently because of the COVID-19 pandemic. It appears to be one of the reasons why some people experience life-threatening symptoms from COVID-19, a medical condition induced by SARS-CoV-2 infection. In situations where natural substances can be exploited as therapeutics to reduce cytokine storm, the drug development process has come to the rescue. In the present study, we tested the potentiality of Andrographolide, labdane diterpenoid targeting several key cytokines that are secreted as a result of cytokine storm. We used molecular docking analyses, molecular dynamics simulations, and pharmacokinetic properties to test the stability of the complexes. The compound's binding energy with some cytokines was over −6.5 Kcal/mol. Furthermore, a post-molecular dynamics (MD) study revealed that Andrographolide was extremely stable with these cytokines. The compound's pharmacokinetic measurements demonstrated excellent properties in terms of adsorption, distribution, metabolism, and excretion. Our research revealed that this compound may be effective in lowering cytokine storm and treating severe symptoms. [ABSTRACT FROM AUTHOR]

For COVID-19 survivors, defeating the virus is just the beginning of a long road to recovery. The inducibility and catastrophic effects of the virus are distributed across multiple organs. The induction of cytokine storms in COVID-19 patients is due to the interaction of the SARS-CoV-2 virus and the host receptor, leading to various immunopathological consequences that may eventually lead to death. So far, COVID-19 has affected tons of people across the world, but there is still no effective treatment. Patients facing complications of COVID-19 after recovery have shown extensive clinical symptoms similar to that of patients recovering from previously circulating coronaviruses. Previous knowledge and literature have opened up ways to treat this disease and manage post-COVID-19 complications, which pose a severe challenge to the health system globally and may exacerbate the fragmentation of diseases. The use of steroids as a treatment has resulted in various health problems and side-effects in COVID-19 patients. This review discusses various post-COVID-19 complications observed and adjunctive therapies used along with common COVID-19 treatment and spotlights their side effects and consequences. This review provides the latest literature on COVID-19, which emphasizes the subsequent complications in various organs, side effects of drugs, and alternative regimens used to treat COVID-19. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease 2019 (COVID-19) is a major health concern and can be devastating, especially for the elderly. It causes a systemic inflammatory response, involving dysregulation and misexpression of many inflammatory cytokines. Objectives: To assess the cytokine profile in COVID-19 patients and detect its relation with disease severity. Patients and methods: This study included 50 COVID-19 patients confirmed by reverse transcription–polymerase chain reaction (RT-PCR), of whom 20 with severe pneumonia, 20 with moderate and 10 with mild disease, and 50 healthy control. Quantitative ELISA tests were performed for tumour necrosis factor alfa (TNF-α) and intercellular adhesion molecule1 (ICAM-1). Results: Level of ICAM-1 is higher in cases of COVID-19 than healthy controls (median for cases = 420 ng/ml). Also TNF-α level is higher in cases with a median of 165 both levels were higher in CORADS 6 and positively correlated with CT findings. Conclusion: Patients with severe COVID-19 might have a cytokine storm syndrome and increased expression of endothelial cell adhesion molecules as ICAM-1, which is related to COVID-19 and disease severity and may contribute to coagulation dysfunction. Levels of ICAM 1 were associated with more severe CT findings and longer hospital stay, also ICAM 1 and TNF can be used as diagnostic measures as they have a higher sensitivity specificity and predictive values. [ABSTRACT FROM AUTHOR]

Objectives: Disruption in the natural immune reaction due to SARS-CoV-2 infection can initiate a potent cytokine storm among COVID-19 patients. An elevated level of IL-6 and IL-10 during a hyperinflammatory state plays a vital role in increasing the risk of severity and mortality. In this study, we aimed to evaluate the potential of circulating IL-6 and IL-10 levels as biomarkers for detecting the severity and mortality of COVID-19. Methods: This study was conducted according to the Cochrane Handbook and PRISMA guidelines. Authorized databases were searched to extract suitable studies using specific search terms. RevMan 5.4 was applied for performing the meta-analysis. Mean differences in IL-6 and IL-10 levels were calculated among COVID-19 patients via a random-effects model. NOS scoring, publication bias and sensitivity analyses were checked to ensure study quality. Results: A total of 147 studies were selected, with 31 909 COVID-19 patients under investigation. In the severity analysis, the mean concentration of IL-6 was significantly higher in the severe COVID-19 cases than in the non-severe cases (MD: 19.98; P <.001; 95% CI: 17.56, 22.40). Similar result was observed for IL-10 mean concentration in severe COVID-19 cases (MD: 1.35; P <.001; 95% CI: 0.90, 1.80). In terms of mortality analysis, circulating IL-6 showed sharp elevation in the deceased patients (MD: 42.11; P <.001; 95% CI: 36.86, 47.36). IL-10 mean concentration was higher in the dead patients than in the survived patients (MD: 4.79; P <.001; 95% CI: 2.83, 6.75). Publication bias was not found except for comparing IL-6 levels with disease severity. Sensitivity analysis also reported no significant deviation from the pooled outcomes. Conclusions: Elevated levels of circulating IL-6 and IL-10 signifies worsening of COVID-19. To monitor the progression of SARS-CoV-2 infection, IL-6 and IL-10 should be considered as potential biomarkers for severity and mortality detection in COVID-19. Systematic review registration: INPLASY registration number: INPLASY202240046. [ABSTRACT FROM AUTHOR]

The emergence of severe acute syndrome coronavirus 2 (SARS-CoV-2) in December 2019 has led to the global COVID-19 pandemic. Although the symptoms of most COVID-19 patients are mild or self-curable, most of severe patients have sepsis caused by cytokine storms, which greatly increases the case fatality rate. Moreover, there is no effective drug that can limit the novel coronavirus thus far, so it is more needed to develop antiviral drugs for the SARS-CoV-2. In our research, we employed the techniques of molecular docking to screen 35 flavonoid compounds among which 29 compounds have Z-scores lower than − 6. Then, (−)-gallocatechin gallate, (+)-gallocatechin and baicalein were identified to have potent inhibitory activity against SARS-CoV-2 Mpro with IC50 values of 5.774 ± 0.805 μM, 13.14 ± 2.081 μM and 5.158 ± 0.928 μM respectively by FRET assay. Molecular docking results also showed that (−)-gallocatechin gallate, (+)-gallocatechin and baicalein can non-covalently bind to Mpro through π-π stacking and hydrogen bonds in the Cys145 catalytic site. We further evaluated the effect of (−)-gallocatechin gallate and baicalein on cytokine storms using a mouse model of sepsis. (−)-Gallocatechin gallate and baicalein significantly reduced sepsis of mouse models on weight, murine sepsis score, and survival rate and reduced the inflammatory factor levels, such as TNF-α, IL-1α, IL-4, and IL-10. Overall, (−)-gallocatechin gallate and baicalein show certain potential of treatment against COVID-19. [ABSTRACT FROM AUTHOR]

Two years have passed since WHO declared a pandemic state for SARS-CoV-2 infection. COVID-19 pathogenesis consists of a first viral phase responsible for early symptoms followed by an inflammatory phase, cytokine-mediated, responsible for late-onset manifestations up to ARDS. The dysregulated immune response has an outstanding role in the progression of pulmonary damage in COVID-19. IL-6, through the induction of pro-inflammatory chemokines and cytokines, plays a key role in the development and maintenance of inflammation, acting as a pioneer of the hyperinflammatory condition and cytokine storm in severe COVID-19. Therefore, drugs targeting both IL-6 and IL-6 receptors have been evaluated in order to blunt the abnormal SARS-CoV-2-induced cytokine release. Sarilumab, a high-affinity anti-IL-6 receptor antibody, may represent a promising weapon to treat the fearsome hyperinflammatory phase by improving the outcome of patients with moderate-to-severe COVID-19 pneumonia. Further prospective and well-designed clinical studies with larger sample sizes and long-term follow-up are needed to assess the efficacy and the safety of this therapeutic approach to achieve improved outcomes in COVID-19. [ABSTRACT FROM AUTHOR]

A new coronavirus, called Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), emerged in late December 2019, Wuhan (Hubei, China). The disease, now known as COVID-19, has spread rampant and has given rise to a pandemic world that has precipitated draconian measures to limit its transmission. COVID-19 has demonstrated a wide spectrum of clinical manifestations, from asymptomatic or paucisymptomatic forms, to severe viral pneumonia with respiratory failure, multi-organ and systemic dysfunction, and high morbidity and mortality. The body's hyper inflammatory response has been associated, along with the possible direct effects of SARS-CoV-2 on organs throughout the body via ACE2. Disseminated intravascular coagulation is another common complication. The inflammatory response caused by COVID-19 in the lung due to the virus itself developing pneumonia, followed by cytokine storm and hemophagocytic syndrome causes a hyper coagulation state manifesting small and large vein and arterial thrombosis and likely DEC. Many hyper coagulation biomarkers such as D-dimer, elevated cytokines such as Il-6, and inflammation parameters such as C reactive protein support this clinical picture. Anticoagulant treatment with heparin and anti platelet should always be ordered. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease 2019 (COVID‐19) is known to cause not only respiratory but also neuropsychiatric symptoms, which are assumed to be derived from a cytokine storm and its effects on the central nervous systems. Patients with COVID‐19 who develop severe respiratory symptoms are known to show severe neuropsychiatric symptoms such as cerebrovascular disease and encephalopathy. However, the detailed clinical courses of patients with neuropsychiatric symptoms caused by mild or asymptomatic COVID‐19 remain poorly understood. Here, we present a case of COVID‐19 who presented with severe and prolonged neuropsychiatric symptoms subsequent to mild respiratory symptoms. Case presentation: A 55‐year‐old female with COVID‐19 accompanied by mild respiratory symptoms showed delusion, psychomotor excitement, and poor communication ability during quarantine outside the hospital. Considering her diminished respiratory symptoms, her neuropsychiatric symptoms were initially regarded as psychogenic reactions. However, as she showed progressive disturbance of consciousness accompanied by an abnormal electroencephalogram, she was diagnosed with post‐COVID‐19 encephalopathy. Although her impaired consciousness and elevated cytokine level improved after steroid pulse therapy, several neuropsychiatric symptoms, including a loss of concentration, unsteadiness while walking, and fatigue, remained. Conclusions: This case suggests the importance of both recognizing that even apparently mild COVID‐19‐related respiratory symptoms can lead to severe and persistent neuropsychiatric symptoms, and elucidating the mechanisms, treatment, and long‐term course of COVID‐19‐related neuropsychiatric symptoms in the future. [ABSTRACT FROM AUTHOR]

Objective: The novel coronavirus, called SARS-CoV-2, causes COVID-19 disease and began a pandemic on a global scale. Uncontrolled cytokine production is observed especially in COVID-19 cases with severe progression and this situation is thought to be one of the causes of more severe disease progression and increased mortality. In our study, we aimed to assess the efficacy of Coupled Plasma Filtration Adsorption (CPFA) treatment in situations with severe disease progression like sepsis, septic shock and multiple organ failure, considered to be secondary to cytokine storm, in COVID-19 disease. Methods: Our study retrospectively screened data from 20 patients admitted to our intensive care unit and administered CPFA. CPFA was administered as 10 hours each session and 2 sessions with 12 hours interval. Results: After our CPFA treatment, there were statistically significant ameliorations in clinical and laboratory findings like SOFA scores, mainly, Horowitz values, fever and IL-6 values. Conclusion: The CPFA treatment removes the uncontrolled production of harmful cytokines/chemokines and toxic substances from the blood and shows promise in the treatment of the cytokine storm that develops in COVID-19 disease. [ABSTRACT FROM AUTHOR]

The Coronavirus Disease-2019 (COVID-19) imposed public health emergency and affected millions of people around the globe. As of January 2021, 100 million confirmed cases of COVID-19 along with more than 2 million deaths were reported worldwide. SARS-CoV-2 infection causes excessive production of pro-inflammatory cytokines thereby leading to the development of "Cytokine Storm Syndrome." This condition results in uncontrollable inflammation that further imposes multiple-organ-failure eventually leading to death. SARS-CoV-2 induces unrestrained innate immune response and impairs adaptive immune responses thereby causing tissue damage. Thus, understanding the foremost features and evolution of innate and adaptive immunity to SARS-CoV-2 is crucial in anticipating COVID-19 outcomes and in developing effective strategies to control the viral spread. In the present review, we exhaustively discuss the sequential key immunological events that occur during SARS-CoV-2 infection and are involved in the immunopathogenesis of COVID-19. In addition to this, we also highlight various therapeutic options already in use such as immunosuppressive drugs, plasma therapy and intravenous immunoglobulins along with various novel potent therapeutic options that should be considered in managing COVID-19 infection such as traditional medicines and probiotics. [ABSTRACT FROM AUTHOR]

Since the beginning of the COVID-19 pandemic in 2019–2020, Cytokine & Growth Factor Reviews has published several Special Issues focused on the biology, pathogenesis and therapeutic options in the treatment of COVID-19 infection, including articles on the involvement of the chemokine system in the cytokine storm in COVID-19, intervention in the early stages of COVID-19 pneumonia, the therapeutic value of corticosteroid treatment, early clinical intervention with type 1 interferons, progress in vaccine development, and organ specific complications of COVID-19. By 2022, multiple highly efficacious vaccines are available and are being administered in countries around the world, therapeutic options have been clinically evaluated and approved, and SARS-CoV-2 has arguably become the most thoroughly studied virus in history. But, with progress has also come unanticipated problems – misinformation, anti-vaxxers, opposition to protective masks, and politically motivated interference disguised as knowledge. With this issue of CGFR, we continue to document the global coronavirus pandemic and provide an update on the emergence of viral variants, the global effort to administer vaccines and the impediments to progress posed by misinformation and anti-vaccine sentiment. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) has a broad range of clinical manifestations, highlighting the need for specific diagnostic tools to predict disease severity and improve patient prognosis. Recently, calprotectin (S100A8/A9) has been proposed as a potential biomarker for COVID-19, as elevated serum S100A8/A9 levels are associated with critical COVID-19 cases and can distinguish between mild and severe disease states. S100A8/A9 is an alarmin that mediates host proinflammatory responses during infection and it has been postulated that S100A8/A9 modulates the cytokine storm; the hallmark of fatal COVID-19 cases. However, it has yet to be determined if S100A8/A9 is a bona-fide biomarker for COVID-19. S100A8/A9 is widely implicated in a variety of inflammatory conditions, such as cystic fibrosis (CF) and chronic obstructive pulmonary disorder (COPD), as well as pulmonary infectious diseases, including tuberculosis and influenza. Therefore, understanding how S100A8/A9 levels correlate with immune responses during inflammatory diseases is necessary to evaluate its candidacy as a potential COVID-19 biomarker. This review will outline the protective and detrimental roles of S100A8/A9 during infection, summarize the recent findings detailing the contributions of S100A8/A9 to COVID-19 pathogenesis, and highlight its potential as diagnostic biomarker and a therapeutic target for pulmonary infectious diseases, including COVID-19. [Display omitted] • Calprotectin (S100A8/A9) as a potential biomarker for COVID-19 can distinguish between mild and severe disease states. • S100A8/A9 is an alarmin that mediates host proinflammatory responses during infection. • Protective and detrimental roles of S100A8/A9 during infection. • Potential as diagnostic biomarker and a therapeutic target for pulmonary infectious diseases, including COVID-19. [ABSTRACT FROM AUTHOR]