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The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality
Abstract
Since December 2019, a viral pneumonia (COVID-19) from Wuhan, China has swept the world. Although the case fatality rate is not high, the number of people infected is large, and there are still a large number of patients dying. With the collation and publication of more and more clinical data, a large number of data suggest that there are mild or severe cytokine storms in severe patients, which is also an important cause of death. Therefore, the treatment of cytokine storm has become an important part of rescuing severe patients. Interleukin-6 (IL-6) plays an important role in cytokine release syndrome (CRS). If it can block the signal transduction pathway of IL-6, it is expected to become a new method for the treatment of severe patients. Tocilizumab is a blocker of IL-6R, which can effectively block IL-6 signal transduction pathway. So, tocilizumab is likely to become an effective drug for patients with severe COVID-19.
... Additionally, the cytokine storm activates the secretion of other inflammatory mediators from the peripheral blood into the site of inflammation, further intensifying the inflammatory response. Increased vascular permeability and fluid accumulation in the alveoli, caused by the activities of these pro-inflammatory cytokines, ultimately lead to respiratory failure [49,50]. ...
... IκB kinase β (IKKβ) facilitates the dissociation of I-κB from NF-κB through phosphorylation induced by lipopolysaccharides, leading to I-κB degradation via the proteasome. This allows NF-κB to enter the nucleus and trigger the production of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α, which are notably elevated in patients with severe COVID-19 [49,51,52]. ...
... Additionally, severe COVID-19 patients often exhibit high levels of IL-10, which plays a significant role in immune proliferation [53,54]. An in vitro study demonstrated that NAC also downregulates IL-10 mRNA expression, however the overall balance appears to favor the anti-inflammatory action [49,50,55,56]. Considering that pain is a common symptom during COVID-19 infection, as evidenced by the presence of neuropathic pain in up to 2.3% of hospitalized patients [57], and its occurrence in post-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) [58], NAC may be a suitable candidate for treating pain, limiting the transition to a chronic condition, and, more broadly, providing neuroprotection [59,60]. ...
Long COVID, characterized by persistent symptoms following COVID-19 infection, significantly impacts individuals’ health and daily functioning due to fatigue and pain. Focusing on pain, this review addresses nociplastic and chronic pain conditions. Interventions designed to reduce inflammation, oxidative stress, and enhance vagal activity may offer a promising approach to managing post-pandemic pain. This review presents individual components of food supplements with demonstrated efficacy in one or more pain conditions, focusing on their proposed mechanisms and clinical activity in pain, including their use in post-COVID-19 pain when available. Many of these substances have a long history of safe use and may offer an alternative to long-term analgesic drug treatment, which is often associated with potential side effects. This review also explores the potential for synergistic effects when combining these substances with each other or with conventional analgesics, considering the advantages for both patients and the healthcare system in using these substances as adjunctive or primary therapies for pain symptoms related to long COVID. While preclinical scientific literature provides a mechanistic basis for the action of several food supplements on pain control mechanisms and signaling pathways, clinical experience, particularly in the field of long COVID-associated pain, is still limited. However, the reviewed literature strongly suggests that the use of food supplements in long COVID-associated pain is an attainable goal, provided that rigorous clinical trials are conducted.
... CRS usually affects immune system-related patients, such as Familial Mediterranean Fever (FMF), organ transplantation and sepsis. 5 . ...
... 3. Surprisingly, taste alteration preceding fever attacks in FMF has been reported amongst the prodromal manifestations. 5 MEFV gene encodes pyrin protein. This protein acts as a major regulatory component of inflammasome complex. ...
... IL-6 is a multitask cytokine with antiinflammatory and pro-inflammatory effect. 5 MEFV gene encodes for pyrin, which is expressed in the cytoplasm of monocytes, and the nucleus of dendritic cells and neutrophils. The PYD domain of pyrin attaches to inflammasome adaptor protein, which consequently mediates production of IL-1β. ...
... Numerous studies have demonstrated the significance of dysregulated immune processes due to SARS-CoV-2 infection in the developing severe and critical COVID-19. The hyperactivation of immune cells (macrophages, NK cells, B and T lymphocytes) leads to abnormal systemic inflammation, with cytokine release syndrome (CRS), which has been identified as a pathogenic mechanism in the progression of severe COVID-19 [3][4][5][6]. ...
... The hyperactivation of the immune system, resulting in abnormal inflammation and cytokine release syndrome, has been established as a pathogenic mechanism in the development of severe and critical COVID-19. The effect of medications that modulate the immune response on the above-mentioned biomarkers has been examined in multiple studies [5,33,42]. In this context, the role of Anakinra, an interleukin-1 receptor antagonist, has been explored in numerous studies [32][33][34][35]37,43]. ...
Background: SARS-CoV-2 can trigger hyperinflammation, leading to severe COVID-19, presenting with pneumonia, acute respiratory distress syndrome (ARDS), and multiple organ failure. Specific biomarkers like leukocytes, CRP, NLR, AST, LDH, D-dimer, ferritin, and IL-6 are associated with disease severity. Anakinra, an IL-1 receptor antagonist, has been proposed to mitigate hyperinflammation, but its clinical efficacy remains uncertain. This study aimed to evaluate the effect of Anakinra on inflammatory biomarkers, oxygenation status, and survival outcomes in hospitalized patients with moderate to severe COVID-19 (according to the National Institute of Health severity scale), compared to standard treatment. Methods: A retrospective analysis included 65 patients (mean age 75.51 ± 9.54 years; 58.5% male, 41.5% female) hospitalized with moderate to severe COVID-19. Patients were divided into two groups: a control group receiving standard treatment (n = 24) and a target group treated with Anakinra (n = 41). Biomarkers and oxygenation status were assessed on Days 0, 3, and 7. Statistical analyses compared the groups for changes in leukocytes, NLR, CRP, AST, LDH, D-dimer, ferritin, and IL-6. Results: Anakinra treatment was associated with significant reductions in leukocytes, NLR, D-dimer, ferritin, IL-6, and CRP by Days 3 and 7. Improvements in oxygenation status were observed, although no survival benefits were noted. The control group showed no significant biomarker changes except for AST and LDH on Day 7. Conclusions: Anakinra demonstrated favorable effects on biomarkers and oxygenation in moderate to severe COVID-19 but did not improve survival. Further studies are needed to validate these findings.
... including CRP, TNF-α, and IL-6 [5][6][7]. IL-1β and IL-6 are involved in priming neutrophils for activation by chemoattractant [8], resulting in neutrophil diapedesis and infiltration into the COVID-19-infected organs [3]. Additionally, neutrophils are involved in platelet activation by releasing the serine protease neutrophils elastase, the most potent activator of platelets [9][10][11]. ...
... Reducing the function and infiltration of granulocyte cells resulted in exerting anti-inflammatory and antifibrotic effects [18,19], leading to the subsequent downregulation of downstream cellular functions of leucocytes [18,20]. Reduced production of a potent proinflammatory cytokine, such as IL-1β, has also resulted in a reduced amount of other proinflammatory, including IL-6, CRP, and TNF-α [6,7,21]. ...
Background
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 virus) has been a major cause of significant morbidity and mortality. Acute kidney injury (AKI) has been seen in COVID-19-infected subjects, and it has frequently resulted in an abnormal estimated glomerular filtration rate. Colchicine, an immunomodulatory drug, was used in several studies in the early stages of the pandemic. Colchicine has been shown to prevent the development of renal failure in patients with Familial Mediterranean Fever (FMF). It has also been reported to reduce fibrosis, which plays a role in chronic kidney disease. We, therefore, aimed to investigate whether using Colchicine, in addition to standard care, was associated with better renal function in patients with severe COVID-19 infection.
Methods
This retrospective cohort study comprised 118 out of 605 hospitalized COVID-19 subjects. Some of the subjects (n = 50) received oral Colchicine plus standard care, called the Col ( +) group. The others (n = 68) received only the standard care, called the Col (-) group. The estimated glomerular filtration rate (eGFR) and other laboratory findings, including lymphocytes, D-dimer, and CRP, were analyzed.
Results
The D-dimer and serum creatine levels were significantly reduced in both groups. The number of lymphocytes showed a significant increase in both groups at discharge. The level of C-reactive protein (CRP) was significantly higher in the Col ( +) group than in the Col (-) group at admission. The reduction of SCr was considerably higher in the Col ( +) group than in the Col (-) group. Similarly, the improvement of eGFR was higher in the Col ( +) group than in the Col (-) group at discharge and 6–12 mounts follow-up.
Conclusion
Our findings indicated the use of Colchicine plus standard care was associated with improved renal function in hospitalized patients with severe COVID-19 infection.
... We therefore also believe that antiviral agents cannot solve the problem, since there is no direct link between viral replication and hyperactivation of the NLRP3 inflammasome. [3][4][5][9][10][11][12][13][14]. 2 Administration of antibodies blocking a given cytokine(s) is also doomed to failure because the cause of the CS, the hyperactivated NLRP3 inflammasome, continues to produce hypercytokinemia [3,4]. In a number of publications, we have demonstrated that blocking the NLRP3 inflammasome is possible with high but, safe doses of colchicine. ...
... (www.preprints.org) | NOT PEER-REVIEWED | Posted: 25 October 2024 doi:10.20944/preprints202410.1998.v112 ...
Despite the enormous efforts and funds spent to find an effective treatment for COVID-19, the results have been disappointing. In previous publications, we have demonstrated the remarkable effect of high-dose colchicine in inhibiting the cytokine storm and preventing multiorgan damage and death. However, this treatment is beneficial only after virus entry into the cell. The question of prophylaxis and entry prohibition should also be explored. We now demonstrate the prophylactic effect of bromhexine hydrochloride (BRH), an over-the-counter, non-invasive, effective, well-tolerated medicine, with proven safety, affordable, and inexpensive on 125 men and women. The effect of BRH is best when given continuously for prophylaxis during peaks in contagion in the wave of COVID-19. Then the probability of infection drops sharply, and if a disease does occur, it proceeds mildly. BRH is also effective when given by inhalation for post-exposure prophylaxis.When COVID-19 manifests itself clinically, the efficacy of BRH drops sharply because the virus is already in the cell. However, BRH inhalations are useful because they limit the spread of the virus and have an anti-inflammatory and possibly antiviral effect.
... Reduced ICU admissions, improved survival in cytokine storm cases [62] TNF-α (Infliximab, Etanercept) ...
Cytokines are pivotal regulators of immune responses. They are critical in mediating inflammation, recruiting immune cells, and driving pathogen clearance. Among these, interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-α) stand out as key players in pediatric immunity, as they exhibit unique expression patterns that reflect the dynamic nature of the developing immune system. This review explores the dual roles of these cytokines in orchestrating immune defense and their potential as diagnostic biomarkers for infection severity in children. It highlights how elevated IL-6, IL-8, and TNF-α levels correlate with the severity of bacterial, viral, and fungal infections and discusses their utility in distinguishing between these etiologies. The article pinpoints current technologies for cytokine detection and their impact on early diagnosis and risk stratification. The relevance of cytokine-targeted therapies in managing hyperinflammatory states is highlighted and argued that integrating cytokine profiling with other diagnostics and personalized medicine has transformative potential in pediatric healthcare. These would pave the way for more precise, timely, and effective management of pediatric infections.
... Bir taraftan İRH'da kullanılan antiromatizmal ilaçların COVID-19 pandemisi varlığında kullanımıyla ilgili yayınlanan yeni rehberlerde ilaçlara ara verilmesi önerilirken diğer taraftan bu ilaçların bazılarının (hidroksiklorokin ve IL-6 gibi) COVID-19 a bağlı oluşan sitokin fırtınasında kullanımıyla ilgili çalışmalar ardarda yapıldı (8)(9)(10). ...
Aim: The object of this study is to search the effect of COVID-19 pandemia on persons with inflammatory rheumatic disease, in terms of their follow-up and treatment, daily life activities, public life, mental state.
Material and methods: Patients with inflammatory rheumatic disease (ankylosing spondylitis, rheumatoid arthritis, psoriatic arthritis) followed up regularly in the İstanbul Physical Therapy and Rehabilitation Hospital Rheumatology Clinic were evaluated retrospectively between April 1, 2020, and January 31, 2021. Sociodemographic data, inflammatory disease records, and COVID-19 records of the patients have been collected. The effects of the pandemic on their daily life and mental state were evaluated via a questionnaire filled out by the patients themselves. For this purpose Coronavirus Anxiety Scale (CAS) and the Fear of COVID-19 (FCV-19S) Scale have been used. Their restrictions in public life were evaluated qualitatively. For statistical analysis, SPSS 18.0 has been used. P<0.05 was accepted as statistically significant.
Results: The average age of the 105 patients in the study was 47.7±12.8, and their duration of disease was 10 (4-16) years. Among the 21 (20%) patients who got COVID-19, only one patient had been hospitalized. Half of the patients had stopped using antirheumatic medicine, and their disease had flared. No difference had been found between patients with positive and negative COVID-19 records in terms of age, gender, socioemographic attributes, diagnosis, duration, medicines used, comorbidities, social activities, habits, FCV-19S, and CAS scale points (p>0.05). Dysfunctional anxiety rate was found to be 1%.
Conclusion: During the COVID-19 pandemic, patients with inflammatory rheumatic disease should be intently followed up in terms of the medicine used, disease activity, and mental state. Patients should show up regularly and comply with the medication guides.
Key words: Ankylosing spondylitis, COVID-19, Fear of COVID-19 Scale) Rheumatoid arthritis.
... The trend toward higher CT scores in ischemic patients suggests greater pulmonary involvement, aligning with the known association between ischemia and extensive lung injury in conditions like COVID-19 and other systemic inflammatory diseases. 11,12 Significantly elevated IL-6 levels in ischemic patients highlight the role of systemic inflammation in ischemic pathology. IL-6 is a proinflammatory cytokine linked to endothelial dysfunction, vascular inflammation, and thrombogenesis. ...
... Further, endothelial and vascular smooth muscle cells may express IL-6 receptors dependent on IL-1 activity, indicating the relevance of IL-6 in atherosclerotic and subsequent ischemic heart disease [102][103][104]. Recently, the IL-6 receptor antagonist Tocilizumab gained relevance as a treatment of cytokine-releasesyndrome during COVID-19 infection [105,106]. While trials have highlighted the anti-inflammatory benefits of Tocilizumab in cardiovascular patients, direct effects on improving clinical outcomes post-MI have not been convincingly demonstrated [107][108][109]. ...
Purpose of Review
The inclusion of immunomodulatory strategies as supportive therapies in ischemic heart disease (IHD) has garnered significant support over recent years. Several such approaches appear to be unified through their ultimate target, the NLRP3 inflammasome. This review presents a brief update on immunomodulatory strategies in the continuum of conditions constituting ischemic heart disease and emphasising on the seemingly unifying mechanism of NLRP3 activation as well as modulation across these conditions.
Recent Findings
The NLRP3 inflammasome is a multiprotein complex assembled upon inflammatory stimulation, causing the release of pro-inflammatory cytokines and initiating pyroptosis. The NLRP3 pathway is relevant in inflammatory signalling of cardiac immune cells as well as non-immune cells in the myocardium, including cardiomyocytes, fibroblasts and endothelial cells. In addition to a focus on clinical outcome and efficacy trials of targeting NLRP3-related pathways, the potential connection between immunomodulation in cardiology and the NLRP3 pathway is currently being explored in preclinical trials. Colchicine, cytokine-based approaches and SGLT2 inhibitors have emerged as promising agents. However, the conditions comprising IHD including atherosclerosis, coronary artery disease (CAD), myocardial infarction (MI) and ischemic cardiomyopathy/heart failure (iCMP/HF) are not equally amenable to immunomodulation with the respective drugs. Atherosclerosis, coronary artery disease and ischemic cardiomyopathy are affected by chronic inflammation, but the immunomodulatory approach to acute inflammation in the post-MI setting remains a pharmacological challenge, as detrimental and regenerative effects of myocardial inflammation are initiated in unison.
Summary
The NLRP3 inflammasome lies at the center of cell mediated inflammation in IHD. Recent trial evidence has highlighted anti-inflammatory effects of colchicine, interleukin-based therapy as well as SGLT2i in IHD and that the respective drugs modulate the NLRP3 inflammasome.
... To manage the hyper-inflammatory response observed in COVID-19, using immunomodulatory agents has been suggested. Agents, such as corticosteroids, IL-6 receptor antagonists, and JAK inhibitors, have shown promise in reducing the hyperinflammatory state associated with severe COVID-19 [51][52][53]. Additionally, targeting specific pathways, like NFκB activation, implicated in endothelial damage, could further reduce the risk of thrombotic and vascular complications [54,55]. ...
Background/ Objectives: Long COVID or post-acute sequelae of SARS-CoV-2 infection (PASC) are symptoms that manifest despite passing the acute infection phase. These manifestations encompass a wide range of symptoms, the most common being fatigue, shortness of breath, and cognitive dysfunction. Genetic predisposition is clearly involved in the susceptibility of individuals to developing these persistent symptoms and the variation in the severity and forms. This review summarizes the role of genetic factors and gene polymorphisms in the development of major pulmonary vascular disorders associated with long COVID. Methods: A comprehensive review of current literature was conducted to examine the genetic contributions to pulmonary complications following SARS-CoV-2 infection. Studies investigating genetic polymorphisms linked to pulmonary hypertension, pulmonary thromboembolism, and pulmonary vascular endothelialitis were reviewed and summarized. Results: Findings show that specific genetic variants contribute to increased susceptibility to pulmonary vascular complications in long COVID patients. Variants associated with endothelial dysfunction, coagulation pathways, and inflammatory responses have been implicated in the development of pulmonary hypertension and thromboembolic events. Genetic predispositions influencing vascular integrity and immune responses appear to influence disease severity and progression. Conclusions: Understanding these mechanisms and genetic predispositions could pave the way for targeted therapeutic interventions to alleviate the burden on patients experiencing long COVID.
... COVID-19, a novel illness caused by SARS-CoV-2, was first identified in Wuhan, China, with severity ranging from mild rhinorrhoea to life-threatening Adverse Drug Reaction (ADR) and non-respiratory manifestations. 1 The spike (S) protein of SARS-CoV-2 plays a critical role in infection. It acts like a key, binding to the ACE-2 receptor on host cells and enabling the virus to fuse and enter. ...
... Excessive production of these pro-inflammatory cytokines, which causes an increased systemic inflammatory response with excessive vascular permeability and multiple organ failure. This is defined as cytokine storm and may contribute to high mortality rates [17,18] . However, the healthy immune system neutralizes the virus, resolves the infection and produces virus-specific antibodies [16,19] . ...
Aim: The aim of this study is to evaluate the relationship between disease severity and serum Zinc(Zn) levels in COVID-19 patients.
Materials and Methods: The study included 153 COVID-19 patients confirmed by RT-PCR test, were divided into two groups according to the severity of the disease: hospitalized COVID-19 patients (n=81) and intensive care unit patients (n=72). Additionally, 78 healthy controls were included. Serum levels of various biomarkers, including WBC, Neutrophil, Lymphocyte, Monocyte, Platelet, PT, APTT, INR, D-Dimer, CRP, PCT, Ferritin, and Zinc, were measured for all participants. Demographic data and length of hospitalization were also recorded.
Results: The study found significant differences between the groups in age, hospitalizations, chronic disease, and length of hospital stay (p≤0.001). COVID-19 patients had lower median zinc levels (89μg/dl) compared to healthy individuals (99.50μg/dl), and this difference was statistically significant (p=0.023). As zinc levels increased, the CORADS score decreased (r=-0.248, p=0.031). There was an inverse relationship between zinc level and intensive care unit admission, indicating that lower zinc levels were associated with a higher probability of intensive care hospitalization (r=-0.260, p=0.023).
Conclusion: This study showed that COVID-19 patients had significantly lower zinc levels than healthy individuals. The difference between the average zinc level of COVID-19 patients and the average zinc level of healthy individuals were found to be statistically significant. Additionally, a significant inverse relationship were found between zinc level and intensive care unit hospitalization; As the zinc level decreases, the likelihood of being hospitalized in intensive care increases.
... This cascade is fueled by increased ROS levels, reduced antioxidant enzyme activity, and disruption of the redox balance. Inflammatory pathways, such as the NF-κB pathway, amplify the production of cytokines such as IL-6, IL-1β, IL-10, and TNF-α, worsening ARDS [20,21]. The reduction in ROS levels is ensured by an antioxidant defense system comprising both enzymatic and non-enzymatic components [17]. ...
The COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has profoundly impacted global health, with pneumonia emerging as a major complication in severe cases. The pathogenesis of COVID-19 is marked by the overproduction of reactive oxygen species (ROS) and an excessive inflammatory response, resulting in oxidative stress and significant tissue damage, particularly in the respiratory system. Antioxidants have garnered considerable attention for their potential role in managing COVID-19 pneumonia by mitigating oxidative stress and modulating immune responses. This review provides a comprehensive overview of the literature on the use of antioxidants in hospitalized patients with mild-to-moderate COVID-19. Studies exploring antioxidants, including vitamins, trace elements, nitric oxide (NO), ozone (O3), glutathione (GSH), L-carnitine, melatonin, bromelain, N-acetylcysteine (NAC), and numerous polyphenols, have yielded promising outcomes. Through their ROS-scavenging properties, these molecules support endothelial function, reduce the thrombosis risk, and may help mitigate the effects of the cytokine storm, a key contributor to COVID-19 morbidity and mortality. Clinical evidence suggests that antioxidant supplementation may improve patient outcomes by decreasing inflammation, supporting immune cell function, and potentially shortening recovery times. Furthermore, these molecules may mitigate the symptoms of COVID-19 by exerting direct antiviral effects that inhibit the infection process and genomic replication of SARS-CoV-2 in host cells. Moreover, antioxidants may work synergistically with standard antiviral treatments to reduce viral-induced oxidative damage. By integrating findings from the literature with real-world data from our clinical experience, we gain a more profound understanding of the role of antioxidants in managing COVID-19 pneumonia. Further research combining comprehensive literature reviews with real-world data analysis is crucial to validate the efficacy of antioxidants and establish evidence-based guidelines for their use in clinical practice.
... It seems sensible, therefore, that treatment strategies should be directed at reducing IL-6 production, and recent studies point to certain drugs such as auranofin, which showed protective action in vivo through the reduction in viral replication, IL-6 production and inflammation in the lungs [62], and siltuximab or tocilizumab, both of which are monoclonal antibodies specifically directed against IL-6 [63,64]. ...
COVID-19 has been a challenge at the healthcare level not only in the early stages of the pandemic, but also in the subsequent appearance of long-term COVID-19. Several investigations have attempted to identify proteomic biomarkers in an attempt to improve clinical care, guide treatment and predict possible patient outcomes. Proteins such as C-reactive protein (CRP) or interleukin 6 (IL-6) are clear markers of severe disease, but many others have been proposed that could help in risk stratification and in the prediction of specific complications. This review aims to bring together the most relevant studies in this regard, providing information to identify the most notable biomarkers in relation to COVID-19 found to date.
... IL-6 with TGF-β promotes the differentiation of naïve CD4+T cells to Th17, and inhibits TGFβ1, that induced Treg differentiation [38]. In this way the elevated circulating IL-6 levels contribute to dysregulation of the Treg/Th17 cell ratio [39]. Tfh is an important subset of CD4+T cell which stimulates B cell proliferation via the activation of co-stimulatory signal CD40. ...
... Several studies have shown that by the down regulation of ACE II due to the SARS-CoV-2 infection, Angiotensin II is elevated which can lead to hypertension, heart failure and lung dysfunction [21][22][23]. Furthermore, severe inflammatory responses among which the cytokine release syndrome [24] (measured by PCT and IL-6) might act as a regulator in cardiomyocyte injury [25], and studies have described the role of inflammation in causing heart failure and myocardial infarction [26][27][28][29][30]. In addition, an inflammatory state in itself also increases the risk of unfavorable outcomes in patients with coronary heart disease [31]. ...
Background
Extubation failure is associated with an increased morbidity, emphasizing the need to identify factors to further optimize extubation practices. The role of biomarkers in the prediction of extubation failure is currently limited. The aim of this study was to investigate the prognostic value of cardiac (N-terminal pro–B-type natriuretic peptide (NT-proBNP), High-sensitivity Troponin T (Hs-TnT)) and inflammatory biomarkers (Interleukin-6 (IL-6) and Procalcitonin (PCT)) for extubation failure in patients with COVID-19 Acute Respiratory Distress Syndrome (C-ARDS).
Materials and methods
In this single-center retrospective cohort study, patient characteristics and laboratory measurements were extracted from electronic medical records. Patients were eligible for inclusion if they were extubated after mechanical ventilation. The primary endpoint was extubation failure, defined as the need for reintubation or death within the next seven days after extubation, regardless of whether post-extubation respiratory support was used. Uni- and multivariable logistic regression was performed to investigate the association between biomarkers and extubation failure. Biomarkers were log 2 transformed.
Results
Of the 297 patients included, 21.5% experienced extubation failure. In univariable analysis, NT-proBNP (OR 1.24, 95% CI 1.06–1.47), Hs-TnT (OR 1.72, 95% CI 1.37–2.19) and PCT (OR 1.38, 95% CI 1.16–1.65) measured on the day of extubation were significantly associated with extubation failure. After multivariable adjustment for clinical variables (age, duration of mechanical ventilation, SOFA score), Hs-TnT was the only biomarker that was independently associated with extubation failure (adjusted OR 1.38, 95% CI 1.02–1.90). Patients with both elevated Hs-TnT (≥ 14 ng/mL) and elevated PCT (≥ 0.25 ng/mL) carried the highest risk of extubation failure (46%), while in patients with normal Hs-TnT and PCT values, only 13% experienced extubation failure.
Conclusions
Hs-TnT, NT-proBNP and PCT measured on the day of extubation are associated with extubation failure in mechanically ventilated patients with C-ARDS. Since Hs-TnT is the only biomarker that is independently associated with extubation failure, Hs-TnT could offer additional objective measures for assessing readiness for extubation. Future studies should focus on an integrative approach of biomarkers combined with relevant clinical factors to predict extubation failure.
... Additionally, IL-6 influences numerous signalling pathways, governs cell proliferation, differentiation, apoptosis, angiogenesis and metastasis, and is implicated in various diseases [112]. Notably, IL-6 plays a key role in cytokine release syndrome [113]. ...
The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has profoundly impacted global healthcare systems and spurred extensive research efforts over the past three years. One critical aspect of the disease is the intricate interplay between the virus and the host immune response, particularly the role of inflammatory gene expression in severe COVID-19. While numerous previous studies have explored the role of genetic polymorphisms in COVID-19, research specifically focusing on inflammatory genes and their associations with disease severity remains limited. This review explores the relationship between severe COVID-19 outcomes and genetic polymorphisms within key inflammatory genes. By investigating the impact of genetic variations on immune responses, which include cytokine production and downstream signalling pathways, we aim to provide a comprehensive overview of how genetic polymorphisms contribute to the variability in disease presentation. Through an in-depth analysis of existing literature, we shed light on potential therapeutic targets and personalized approaches that may enhance our understanding of disease pathogenesis and treatment strategies.
... During the COVID-19 pandemic, numerous drugs have been used as antagonists of specific cytokine receptors. Tocilizumab (TCZ), an IL-6 receptor antagonist, can inhibit cytokine storms by blocking the IL-6 signal transduction pathway [212]. In another study by Meng et al. showed that Dexamethasone [213] resulted in reduced inflamed cells by targeting the cytokines receptors and suppressed activated macrophages and DCs. ...
Health and disease are intricately intertwined and often determined by the delicate balance of biological processes. Cytokines, a family of small signalling molecules, are pivotal in maintaining this balance, ensuring the body's immune system functions optimally. In a healthy condition, cytokines act as potent mediators of immune responses. They orchestrate the activities of immune cells, coordinating their proliferation, differentiation, and migration. This intricate role of cytokine signalling enables the body to effectively combat infections, repair damaged tissues, and regulate inflammation. However, the delicate equilibrium of cytokine production is susceptible to disruption. Excessive or abnormal cytokine levels can lead to a cascade of pathological conditions, including autoimmune diseases, chronic inflammation, infections, allergies, and even cancer. Interestingly, from the bunch of cytokines, few cytokines play an essential role in maintaining the balance between normal physiological status and diseases. In this review, we have appraised key cytokines' potential role and feedback loops in augmenting the imbalances in the body's biological functions, presenting a critical link between inflammation and disease pathology. Moreover, we have also highlighted the significance of cytokines and their molecular interplay, particularly in the recent viral pandemic COVID-19 disease. Hence, understandings regarding the interplay between viral infection and cytokine responses are essential and fascinating for developing effective therapeutic strategies.
... It is caused by the innate immune response triggering an uncontrolled release of an excessive amount of pro-inflammatory signaling molecules known as cytokines. While cytokines are essential components of the body's immune response to infection, their unanticipated large-scale release can lead to multiple-organ failure and even death [78]. IFNs represent a prominent class of cytokines, serving as signaling proteins produced and released by host cells upon encountering various viruses. ...
Dengue fever is currently a major global issue, especially in tropical and subtropical countries. The absence of specific antiviral medications supports alternative dengue treatment strategies. South Asian countries have been using Carica papaya leaves as a traditional remedy for dengue for many years. Carica papaya possesses several biological features, including anti-inflammatory, antiviral, cancer-fighting, anti-diabetic, and antioxidant qualities. Additionally, numerous studies have demonstrated that bioactive compounds found in papaya leaf extracts, including carpaine, dehydrocarpaine I and II, chymopapain, and papain, significantly influence platelet counts, while phenolic compounds, such as chlorogenic acid, kaemferol, protocatechuic acid, quercetin, and 5,7-dimethoxycoumarin significantly inhibit viral replication in dengue patients, with negligible side effects. Carica papaya may be considered a viable pharmacological candidate with several targets for treating dengue. It has been shown to prevent infections, reduce oxidative stress, control cytokine storms and the immune system, lessen thrombocytopenia, and increase the body’s protein and hemoglobin levels. This literature review highlights the pathophysiological mechanism of dengue, as well as the pharmacological action of Carica papaya, both of which combat this debilitating disease. Despite these findings, additional investigation, including clinical studies, is necessary to confirm the effectiveness and safety of papaya-based treatments. It is necessary to address issues like standardizing papaya extracts, figuring out the best dosages, and assessing any drug interactions.
... These patients may require intensive care measures for respiratory support, while also needing close monitoring and treatment for their IBD [22]. The use of certain medications, such as tocilizumab, an interleukin-6 inhibitor used in severe COVID-19 cases, may have implications for IBD management, as it could potentially influence intestinal inflammation [23]. ...
The COVID-19 pandemic posed significant challenges in the treatment of chronic diseases, particularly inflammatory bowel diseases (IBDs) such as Crohn's disease and ulcerative colitis. These challenges are multifaceted, encompassing difficulties in maintaining routine care, concerns about the safety of immunosuppressive therapies, disruptions in healthcare delivery, and the complexities of managing IBD in patients who contract COVID-19. This article explores the various obstacles faced in the treatment of IBD during the pandemic and discusses potential strategies to overcome these challenges.
... Numerous strategies have been investigated for minimizing the COVID-19 cytokine storm, such as the use of corticosteroids and tocilizumab (an anti-IL-6 monoclonal antibody), and other targeted medicines that inhibit particular cytokines [155][156][157]. Nonetheless, the intricate and ever-changing inflammatory response to COVID-19 poses difficulties since focusing on one specific cytokine route could result in counteractive immunological reactions [158]. ...
The complex link between COVID‐19 and immunometabolic diseases demonstrates the important interaction between metabolic dysfunction and immunological response during viral infections. Severe COVID‐19, defined by a hyperinflammatory state, is greatly impacted by underlying chronic illnesses aggravating the cytokine storm caused by increased levels of Pro‐inflammatory cytokines. Metabolic reprogramming, including increased glycolysis and altered mitochondrial function, promotes viral replication and stimulates inflammatory cytokine production, contributing to illness severity. Mitochondrial metabolism abnormalities, strongly linked to various systemic illnesses, worsen metabolic dysfunction during and after the pandemic, increasing cardiovascular consequences. Long COVID‐19, defined by chronic inflammation and immune dysregulation, poses continuous problems, highlighting the need for comprehensive therapy solutions that address both immunological and metabolic aspects. Understanding these relationships shows promise for effectively managing COVID‐19 and its long‐term repercussions, which is the focus of this review paper.
... These patients may require intensive care measures for respiratory support, while also needing close monitoring and treatment for their IBD [22]. The use of certain medications, such as tocilizumab, an interleukin-6 inhibitor used in severe COVID-19 cases, may have implications for IBD management, as it could potentially influence intestinal inflammation [23]. ...
The COVID-19 pandemic posed significant challenges in the treatment of chronic diseases, particularly inflammatory bowel diseases (IBDs) such as Crohn’s disease and ulcerative colitis. These challenges are multifaceted, encompassing difficulties in maintaining routine care, concerns about the safety of immunosuppressive therapies, disruptions in healthcare delivery, and the complexities of managing IBD in patients who contract COVID-19. This article explores the various obstacles faced in the treatment of IBD during the pandemic and discusses potential strategies to overcome these challenges.
... TT genotype of rs763780 locus in IL-17F gene was not found to confer any susceptibility to any severe COVID-19, which is an important reason of death. 55 On the other hand, polymorphisms in the IL6 was linked to certain viral infections like hepatitis C (HCV), in uenza virus, and hepatitis B virus (HBV). 56 Mao et al. revealed that IL6 rs1800795 G allele could act as a protective factor while IL10 rs1800896 A allele could act as a risk indicator in pneumonia-induced sepsis in Chinese Han patients. ...
The pathogenesis of COVID-19 implicates a potent in ammatory response resulting in cytokine storm. We aimed to evaluate association between polymorphisms in IL-6 gene at rs1800796/rs1800795, IL-6R at rs2228145, IL-10 at rs1800896 and rs1800871, IL-17 at rs2275913 and rs76378, and the prevalence (per million) and mortality rates (per million) of COVID-19 among populations. AG and GG genotypes of rs2275913 in IL-17A was found to be correlated with prevalence and mortality rates, especially in Spain and Brazil populations (p<0.05) while TT genotype of rs763780 in IL-17F was not dependent on the high frequencies in all populations. However, the polymorphisms in IL-6, IL-6R and IL-10 appear not to be correlated with prevalence and mortality rates. The variations in the prevalence of COVID-19 and its mortality rates among countries may be explained by cytokine storm differed by the polymorphisms of rs2275913 locus in IL-17A gene. However, the prevalence of infection differs from severity of COVID-19, based on many factors such as public awareness, behaviors and antiviral policy of countries. Yet, the severity of disease induced by viral infection might be associated with genetic host factors including immune pro ling.
... Added to that, the CRP level has also been reported as a reliable biomarker for treatment responses in COVID-19 patients 19 ; in fact, this marker could be used to select patients who would benefit from treatment with tocilizumab, another IL-6 receptor inhibitor similar to sarilumab. 54,55 Our findings indicated that NLR and CRP are good predictors of unfavorable outcome. The reported excellent accuracy of these parameters in the prediction of COVID-19 patients' outcome corroborates findings of the studies of Yang and al. 31 and. ...
Background
COVID-19 disease has spread rapidly worldwide, causing high mortality. Accessible biomarkers capable of early identification of patients at risk of severe form are needed in clinical practice. The aim of the study was to determine the biological markers that predict a critical condition.
Methods
Retrospective study including patients with confirmed COVID-19 hospitalized between September 2020 and June 2021. The primary endpoint was progression to critical status within 7 days from admission. We defined two groups:
Critical group: Patients who developed a critical condition or died or transferred to the ICU before or at 7th day.
Non-critical group: Patients who remained in non-critical respiratory status until 7th day or discharged before or at 7th day.
Results
Our study included 456 patients, with a sex ratio of 1.32 and an average age of 62 years. At the 7th day of hospitalization, 115 (25.2%) patients were in the critical group and 341 (74.8%) patients were in the non-critical group. The univariate logistic regression indicated that laboratory findings between non-critical and critical groups showed that C-reactive protein (CRP) (p=0.047), D-Dimer (p=0.011), creatinine (0.026), creatine kinase (p=0.039), lactate dehydrogenase (p=0.04), and troponin (p=0.001) were all higher among patients in critical group. However, lymphocyte (p<0.001) and platelet (p<0.001) counts were significantly lower among the critical group. Multivariate logistic regression model, identified four independent risk factors: lymphopenia (OR=2.771, 95%CI=1.482-5.181, p=0.001), Neutrophil to Lymphocyte Ratio (NLR) (OR=2.286, 95%CI=1.461-3.578, p<0.001), thrombocytopenia (OR=1.944, 95%CI=1.092-3.459, p=0.024), and CRP>71.5 (OR=1.598, 95% CI=1.042-2.45, p=0.032) were associated to critical group.
Conclusions
Our results show the predictive value of lymphopenia, thrombocytopenia, high NLR and CRP levels to evaluate the prognosis of COVID-19 pneumonia. A prognostic score could be proposed for guiding clinical care and improving patient outcomes.
... IL-6 is a predominant component of cytokine storm syndrome (CSS) and leads to multiple organ failure-a . This is further supported by the fact that treatment with Tocilizumab (IL-6 receptor blocker) resulted in improvement of critical ill COVID-19 patients (23). Based on the aforementioned fact, it is evident that cytokine storm syndrome is one of the many ways used by SARS-CoV-2 to damage the brain indirectly. ...
Background: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with many neurological symptoms but there is a little evidence-based published material on the neurological manifestations of COVID-19. The purpose of this article is to review the spectrum of the various neurological manifestations and underlying associated pathophysiology in COVID-19 patients. Method: We conducted a review of the various case reports and retrospective clinical studies published on the neurological manifestations, associated literature, and related pathophysiology of COVID-19 using PUBMED and subsequent proceedings. A total of 118 articles were thoroughly reviewed in order to highlight the plausible spectrum of neurological manifestations of COVID 19. Every article was either based on descriptive analysis, clinical scenarios, correspondence, and editorials emphasizing the neurological manifestations either directly or indirectly. We then tried to highlight the significant plausible manifestations and complications that could be related to the pandemic. With little known about the dynamics and the presentation spectrum of the virus apart from the respiratory symptoms, this area needs further consideration. Conclusion: The neurological manifestations associated with COVID-19 such as Encephalitis, Meningitis, acute cerebrovascular disease, and Guillain Barré Syndrome (GBS) are of great concern. But in the presence of life-threatening abnormal vitals in severely ill COVID-19 patients, these are not usually underscored. There is a need to diagnose these manifestations at the earliest to limit long term sequelae. Much research is needed to explore the role of SARS-CoV-2 in causing these neurological manifestations by isolating it either from cerebrospinal fluid or brain tissues of the deceased on autopsy. We also recommend exploring the risk factors that lead to the development of these neurological manifestations.
... ARDS can occur in a variety of clinical situations including pneumonia, sepsis, pancreatitis, blood transfusion being associated with an elevated mortality. Cytokine storm occurs during infection of several viruses including influenza viruses and coronaviruses, 3,4 and is the main reason for acute lung injury and subsequent development of ARDS. In COVID-19 infection, ARDS represents the most serious consequence of the so-called "cytokine storm". ...
CXCL10 (rs201830102) is a chemokine involved in immune cell recruitment, while its receptor, CXCR3 (rs779120264), mediates immune responses through the activation of T cells. These genes are critical in the immune response to viral infections, including COVID-19. The study aimed to explore the relationship between polymorphisms in the CXCL10 gene and CXCR3 receptor with disease severity in COVID-19 patients. In this cross-sectional analytical study, 100 COVID-19 patients were enrolled after ethical approval, and written informed consent was obtained from each participant. Polymorphisms in CXCL10 and CXCR3 were analyzed by sequencing, while biochemical and hematological parameters were assessed using appropriate methods. Descriptive and inferential statistics were employed to analyze continuous and categorical data. Significant associations were observed between severe COVID-19 cases and elevated levels of serum D-dimer, ferritin, random blood sugar (RBS), neutrophils, and erythrocyte sedimentation rate (ESR), along with reduced hemoglobin levels. Lymphocyte and platelet counts were significantly lower with increased disease severity. The wild genotype of CXCL10 was notably associated with elevated ferritin levels, suggesting that certain gene variants may offer protective effects. However, no significant correlation was found between CXCR3 and CXCL10 polymorphisms and other serum biomarkers. Our study confirmed a significant rise in serum D-dimer, ferritin, RBS, neutrophils, and ESR, along with a reduction in hemoglobin, lymphocyte, and platelet counts in severe COVID-19 cases compared to mild ones. Notably, mutations in the CXCL10 gene were linked to less severe COVID-19 outcomes.
... In severe cases, significant alterations in IL-1β, IL-6, and TNF-α levels, along with a decline in CD8 + T lymphocytes, correlate strongly with disease severity [27,32]. These biomarkers are likely involved in the inflammatory response and immune regulation during severe COVID-19 infections [33,34]. Therefore, we conducted analyses on these aforementioned markers and included them as references (Supplementary Fig. 2). ...
Background
Immunocompromised patients face higher risks of Severe Acute Respiratory Syndrome Coronavirus 2 infection and co-infections, leading to a possibility of high disease severity and poor outcomes. Conversely, immunosuppression can mitigate the excessive inflammatory response induced by the virus, potentially reducing disease severity. This study aims to investigate the prognostic differences and early inflammatory response characteristics in various types of immunocompromised patients with severe coronavirus disease 2019 (COVID-19) admitted to intensive care unit (ICU), summarize their clinical features, and explore potential mechanisms.
Methods
A retrospective analysis was conducted on critically ill COVID-19 patients admitted to the ICU of 59 medical centers in mainland China during the Omicron outbreak from November 2022 to February 2023. Patients were categorized into two groups based on their immunosuppression status: immunocompromised and immunocompetent. Immunocompromised patients were further subdivided by etiology into cancer patients, solid organ transplant (SOT) patients, and other immunocompromised groups, with immunocompetent patients serving as controls. The mortality rates, respiratory support, complications, and early inflammatory cytokine dynamics upon ICU admission among different populations were analyzed.
Results
A total of 2030 critically ill COVID-19 patients admitted to ICU were included, with 242 in the immunocompromised group and 1788 in the immunocompetent group. Cancer patients had a higher median age of 69 years (IQR 59, 77), while SOT patients were generally younger and had less severe illness upon ICU admission, with a median APACHE II score of 12.0 (IQR 8.0, 20.0). Cancer patients had a twofold increased risk of death (OR = 2.02, 95% CI 1.18–3.46, P = 0.010) compared to immunocompetent patients. SOT and cancer patients exhibited higher C-reactive protein and serum ferritin levels than the immunocompetent group in their early days of ICU admission. The CD8⁺ T cells dynamics were inversely correlated in cancer and SOT patients, with Interleukin-6 levels consistently lower in the SOT group compared to both immunocompetent and cancer patients.
Conclusion
Critically ill COVID-19 patients admitted to the ICU exhibit distinct clinical outcomes based on their immunosuppression status, with cancer patients facing the highest mortality rate due to variations in inflammatory responses linked to their immunosuppression mechanisms. Monitoring dynamic changes in inflammatory markers and immune cells, particularly CD8⁺ T lymphocytes and IL-6, may offer valuable prognostic insights for these patients.
... IL-6 with TGF-β promotes the differentiation of naïve CD4+T cells to Th17, and inhibits TGFβ1, that induced Treg differentiation [38]. In this way the elevated circulating IL-6 levels contribute to dysregulation of the Treg/Th17 cell ratio [39]. Tfh is an important subset of CD4+T cell which stimulates B cell proliferation via the activation of co-stimulatory signal CD40. ...
COVID-19. demands a world-wide emergency in this century is caused by. the virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Scientists throughout the world are looking for a remedy to cure human beings from this, pandemic. To understand how our immune system responds to this dreadful virus, we need to investigate very precisely the immunopathology of COVID-19. Dendritic cell (DC) is a component of our innate immune system and makes a bridge between our innate and adaptive immunity and it also presents antigen to T cell. DCs and T cells both play a crucial role in several viral diseases. In this review, we summarize the dynamic changes of different subsets of dendritic cell like conventional dendritic cells (cDCs), plasmacytoid dendritic cell (pDCs), monocyte-derived dendritic cell (moDCs), and different types of T cells like CD8+T cytotoxic cell and CD4+T helper cell subsets (T helper1, Th2, Th17, Treg, Tfh) in mild and severe COVID-19 patients as compared to healthy donors. This review may help to better understand the maturational and functional status of DCs and T cells response in COVID-19 patients and provide immunotherapeutic strategies for patients.
... Frontiers in Public Health 08 frontiersin.org of inflammatory cytokines when compared to individuals with mild to moderate COVID-19, suggesting the involvement of a "cytokine storm" as a potential causal factor (38). Cytokine release syndrome has also been implicated in the pathology of COVID-19 (39). ...
Objective
The purpose of this study was to identify independent risk factors affecting patient survival and explore predictors of severe cases of coronavirus disease 2019 (COVID-19).
Methods
We conducted a retrospective, observational, case–control study on adult patients with severe COVID-19 who were admitted to affiliated hospitals in Tianjin between December 18, 2022, and January 31, 2023. We used univariate and multifactorial logistic regression analyses to analyze demographic indicators, comorbidity profiles, and laboratory parameters in two groups of patients (deceased and surviving) to identify independent risk factors for death in patients with severe COVID-19.
Results
Patients in the deceased group were older than those in the survival group (p = 0.018), and there were more cases of coexisting respiratory insufficiency in the deceased group (p = 0.002). Additionally, laboratory test results for white blood cell count (WBC) and creatine kinase (CK) showed significantly higher values in the deceased group (p = 0.047 and p = 0.029, respectively), while arterial oxygen partial pressure (PAO2) showed significantly lower values compared to the survival group (p = 0.021). Age, respiratory insufficiency, WBCH (highest WBC value), CKH (highest CK value), and PAO2F (first PAO2 value) had area under curve (AUC) values of 0.698, 0.838, 0.721, 0.744, and 0.633, respectively.
Conclusion
The main risk factors for mortality in patients with severe COVID-19 that we identified in this study were the advanced age of patients, coexisting respiratory insufficiency, elevated levels of WBC and CK, and decreased levels of PAO2. Elevated WBC and CK laboratory parameters, in particular, demonstrated good predictive value for in-hospital mortality risk.
... In severe SARS-CoV-2 infection, there is dysregulation of the immune system in the form of a hyperactive innate response, inhibition of expression signals for the formation of interferon-1 (IFN-1), which has antiviral activity, as well as the initiation of death and exhaustion in T lymphocyte cells, causing lymphopenia. This chaotic immune response causes uncontrolled production of proinflammatory 4,5 cytokines called a cytokine storm. SARS-CoV-2 infection also triggers infiltration and activation of immune cells such as neutrophils and monocytes. ...
Severe and critical COVID-19 patients are known to experience hyperinflammatory conditions and endothelial damage primarily characterized by increased levels of IL-6 and D-dimer. This group of patients is also considered at risk of experiencing hemostasis disorders including decreased platelet counts, prolonged PT and APTT, as well as increased fibrinogen. Therefore, this study aimed to determine the correlation between IL-6 and D-dimer in severe and critical COVID-19 patients. The relationship between IL-6 and other hemostasis parameters such as platelet count, PT, APTT, and fibrinogen were also analyzed. A descriptive-correlative observational design was used with a retrospective cross-sectional approach. The subjects were severe and critical COVID-19 patients at Hasan Sadikin Hospital, Bandung treated between January to December 2021 and met the inclusion and exclusion criteria. Secondary data were taken from medical records and the Laboratory Information System (LIS). Correlation analysis between IL-6 and D-dimer as well as hemostasis parameters was carried out using the Spearman test. The results showed that among the total 167 subjects, the median age was 60 years. The number of male subjects was 110 (65.86%), while the most common comorbidity was hypertension (45.51%). The analysis showed a very weak and insignificant correlation between IL-6 and platelets (r= -0.044; p=0.571), IL-6 and PT (r=0.115; p=0.137), IL-6 and APTT (r=0.109; p=0.159), as well as IL-6 and fibrinogen (r= -0.087; p=0.264). However, the correlation between IL-6 and D-dimer was significant (r= 0.199; p=0.010). Interleukin-6 did not correlate with hemostasis parameters but correlated with D-dimer. This means that IL-6 and D-dimer may provide information about the inflammatory response in COVID-19 patients and help monitor disease progression.
A 72-year-old male on maintenance hemodialysis presented with rare and severe hyporesponsiveness to erythropoiesis-stimulating agents (ESAs). Despite a weekly administration of 24,000 IU of recombinant human erythropoietin (rhuEPO), in line with the patient’s weight of 62 kg, he continued to require frequent blood transfusions, and his hemoglobin (Hb) levels plummeted precipitously over a brief period. The etiology of his refractory anemia was elusive. The patient presented with a high reticulocyte count, and no signs of iron deficiency, impaired iron utilization, overt infection, secondary hyperparathyroidism, hemolytic anemia, or significant gastrointestinal bleeding were observed. Interestingly, upon initiation of treatment with roxadustat, a marked reduction in transfusion frequency and iron supplementation dosage was observed, concurrent with a substantial elevation in hemoglobin levels. The efficacy of roxadustat in this patient suggested that it would be an alternative therapy for those with ESA hyporesponsiveness in renal anemia. Clearly, as the mechanistically new type of drug for renal anemia, it is worthwhile to further understand its unique role in the treatment of renal anemia.
One patient on peritoneal dialysis with renal anemia underwent laparoscopic surgery due to the omentum wrapping the peritoneal dialysis catheter. Postoperative abdominal bleeding aggravated the anemia. Roxadustat rapidly increased the hemoglobin level and avoided re-transfusion, thus ensuring the safety of perioperative period.
Anemia is a common complication in patients with chronic kidney disease, closely related to hospitalization rate, transfusion rate, mortality rate, and other complications. Here, we report anemia related issues in an elderly male patient undergoing maintenance hemodialysis. At first, he was receiving high doses of ESA combined with Roxadustat, which kept his hemoglobin stable. Unfortunately, he got COVID-19, and after adjusting the anemia management plan, he still needed repeated blood transfusion to improve anemia symptoms. After excluding other anemia related factors, we considered that the aggravation of anemia was related to COVID-19. Then, adjust the dosage of ESA to 6000 U three times a week and use it in combination with Roxadustat at a dose of 200 mg three times a week. After 2 months, the hemoglobin level remained at 8.0-12.2 g/dL. Taken together, we reported a case of stable anemia that was aggravated after COVID-19 infection and required repeated blood transfusion, and could be corrected after reasonable program adjustment. There are many factors that affect anemia. This case shows that COVID-19 is may one of the important factors that aggravate anemia.
We present a case study of a 44-year-old female patient who has been suffering from longstanding diabetes mellitus, hypertension, and chronic kidney disease (CKD). She was hospitalized due to persistent fatigue and proteinuria over a four-year period. Initially, the patient received treatment for renal anemia with subcutaneous injections of recombinant human erythropoietin (rHuEPO) and oral supplementation of a polysaccharide iron complex. However, as the disease progressed, the need for maintenance hemodialysis became apparent. Microinflammatory states are common in patients treated with dialysis. Despite the presence of a microinflammatory state, the patient showed a suboptimal response to rHuEPO therapy. Roxadustat was introduced in the treatment regimen. This agent is capable of globally regulating erythropoiesis, irrespective of the presence of microinflammation. Its mechanisms of action include modulation of inflammatory cytokines, enhancement of iron utilization efficiency, alteration of the gut microbiome, and attenuation of erythropoietin resistance. Following the initiation of roxadustat, the patient demonstrated a significant increase in hemoglobin levels, which were subsequently maintained within a stable range.
Multiple confounding factors increase the difficulty of treating anemia in patients with systemic lupus erythematosus (SLE). Here, we described a 39-year-old female patient with SLE and lupus nephritis (LN) suffering from complications of anemia, acute kidney injury, and infection. During the treatment period, she received 120 mg roxadustat orally three times per week. Her hemoglobin (HGB) level steadily increased from 56 to 151 g/L. After the dosage of roxadustat was reduced to 50 mg three times per week, the HGB level gradually decreased and remained at 132 g/L. In this complicated case, roxadustat exhibited efficacy in treating anemia in a patient with autoimmune disease and infectious complications.
We present a case report of a 58-year-old male on peritoneal dialysis with a history of diabetic nephropathy. The patient was admitted to the hospital due to with extremely high hemoglobin concentration, with a hemoglobin level of 212 g/L. To explore the cause of anemia, bone marrow puncture was performed. The patient’s bone marrow showed that granuloid and erythroid were not significantly abnormal. Roxadustat, a hypoxia-inducing factor prolyl hydroxylase inhibitor, can improve renal anemia by promoting EPO expression and improving iron metabolism. In this case, roxadustat demonstrated efficacy in improving both the anemia condition and iron metabolism of the patient. However, it also serves as a reminder of the critical importance of routinely monitoring hemoglobin levels and making appropriate dosage adjustments during the course of roxadustat treatment. It is essential to avert potential adverse reactions that may arise from an abnormal increase in hemoglobin concentration.
A case of a middle-aged male patient on maintenance hemodialysis with a previously stable dialysis condition and clinically improved complications following treatment. This time, after exertion, the patient developed a rapidly progressing pneumonia, leading to respiratory failure and hypotension within two days. After three weeks of intensive anti-infective therapy, his clinical symptoms were alleviated, and his body temperature returned to normal. During this period, hemoglobin levels progressively decreased from 113 g/L to 65 g/L within one month. Despite routine treatment with EPO to correct anemia under the premise of active infection control, hemoglobin continued to decline. Following a switch to roxadustat (a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI)) treatment, hemoglobin increased by 16 g/L after four weeks and by 34 g/L after eight weeks, with anemia essentially corrected.
Erythropoiesis-stimulating agents (ESAs) have been the mainstay of renal anemia treatment. However, an unmet clinical need remains owing to the ESAs hyporesponsiveness. Bone marrow hypoplasia is one of the important mechanisms contributing to ESAs hyporesponsiveness. Herein we report a middle-aged female patient undergoing maintenance hemodialysis with ESAs hyporesponsiveness and bone marrow hypoplasia. Before hospitalization, a high dose of ESA supplement (r-HuEPO 16000 U/week) was given, but the patient seemed unresponsive (haemoglobin level 5.9 g/dL). Then, the patient’s medication was switched from r-HuEPO to roxadustat at a dosage of 120 mg three times per week. Unfortunately, she still showed a poor response to the conventional recommended dose of roxadustat. Given the patient’s past medical history and clinical use of roxadustat, we prescribed a dose of roxadustat of 150 mg three times per week, and the haemoglobin level increased gradually to 9.8 g/dL after 1 month. Taken together, we report the case of an anemic patient with bone marrow hypoplasia who exhibited a poor response to high-dose ESAs. Although the dosage of roxadustat used was higher than the conventional recommended dosage, it was shown that roxadustat could correct renal anemia effectively and safely. Therefore, this case provides unique experience for the use of this new class of drug to treat patients with ESA hyporesponsiveness.
A 66-year-old female with type 2 diabetes, hypertension, and stage III diabetic nephropathy experienced worsening renal function and developed moderate anemia. Despite standard treatments, her condition did not improve. Roxadustat, a novel HIF-PHI, was initiated at a dosage of 100 mg three times weekly, along with oral iron supplementation, leading to a significant increase in hemoglobin levels from 69 to 105 g/L within a month and a reduction in serum creatinine levels from 626 to 461 μmol/L. This case demonstrates the effectiveness of roxadustat in correcting anemia and potentially delaying the progression of kidney disease in a patient with chronic kidney disease who was not on dialysis, highlighting its role in improving iron absorption and utilization.
Pulmonary homeostasis can be agitated either by external environmental insults or endogenous factors produced during respiratory/pulmonary diseases. The lungs counter these insults by initiating mechanisms of inflammation as a localized, non-specific first-line defense response. Cytokines are small signaling glycoprotein molecules that control the immune response. They are formed by numerous categories of cell types and induce the movement, growth, differentiation, and death of cells. During respiratory diseases, multiple proinflammatory cytokines play a crucial role in orchestrating chronic inflammation and structural changes in the respiratory tract by recruiting inflammatory cells and maintaining the release of growth factors to maintain inflammation. The issue aggravates when the inflammatory response is exaggerated and/or cytokine production becomes dysregulated. In such instances, unresolving and chronic inflammatory reactions and cytokine production accelerate airway remodeling and maladaptive outcomes. Pro-inflammatory cytokines generate these deleterious consequences through interactions with receptors, which in turn initiate a signal in the cell, triggering a response. The cytokine profile and inflammatory cascade seen in different pulmonary diseases vary and have become fundamental targets for advancement in new therapeutic strategies for lung diseases. There are considerable therapeutic approaches that target cytokine-mediated inflammation in pulmonary diseases; however, blocking specific cytokines may not contribute to clinical benefit. Alternatively, broad-spectrum anti-inflammatory approaches are more likely to be clinically effective. Herein, this comprehensive review of the literature identifies various cytokines (e.g., interleukins, chemokines, and growth factors) involved in pulmonary inflammation and the pathogenesis of respiratory diseases (e.g., asthma, chronic obstructive pulmonary, lung cancer, pneumonia, and pulmonary fibrosis) and investigates targeted therapeutic treatment approaches.
In the initial stage of the COVID‐19 pandemic, high case fatality was noted. The case fatality during this was associated with the cytokine storm (CS) or cytokine storm syndrome (CSS). Sometimes, virus infections are due to the excessive secretion of pro‐inflammatory cytokines, leading to cytokine storms, which might be directed to ARDS, multi‐organ failure, and death. However, it was noted that several miRNAs are involved in regulating cytokines during SARS‐CoV‐2 and other viruses such as IFNs, ILs, GM‐CSF, TNF, etc. The article spotlighted several miRNAs involved in regulating cytokines associated with the cytokine storm caused by SARS‐CoV‐2 and other viruses (influenza virus, MERS‐CoV, SARS‐CoV, dengue virus). Targeting those miRNAs might help in the discovery of novel therapeutics, considering CS or CSS associated with different virus infections.
Objectives. To determine the overall mortality and risk factors of COVID-19 patients who were admitted to the Home Isolation (HI) program in Bangkok, Thailand, during the epidemic crisis in 2021.
Methods. We conducted a retrospective cohort study using the data from a government telehealth application from July to December 2021. The vital status was verified from the government database on September 20, 2022. We used survival analysis to analyze the 28-day mortality and independently associated factors.
Results. Of 90 854 reported cases, the average age was 37.27 years, and half were men. Initial symptoms included being asymptomatic (51.66%), having mild symptoms (35.60%), or experiencing severe symptoms requiring nonurgent (11.27%) or urgent referral (1.47%). The 28-day mortality rate was 0.80%. Factors associated with 28-day mortality included older age, male gender, higher body mass index, severity of initial symptoms, and time to admission.
Conclusions. The Home Isolation program was able to manage a high volume of patients, including severe cases, exceeding its initial design. Thailand’s COVID-19 mortality rate remained relatively low compared with other countries. Proactive bed surge planning and continuous plan improvement were crucial for future preparedness. ( Am J Public Health. Published online ahead of print January 30, 2025:e1–e12. https://doi.org/10.2105/AJPH.2024.307922 )
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a respiratory disease that can range in presentation from mild symptoms to severe conditions such as pneumonia and acute respiratory distress syndrome. SARS-CoV-2, a single-stranded RNA virus, spreads through aerosols and respiratory droplets. It enters human cells by binding to the angiotensin-converting enzyme 2 receptor, leading to various complications, including significant alterations in red blood cells and potential disruptions in haemoglobin function and oxygen transport. During infection, the interaction between hypoxia, inflammation, and haematopoiesis affects erythropoiesis at multiple levels. Hypoxia and inflammation, resulting from lung complications and a reduced red blood cell count, influence the regulation of hepcidin, a key regulator of iron levels in the blood. Elevated hepcidin levels are associated with hypoxia and the suppression of erythroferrone, a hormone that normally inhibits hepcidin production. Despite high levels of inflammation, patients in intensive care units often exhibit elevated ferritin levels, which, rather than indicating low hepcidin, suggest disrupted iron metabolism and the development of severe anaemia. Iron is kept in stores, likely due to paradoxically high hepcidin levels, which explains the elevated ferritin measurements. An increase in immature blood cells and a decrease in CD71+ erythroid cells are observed. The elevated levels of CD71+ erythroid cells highlight their dual role in modulating hyper-inflammation and immune response during disease progression. This review examines the pathway by which SARS-CoV-2 affects red blood cell production and the haematopoietic system and how it triggers cytokine storms through interleukins, immature blood cells, and CD71+ erythroid cells. Understanding these processes provides novel pathways for managing haematological manifestations and immune responses in patients with COVID-19.
Background: We aimed to evaluate calcium (Ca) metabolism disorders in patients with COVID-19, a novel virus with numerous unknown aspects and potential complications. This study was conducted due to the scarcity of evidence on this subject and the crucial importance of conducting a comprehensive assessment. Objectives: We hypothesized that this research would shed light on this previously unexplored phenomenon. Methods: This study was a descriptive cross-sectional study conducted on COVID-19 patients admitted to Afzalipur Kerman Medical Center, Iran, in 2021. Data collection involved demographic characteristics and laboratory results. A 5 cc blood sample was collected in a clot test tube to perform total Ca tests using the photometric method (Arsenazo III kit), ionized Ca tests via the ISE method, magnesium measurements with the photometric method using the Xylidyl blue kit, iPTH (intact parathyroid hormone) assessments, and 25-OH-VITD3 measurements using the ELISA technique with the Monobind kit. Results: The present study included 162 participants, comprising 59% males and 41% females, with an average age of 49 years. Among the patients, the most prevalent Ca metabolism disorders were low vitamin D levels, including both deficiency and insufficiency (59%), as well as elevated ionized Ca levels (43%). Conversely, the least common Ca metabolism disorders in these patients were hyperparathyroidism (7%) and excessive Ca adjustment (8%). Conclusions: The findings suggest the possibility of Ca metabolism disorders, particularly hypocalcemia, in COVID-19 patients. Given the nature of this study, we recommend conducting longitudinal and more comprehensive research in this field to investigate contributing factors in more detail and establish a cause-and-effect relationship.
BACKGROUND: Lymphopenia in patients with coronavirus infection COVID-19 is associated with the risk of developing severe forms and unfavorable outcome. One of the reasons for the development of lymphopenia is apoptosis. AIM: Evaluation of the severity of peripheral blood lymphocytes' apoptosis in patients with moderate and severe COVID-19. MATERIAL AND METHODS: A total of 42 patients with COVID-19 aged 37 to 90 years were examined. They were hospitalized at the Republican Clinical Infectious Diseases Hospital named after Professor A.F. Agafonov, Kazan, from October 24, 2021 to March 1, 2022. In 13 patients, the lung lesion volume ranged from 10 to 25% (CT-1), in 20 — from 25 to 50% (CT-2), in 9 — from 50 to 75% (CT-3). Ribonucleic acid of the SARS-CoV-2 virus was isolated from the nasopharynx in 35 (83%) patients. COVID-19 was moderate in 14 patients, and severe in 28 patients. The control group consisted of 10 conditionally healthy people of the same age. Lymphocyte apoptosis was assessed by quantifying hypodiploid cells by changing the intensity of their staining with propidium iodide using flow cytometry. To determine the reliability of differences in indicators between the compared groups, the Mann–Whitney U-test was used, and when comparing percentages, the χ2 criterion was used. The reliability of differences was established at p 0.05. RESULTS: It was found that patients with COVID-19 had significantly higher lymphocyte apoptosis activity compared to the control group. The median of the studied indicator in patients with COVID-19 was 39.3%, while in the control group it was 15.1% (p 0.001). The severity of lymphocyte apoptosis correlated with the severity of the disease: the highest rates were recorded in patients with severe COVID-19 (p=0.02). Moreover, lymphocyte apoptosis 55% was associated with the risk of death (p=0.03). A moderate correlation was established between lymphocyte apoptosis rates and blood ferritin levels (Spearman coefficient p=0.39, p 0.05). CONCLUSION: Coronavirus infection COVID-19 was accompanied by an increase in the activity of peripheral blood lymphocyte apoptosis; the highest apoptosis rates were recorded in patients with severe COVID-19.
Significance
In patients with coronavirus disease 2019, a large number of T lymphocytes and mononuclear macrophages are activated, producing cytokines such as interleukin-6 (IL-6), which bind to the IL-6 receptor on the target cells, causing the cytokine storm and severe inflammatory responses in lungs and other tissues and organs. Tocilizumab, as a recombinant humanized anti-human IL-6 receptor monoclonal antibody, can bind to the IL-6 receptor with high affinity, thus preventing IL-6 itself from binding to its receptor, rendering it incapable of immune damage to target cells, and alleviating the inflammatory responses.
Background:
A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients.
Methods:
All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not.
Findings:
By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0-58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0-13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα.
Interpretation:
The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies.
Funding:
Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
Objective
To assess the risk of major adverse cardiovascular events (MACE) in patients with rheumatoid arthritis (RA) treated with tocilizumab compared to those treated with the tumor necrosis factor inhibitor etanercept.
Methods
This randomized, open‐label, parallel‐group trial enrolled patients with active seropositive RA (n = 3,080) who had an inadequate response to conventional synthetic disease‐modifying antirheumatic drugs and who had at least 1 cardiovascular (CV) risk factor. Patients were randomly assigned 1:1 to receive open‐label tocilizumab at 8 mg/kg/month or etanercept at 50 mg/week. All patients were followed up for a mean of 3.2 years. The primary end point was comparison of time to first occurrence of MACE. The trial was powered to exclude a relative hazard ratio for MACE of 1.8 or higher in the tocilizumab group compared to the etanercept group.
Results
By week 4 of treatment, the serum low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, and triglyceride levels were a median 11.1%, 5.7%, and 13.6% higher, respectively, in patients receiving tocilizumab compared to those receiving etanercept (each P < 0.001). During follow‐up, 83 MACE occurred in the tocilizumab group compared to 78 MACE in the etanercept group. The estimated hazard ratio for occurrence of MACE in the tocilizumab group relative to the etanercept group was 1.05 (95% confidence interval 0.77–1.43). Results were similar in sensitivity analyses and in the on‐treatment population analysis. Adverse events occurred more frequently in the tocilizumab group, including serious infection and gastrointestinal perforation.
Conclusion
The results of this trial, which provide insights into the CV safety of tocilizumab as compared to etanercept, ruled out a risk for occurrence of MACE of 1.43 or higher in patients treated with tocilizumab. This result should be interpreted in the context of the clinical efficacy and non‐CV safety of tocilizumab.
The mammalian lung´s structural design is optimized to serve its main function: gas exchange. It takes place in the alveolar region (parenchyma) where air and blood are brought in close proximity over a large surface. Air reaches the alveolar lumen via a conducting airway tree. Blood flows in a capillary network embedded in inter-alveolar septa. The barrier between air and blood consists of a continuous alveolar epithelium (a mosaic of type I and type II alveolar epithelial cells), a continuous capillary endothelium and the connective tissue layer in-between. By virtue of its respiratory movements, the lung has to withstand mechanical challenges throughout life. Alveoli must be protected from over-distension as well as from collapse by inherent stabilizing factors. The mechanical stability of the parenchyma is ensured by two components: a connective tissue fiber network and the surfactant system. The connective tissue fibers form a continuous tensegrity (tension + integrity) backbone consisting of axial, peripheral and septal fibers. Surfactant (surface active agent) is the secretory product of type II alveolar epithelial cells and covers the alveolar epithelium as a biophysically active thin and continuous film. Here, we briefly review the structural components relevant for gas exchange. Then we describe our current understanding of how these components function under normal conditions and how lung injury results in dysfunction of alveolar micromechanics finally leading to lung fibrosis.
The IL-6 family of cytokines consists of IL-6, IL-11, IL-27, IL-31, oncostatin M (OSM), leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin 1 (CT-1) and cardiotrophin-like cytokine factor 1 (CLCF1). Membership of this cytokine family is defined by usage of common β-receptor signalling subunits, which activate various intracellular signalling pathways. Each IL-6 family member elicits responses essential to the physiological control of immune homeostasis, haematopoiesis, inflammation, development and metabolism. Accordingly, distortion of these cytokine activities often promotes chronic disease and cancer; the pathological importance of this is exemplified by the successful treatment of certain autoimmune conditions with drugs that target the IL-6 pathway. Here, we discuss the emerging roles for IL-6 family members in infection, chronic inflammation, autoimmunity and cancer and review therapeutic strategies designed to manipulate these cytokines in disease.
Background: IL-6 classic signaling is linked to anti-inflammatory functions while the trans-signaling is associated with pro-inflammatory responses. Classic signaling is induced via membrane-bound IL-6 receptor (IL-6R) whereas trans-signaling requires prior binding of IL-6 to the soluble IL-6R. In both cases, association with the signal transducing gp130 receptor is compulsory. However, differences in the downstream signaling mechanisms of IL-6 classic- versus trans-signaling remains largely elusive.
Methods: In this study, we used flow cytometry, quantitative PCR, ELISA and immuno-blotting techniques to investigate IL-6 classic and trans-signaling mechanisms in Human Umbilical Vein Endothelial Cells (HUVECs).
Results: We show that both IL-6R and gp130 are expressed on the surface of human vascular endothelial cells, and that the expression is affected by pro-inflammatory stimuli. In contrast to IL-6 classic signaling, IL-6 trans-signaling induces the release of the pro-inflammatory chemokine Monocyte Chemoattractant Protein-1 (MCP-1) from human vascular endothelial cells. In addition, we reveal that the classic signaling induces activation of the JAK/STAT3 pathway while trans-signaling also activates the PI3K/AKT and the MEK/ERK pathways. Furthermore, we demonstrate that MCP-1 induction by IL-6 trans-signaling requires simultaneous activation of the JAK/STAT3 and PI3K/AKT pathways.
Conclusions: Collectively, our study reports molecular differences in IL-6 classic- and trans-signaling in human vascular endothelial cells; and elucidates the pathways which mediate MCP-1 induction by IL-6 trans-signaling.
Keywords: Interleukin-6 signaling, Monocyte chemoattractant Protein-1, Pro-inflammatory cytokines, Endothelium, HUVECs
Objective
Multiple studies have shown seemingly unfavorable changes in lipid profiles associated with interleukin‐6 receptor (IL‐6R) antagonists and some other therapies for rheumatoid arthritis. The aim of this study was to assess the real‐world cardiovascular disease (CVD) risk associated with tocilizumab, the first anti–IL‐6R medication approved for the treatment of RA.
Methods
We conducted a cohort study using 2006–2015 Medicare and MarketScan claims for patients with RA in whom treatment with biologic disease‐modifying antirheumatic drugs was initiated after January 1, 2010. The primary outcome was a composite of myocardial infarction, stroke, and fatal CVD, assessed using a validated method. The influence of potential confounding due to RA disease activity was assessed in a subgroup analysis (~5–10% of biologic therapy initiations) using the multi‐biomarker disease activity (MBDA) score.
Results
A total of 88,463 patients with RA were included. The crude incidence rate (IR) per 1,000 patient‐years for composite CVD events among Medicare patients ranged from 11.8 (95% confidence interval [95% CI] 9.7–14.4) for etanercept users to 17.3 (95% CI 15.2–19.7) for infliximab users. The crude IR for pooled users of a tumor necrosis factor inhibitor was 15.0 (95% CI 13.9–16.3). Compared to tocilizumab, the corresponding adjusted hazard ratios (HRs) were 1.01 (95% CI 0.79–1.28) for abatacept, 1.16 (95% CI 0.89–1.53) for rituximab, 1.10 (95% CI 0.80–1.51) for etanercept, 1.33 (95% CI 0.99–1.80) for adalimumab, and 1.61 (95% CI 1.22–2.12) for infliximab. There were no statistically significant differences in the risk of CVD between tocilizumab and any other biologic when MarketScan data were used. Results were robust in numerous subgroup analyses and after external adjustment to control for RA disease activity in the subgroup of patients with linked MBDA test results (n = 4,156).
Conclusion
Tocilizumab was associated with a CVD risk comparable to that for etanercept as well as a number of other biologics used for the treatment of RA.
During the last decade the field of cancer immunotherapy has witnessed impressive progress. Highly effective immunotherapies such as immune checkpoint inhibition, and T-cell engaging therapies like bispecific T-cell engaging (BiTE) single-chain antibody constructs and chimeric antigen receptor (CAR) T cells have shown remarkable efficacy in clinical trials and some of these agents have already received regulatory approval. However, along with growing experience in the clinical application of these potent immunotherapeutic agents comes the increasing awareness of their inherent and potentially fatal adverse effects, most notably the cytokine release syndrome (CRS). This review provides a comprehensive overview of the mechanisms underlying CRS pathophysiology, risk factors, clinical presentation, differential diagnoses, and prognostic factors. In addition, based on the current evidence we give practical guidance to the management of the cytokine release syndrome.
In the clinic, chimeric antigen receptor-modified T (CAR T) cell therapy is frequently associated with life-threatening cytokine-release syndrome (CRS) and neurotoxicity. Understanding the nature of these pathologies and developing treatments for them are hampered by the lack of appropriate animal models. Herein, we describe a mouse model recapitulating key features of CRS and neurotoxicity. In humanized mice with high leukemia burden, CAR T cell-mediated clearance of cancer triggered high fever and elevated IL-6 levels, which are hallmarks of CRS. Human monocytes were the major source of IL-1 and IL-6 during CRS. Accordingly, the syndrome was prevented by monocyte depletion or by blocking IL-6 receptor with tocilizumab. Nonetheless, tocilizumab failed to protect mice from delayed lethal neurotoxicity, characterized by meningeal inflammation. Instead, the IL-1 receptor antagonist anakinra abolished both CRS and neurotoxicity, resulting in substantially extended leukemia-free survival. These findings offer a therapeutic strategy to tackle neurotoxicity and open new avenues to safer CAR T cell therapies.
Interleukin (IL-)6 is the major pro-inflammatory cytokine within the IL-6 family. IL-6 signals via glycoprotein 130 (gp130) and the membrane-bound or soluble IL-6 receptor (IL-6R), referred to as classic or trans-signaling, respectively. Whereas inflammation triggers IL-6 expression, eventually rising to nanogram per mL serum levels, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130) are constitutively present in the upper nanogram per mL range. Calculations based on intermolecular affinities have suggested that systemic IL-6 is immediately trapped in IL-6:sIL-6R and IL-6:sIL-6R:sgp130 complexes, indicating that sIL-6R and sgp130 constitute a buffer system that increases the serum half-life of IL-6 or restricts systemic IL-6 signaling. However, this scenario has not been experimentally validated. Here, we quantified IL-6:sIL-6R and IL-6:sIL-6R:sgp130 complexes over a wide concentration range. The amounts of IL-6 used in this study reflect concentrations found during active inflammatory events. Our results indicated that most IL-6 is free and not complexed with sIL-6R or sgp130, indicating that the level of endogenous sgp130 in the bloodstream is not sufficient to block IL-6 trans-signaling via sIL-6R. Importantly, addition of the single-domain antibody VHH6, which specifically stabilizes IL-6:sIL-6R complexes but did not bind to IL-6 or sIL-6R alone, drove free IL-6 into IL-6:sIL-6R complexes and boosted trans-signaling but not classic signaling, demonstrating that endogenous sIL-6R has a least the potential to form complexes with IL-6 . Our findings indicate that even though high concentrations of sIL-6R and sgp130 are present in human serum, the relative ratio of free IL-6 to IL-6:sIL-6R allows for simultaneous classic and trans-signaling.
Lung epithelial cells are increasingly recognized to be active effectors of microbial defense, contributing to both innate and adaptive immune function in the lower respiratory tract. As immune sentinels, lung epithelial cells detect diverse pathogens through an ample repertoire of membrane-bound, endosomal, and cytosolic pattern-recognition receptors (PRRs). The highly plastic epithelial barrier responds to detected threats via modulation of paracellular flux, intercellular communications, mucin production, and periciliary fluid composition. Epithelial PRR stimulation also induces production of cytokines that recruit and sculpt leukocyte-mediated responses, and promotes epithelial generation of antimicrobial effector molecules that are directly microbicidal. The epithelium can alternately enhance tolerance to pathogens, preventing tissue damage through PRR-induced inhibitory signals, opsonization of pathogen-associated molecular patterns, and attenuation of injurious leukocyte responses. The inducibility of these protective responses has prompted attempts to therapeutically harness epithelial defense mechanisms to protect against pneumonias. Recent reports describe successful strategies for manipulation of epithelial defenses to protect against a wide range of respiratory pathogens. The lung epithelium is capable of both significant antimicrobial responses that reduce pathogen burdens and tolerance mechanisms that attenuate immunopathology. This manuscript reviews inducible lung epithelial defense mechanisms that offer opportunities for therapeutic manipulation to protect vulnerable populations against pneumonia.
Infectious diseases are a leading cause of death worldwide. Sepsis is a severe clinical syndrome related to the host response to infection. The severity of infections is due to an activation cascade that will lead to an autoamplifying cytokine production: the cytokine storm. Cytokines are a broad category of relatively small proteins (<40 kDa) that are produced and released with the aim of cell signaling. Our understanding of the processes that trigger this tremendous amount of cytokine production has made dramatic progress over the last decades, but unfortunately, these findings could not translate yet into effective treatments; so far, all clinical trials targeting cytokine production or effects failed. This review aims to summarize the pathophysiology of the cytokine storm; to describe the type, effects, and kinetics of cytokine production; and to discuss the therapeutic challenges of targeting cytokines. New promising therapeutic strategies focusing on the endothelium, as a source and a target of cytokines, are described.
Interleukin-6 (IL-6) is a pleiotropic cytokine that not only regulates the immune and inflammatory response but also affects hematopoiesis, metabolism, and organ development. IL-6 can simultaneously elicit distinct or even contradictory physiopathological processes, which is likely discriminated by the cascades of signaling pathway, termed classic and trans-signaling. Besides playing several important physiological roles, dysregulated IL-6 has been demonstrated to underlie a number of autoimmune and inflammatory diseases, metabolic abnormalities, and malignancies. This review provides an overview of basic concept of IL-6 signaling pathway as well as the interplay between IL-6 and renal-resident cells, including podocytes, mesangial cells, endothelial cells, and tubular epithelial cells. Additionally, we summarize the roles of IL-6 in several renal diseases, such as IgA nephropathy, lupus nephritis, diabetic nephropathy, acute kidney injury, and chronic kidney disease.
Kinases of the Jak ('Janus kinase') family and transcription factors (TFs) of the STAT ('signal transducer and activator of transcription') family constitute a rapid membrane-to-nucleus signaling module that affects every aspect of the mammalian immune system. Research on this paradigmatic pathway has experienced breakneck growth in the quarter century since its discovery and has yielded a stream of basic and clinical insights that have profoundly influenced modern understanding of human health and disease, exemplified by the bench-to-bedside success of Jak inhibitors ('jakinibs') and pathway-targeting drugs. Here we review recent advances in Jak–STAT biology, focusing on immune cell function, disease etiology and therapeutic intervention, as well as broader principles of gene regulation and signal-dependent TFs.
Objective:
While tocilizumab (TCZ) is known to increase LDL cholesterol, it is unclear whether TCZ increases cardiovascular (CV) risks in patients with rheumatoid arthritis (RA).
Methods:
To examine comparative CV safety, we conducted a cohort study of RA patients who newly started TCZ or TNFi using claims data from Medicare, IMS PharMetrics and MarketScan. All patients were required to have previously used a different TNFi, abatacept, or tofacitinib. The primary outcome was a composite CV endpoint of hospitalization for myocardial infarction (MI) or stroke. TCZ initiators were propensity score (PS) matched to TNFi initiators with a variable ratio of 1:3 within each database controlling for >65 baseline characteristics. A fixed-effects model combined database-specific hazard ratios (HR).
Results:
We included 9,218 TCZ initiators PS-matched to 18,810 TNFi initiators across all three databases. Mean age was 72 years in Medicare, 51 in PharMetrics and 53 in MarketScan. 14.3% of TCZ initiators and 13.5% of TNFi had baseline CV disease. During the study period (mean±SD: 0.9±0.7 years, maximum: 4.5 years), 125 composite CV events occurred resulting in the incidence rate of 0.52 per 100 person-years in TCZ initiators and 0.59 per 100 person-years among TNFi initiators. The risk of CV events associated with TCZ use versus TNFi was similar across all three databases with a combined HR of 0.84 (95%CI 0.56-1.26).
Conclusion:
This multi-database population-based cohort study found no evidence of an increased CV risk among RA patients who switched from a different biologic drug or tofacitinib to TCZ versus to a TNFi. This article is protected by copyright. All rights reserved.
Interleukin 6 (IL-6) is a pleiotropic four-helix-bundle cytokine that exerts multiple functions in the body. In the liver, IL-6 is an important inducer of the acute phase response and infection defense. IL-6 is furthermore crucial for hepatocyte homeostasis and is a potent hepatocyte mitogen. It is not only implicated in liver regeneration, but also in metabolic function of the liver. However, persistent activation of the IL-6 signaling pathway is detrimental to the liver and might ultimately result in the development of liver tumors. On target cells IL-6 can bind to the signal transducing subunit gp130 either in complex with the membrane-bound or with the soluble IL-6 receptor to induce intracellular signaling. In this review we describe how these different pathways are involved in the physiology and pathophyiology of the liver. We furthermore discuss how IL-6 pathways can be selectively inhibited and therapeutically exploited for the treatment of liver pathologies.
Interleukin 6 (IL-6) has a broad effect on cells of the immune system and those not of the immune system and often displays hormone-like characteristics that affect homeostatic processes. IL-6 has context-dependent pro- and anti-inflammatory properties and is now regarded as a prominent target for clinical intervention. However, the signaling cassette that controls the activity of IL-6 is complicated, and distinct intervention strategies can inhibit this pathway. Clinical experience with antagonists of IL-6 has raised new questions about how and when to block this cytokine to improve disease outcome and patient wellbeing. Here we discuss the effect of IL-6 on innate and adaptive immunity and the possible advantages of various antagonists of IL-6 and consider how the immunobiology of IL-6 may inform clinical decisions.
Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members, the expression of which is elevated in many diseases including inflammatory bowel diseases and colorectal cancer. Here we show in mice and human cells that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.
The pulmonary epithelium serves as a barrier to prevent access of the inspired luminal contents to the subepithelium. In addition, the epithelium dictates the lung's initial responses to both infectious and non-infectious stimuli. One mechanism that the epithelium does this is by coordinating transport of diffusible molecules across the epithelial barrier, both through the cell and between cells. In this review we will discuss a few emerging paradigms of permeability changes through altered ion transport and paracellular regulation by which the epithelium gates its response to potentially detrimental luminal stimuli.
Copyright © 2014, American Journal of Physiology - Lung Cellular and Molecular Physiology.
IL-6 is implicated in the pathogenesis of various neuroinflammatory and neurodegenerative disorders of the CNS. IL-6 signals via binding to either the membrane bound IL-6Rα (classic signaling) or soluble (s)IL-6Ra (trans-signaling) that then form a complex with gp130 to activate the JAK/STAT signaling pathway. The importance of classic versus trans-signaling in mediating IL-6 actions in the living CNS is relatively unknown and was the focus of this investigation. Bigenic mice (termed GFAP-IL6/sgp130 mice) were generated with CNS-restricted, astrocyte-targeted production of IL-6 and coproduction of the specific inhibitor of IL-6 trans-signaling, human sgp130-Fc. Transgene-encoded IL-6 mRNA levels were similar in the brain of GFAP-IL6 and GFAP-IL6/sgp130 mice. However, GFAP-IL6/sgp130 mice had decreased pY(705)-STAT3 in the brain due to a reduction in the total number of pY(705)-STAT3-positive cells and a marked loss of pY(705)-STAT3 in specific cell types. Blockade of trans-signaling in the brain of the GFAP-IL6 mice significantly attenuated Serpina3n but not SOCS3 gene expression, whereas vascular changes including angiogenesis and blood-brain barrier leakage as well as gliosis were also reduced significantly. Hippocampal neurogenesis which was impaired in GFAP-IL6 mice was rescued in young GFAP-IL6 mice with cerebral sgp130 production. Finally, degenerative changes in the cerebellum characteristic of GFAP-IL6 mice were absent in GFAP-IL6/sgp130 mice. The findings indicate that in the CNS: (1) sgp130 is able to block IL-6 trans-signaling, (2) trans-signaling is important for IL-6 cellular communication with selective cellular and molecular targets, and (3) blocking of trans-signaling alleviates many of the detrimental effects of IL-6.
Blinatumomab is a CD19/CD3-bispecific T-cell receptor-engaging (BiTE) antibody with efficacy in refractory B-precursor acute lymphoblastic leukemia. Some patients treated with blinatumomab and other T cell-activating therapies develop cytokine release syndrome (CRS). We hypothesized that patients with more severe toxicity may experience abnormal macrophage activation triggered by the release of cytokines by T-cell receptor-activated cytotoxic T cells engaged by BiTE antibodies and leading to hemophagocytic lymphohistiocytosis (HLH). We prospectively monitored a patient during blinatumomab treatment and observed that he developed HLH. He became ill 36 hours into the infusion with fever, respiratory failure, and circulatory collapse. He developed hyperferritinemia, cytopenias, hypofibrinogenemia, and a cytokine profile diagnostic for HLH. The HLH continued to progress after discontinuation of blinatumomab; however, he had rapid improvement after IL-6 receptor-directed therapy with tocilizumab. Patients treated with T cell-activating therapies, including blinatumomab, should be monitored for HLH, and cytokine-directed therapy may be considered in cases of life-threatening CRS. This trial was registered at www.clinicaltrials.gov as #NCT00103285.
Gastrointestinal cancers are frequently associated with chronic inflammation and excessive secretion of IL-6 family cytokines, which promote tumorigenesis through persistent activation of the GP130/JAK/STAT3 pathway. Although tumor progression can be prevented by genetic ablation of Stat3 in mice, this transcription factor remains a challenging therapeutic target with a paucity of clinically approved inhibitors. Here, we uncovered parallel and excessive activation of mTOR complex 1 (mTORC1) alongside STAT3 in human intestinal-type gastric cancers (IGCs). Furthermore, in a preclinical mouse model of IGC, GP130 ligand administration simultaneously activated mTORC1/S6 kinase and STAT3 signaling. We therefore investigated whether mTORC1 activation was required for inflammation-associated gastrointestinal tumorigenesis. Strikingly, the mTORC1-specific inhibitor RAD001 potently suppressed initiation and progression of both murine IGC and colitis-associated colon cancer. The therapeutic effect of RAD001 was associated with reduced tumor vascularization and cell proliferation but occurred independently of STAT3 activity. We analyzed the mechanism of GP130-mediated mTORC1 activation in cells and mice and revealed a requirement for JAK and PI3K activity but not for GP130 tyrosine phosphorylation or STAT3. Our results suggest that GP130-dependent activation of the druggable PI3K/mTORC1 pathway is required for inflammation-associated gastrointestinal tumorigenesis. These findings advocate clinical application of PI3K/mTORC1 inhibitors for the treatment of corresponding human malignancies.
IL-6 is a pleiotropic cytokine involved in the physiology of virtually every organ system. Recent studies have demonstrated that IL-6 has a very important role in regulating the balance between IL-17-producing Th17 cells and regulatory T cells (Treg). The two T-cell subsets play prominent roles in immune functions: Th17 cell is a key player in the pathogenesis of autoimmune diseases and protection against bacterial infections, while Treg functions to restrain excessive effector T-cell responses. IL-6 induces the development of Th17 cells from naïve T cells together with TGF-beta; in contrast, IL-6 inhibits TGF-beta-induced Treg differentiation. Dysregulation or overproduction of IL-6 leads to autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA), in which Th17 cells are considered to be the primary cause of pathology. Given the critical role of IL-6 in altering the balance between Treg and Th17 cells, controlling IL-6 activities is potentially an effective approach in the treatment of various autoimmune and inflammatory diseases. Here, we review the role of IL-6 in regulating Th17/Treg balance and describe the critical functions of IL-6 and Th17 in immunity and immune-pathology.
The chromosomal DNA segment of human B cell stimulatory factor-2 (BSF-2/IL-6) was isolated and characterized by nucleotide sequence analysis. The human BSF-2/IL-6 gene consists of five exons and four introns and its organization shows a distinctive similarity to granulocyte colony-stimulating factor gene. The two genes have the same number of exons and introns and the size of each exon is strikingly similar. The BSF-2/IL-6 mRNA was found to be constitutively expressed in a human T cell leukemia virus-1 transformed T cell line, TCL-Na1, a bladder cell carcinoma line, T24, and an amnion derived cell line, FL. The BSF-2/IL-6 mRNA was also found to be inducible with interleukin-1 beta in an astrocytoma line, U373 and a glioblastoma line, SK-MG-4. S1 mapping and primer extension analyses showed the presence of multiple initiation sites and the preferential utilization of a different initiation site for each individual tissue tested.
Two mRNA species that produce biologically active interferon were isolated from human fibroblasts and studied by size fractionation and cloning in Escherichia coli plasmid pBR322. The major fibroblast interferon (Hu IFN-beta 1) is coded for by the smaller of the two mRNAs, an 11S species, 900 nucleotides long, which in cell-free systems yields a 20,000 Mr protein. The second interferon mRNA species (Hu IFN-beta 2) is 14S, about 1300 nucleotides long, and codes for another protein of 23,000-26,000 Mr. The two interferon mRNAs do not cross-hybridize. Both are induced by poly(rI.rC), but IFN-beta 2 mRNA is induced to about 10% in cells by cycloheximide treatment alone whereas under these conditions IFN-beta 1 is not induced.
The IL (interleukin)-6-type cytokines IL-6, IL-11, LIF (leukaemia inhibitory factor), OSM (oncostatin M), ciliary neurotrophic factor, cardiotrophin-1 and cardiotrophin-like cytokine are an important family of mediators involved in the regulation of the acute-phase response to injury and infection. Besides their functions in inflammation and the immune response, these cytokines play also a crucial role in haematopoiesis, liver and neuronal regeneration, embryonal development and fertility. Dysregulation of IL-6-type cytokine signalling contributes to the onset and maintenance of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis and various types of cancer (e.g. multiple myeloma and prostate cancer). IL-6-type cytokines exert their action via the signal transducers gp (glycoprotein) 130, LIF receptor and OSM receptor leading to the activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) cascades. This review focuses on recent progress in the understanding of the molecular mechanisms of IL-6-type cytokine signal transduction. Emphasis is put on the termination and modulation of the JAK/STAT signalling pathway mediated by tyrosine phosphatases, the SOCS (suppressor of cytokine signalling) feedback inhibitors and PIAS (protein inhibitor of activated STAT) proteins. Also the cross-talk between the JAK/STAT pathway with other signalling cascades is discussed.
Appropriate control of leukocyte recruitment and activation is a fundamental requirement for competent host defense and resolving inflammation. A pivotal event that defines the successful outcome of any inflammatory event is the transition from innate to acquired immunity. In IL-6 deficiency, this process appears defective, and a series of in vivo studies have documented important roles for IL-6 in both the resolution of innate immunity and the development of acquired immune responses. Within this review, particular attention will be given to the regulatory properties of the soluble IL-6 receptor and how its activity may affect chronic disease progression.
Interleukin-6 (IL-6) and its soluble receptor (sIL-6R) are major factors for maintenance and expansion of hematopoietic stem cells (HSCs). Sensitivity of HSCs to IL-6 has been previously studied, in part by measuring the expression of IL-6R on the membrane (mIL-6R). Several studies have described the regulation of cell surface expression of IL-6R by several cytokines, but the role of glycoprotein 130 activation has not yet been investigated. In this study, CD133(+) cells were purified from adult peripheral blood and were precultured in the absence or presence of 5-fluorouracil (5-FU) for selection of quiescent HSCs. Cells were cultured with continuous or pulsed stimulations of an IL-6-sIL-6R fusion protein (hyperinterleukin-6 [HIL-6]) to 1) detect mIL-6R by flow cytometry, 2) assess mIL-6R and sIL-6R RNAs by reverse transcription-polymerase chain reaction, 3) measure sIL-6R in supernatants by enzyme-linked immunosorbent assay, 4) analyze cell-cycle status, and 5) perform long-term culture-initiating cell assays. The level of mIL-6R(-) cells was preserved by 5-FU incubation. HIL-6 increased steady-state mIL-6R RNA and expression rate on HSCs, independently of treatment with 5-FU. Enhanced production of sIL-6R was observed with short pulses of HIL-6 on CD133(+) 5-FU-pretreated cells. This overproduction of sIL-6R was abrogated by tumor necrosis factor-alpha protease inhibitor-1, an inhibitor of a disintegrin and metalloprotease proteases, suggesting the shedding of mIL-6R. This phenomenon was mediated through the phosphatidylinositol-3'-kinase pathway and was involved in the maintenance of primitive HSCs. In conclusion, expression and production of IL-6R are tightly regulated and stage specific. We assume that sIL-6R produced by shedding should be involved in autocrine and paracrine loops in the HSC microenvironment.
目的： 新型冠状病毒肺炎在武汉暴发流行以来，已在全国范围内蔓延。对截至2020年2月11日中国内地报告所有病例的流行病学特征进行描述和分析。 方法： 选取截至2020年2月11日中国内地传染病报告信息系统中上报所有新型冠状病毒肺炎病例。分析包括：①患者特征；②病死率；③年龄分布和性别比例；④疾病传播的时空特点；⑤所有病例、湖北省以外病例和医务人员病例的流行病学曲线。 结果： 中国内地共报告72 314例病例，其中确诊病例44 672例（61.8%），疑似病例16 186例（22.4%），临床诊断病例10 567例（14.6%），无症状感染者889例（1.2%）。在确诊病例中，大多数年龄在30～79岁（86.6%），湖北省（74.7%），轻/中症病例为主（80.9%）。确诊病例中，死亡1 023例，粗病死率为2.3%。个案调查结果提示，疫情在2019年12月从湖北向外传播，截至2020年2月11日，全国31个省的1 386个县区受到了影响。流行曲线显示在1月23－26日达到峰值，并且观察到发病数下降趋势。截至2月11日，共有1 716名医务工作者感染，其中5人死亡，粗病死率为0.3%。 结论： 新型冠状病毒肺炎传播流行迅速，从首次报告病例日后30 d蔓延至31个省（区/市），疫情在1月24－26日达到首个流行峰，2月1日出现单日发病异常高值，而后逐渐下降。随着人们返回工作岗位，需积极应对可能出现的疫情反弹。.
Copyright© by the Editorial Department of Journal of Forensic Medicine.
IL-6 is implicated in the development and progression of autoimmune diseases in part by influencing CD4 T cell lineage and regulation. Elevated IL-6 levels drive inflammation in a wide range of autoimmune diseases, some of which are also characterized by enhanced T cell responses to IL-6. Notably, the impact of IL-6 on inflammation is contextual in nature and dependent on the cell type, cytokine milieu and tissue. Targeting the IL-6/IL-6R axis in humans has been shown to successfully ameliorate a subset of autoimmune conditions. In this review, we discuss recent studies investigating how IL-6 regulates the CD4 T cell response in the context of autoimmune disease and highlight how blocking different aspects of the IL-6 pathway is advantageous in the treatment of disease.
Implications for practice:
Severe or life-threatening chimeric antigen receptor (CAR) T cell-induced cytokine release syndrome (CRS) requires urgent treatment to prevent fatal outcomes. In two independent cohorts, the majority of patients with severe or life-threatening CAR T cell-induced CRS responded to treatment with one or two doses of tocilizumab in addition to advanced supportive care. More research is needed to determine the optimal dose and schedule of tocilizumab for treatment of CAR T cell-induced CRS.
The IL-6/JAK/STAT3 signalling pathway is aberrantly hyperactivated in patients with chronic inflammatory conditions and in those with haematopoietic malignancies or solid tumours
Multiple cell types in the tumour microenvironment produce IL-6, leading to activation of JAK/STAT3 signalling in both tumour cells and tumour-infiltrating immune cells, which can promote tumour-cell proliferation, survival, invasiveness, and metastasis
STAT3 is hyperactivated in tumour-infiltrating immune cells and acts to negatively regulate neutrophils, natural killer cells, effector T cells, and dendritic cells while positively regulating populations of myeloid-derived suppressor cells and regulatory T cells
Targeting components of the IL-6/JAK/STAT3 signalling pathway can inhibit tumour cell growth and relieve immunosuppression in the tumour microenvironment
Inhibitors of IL-6, the IL-6 receptor, or JAKs have all received FDA approval for various malignancies, and other novel inhibitors of the IL-6/JAK/STAT3 signalling pathway are currently in clinical and/or preclinical development
Investigations of the efficacy of IL-6/JAK/STAT3 inhibitors, in combination with immune-checkpoint inhibitors, are warranted
OBJECTIVE: To study the molecular mechanism of ribavirin and interferon-α in the treatment of Middle East Respiratory Syndrome (MERS) by bio-informatic methods.
Interleukin-6 (IL-6) plays a paradoxical role in inflammation and metabolism. The pro-inflammatory effects of IL-6 are mediated via IL-6 "trans-signaling," a process where the soluble form of the IL-6 receptor (sIL-6R) binds IL-6 and activates signaling in inflammatory cells that express the gp130 but not the IL-6 receptor. Here we show that trans-signaling recruits macrophages into adipose tissue (ATM). Moreover, blocking trans-signaling with soluble gp130Fc protein prevents high-fat diet (HFD)-induced ATM accumulation, but does not improve insulin action. Importantly, however, blockade of IL-6 trans-signaling, unlike complete ablation of IL-6 signaling, does not exacerbate obesity-induced weight gain, liver steatosis, or insulin resistance. Our data identify the sIL-6R as a critical chemotactic signal for ATM recruitment and suggest that selectively blocking IL-6 trans-signaling may be a more favorable treatment option for inflammatory diseases, compared with current treatments that completely block the action of IL-6 and negatively impact upon metabolic homeostasis.
Copyright © 2015 Elsevier Inc. All rights reserved.
Interleukin-6 (IL-6) is a pleiotropic cytokine that participates in normal functions of the immune system, hematopoiesis, metabolism, as well as in the pathogenesis of metabolic and cardiovascular diseases. Both pro- and anti-inflammatory roles of IL-6 have been described, which are possibly discriminated by the cascades of signaling transduction, namely classic and trans-signaling. The present review summarizes the basic principles of IL-6 signaling and discusses its roles in diabetes and associated cardiovascular complications, with emphasis on the distinct destinations diverged by the two arms of IL-6 signaling and the value of developing therapeutic strategies to specifically target the deleterious trans-signaling of IL-6.
Cytokines receptors exist in membrane bound and soluble form. A soluble form of the human IL-6R is generated by limited proteolysis and alternative splicing. The complex of IL-6 and soluble IL-6R stimulates target cells not stimulated by IL-6 alone, since they do not express the membrane bound IL-6R. We have named this process trans-signaling. Soluble gp130 is the natural inhibitor of IL-6/soluble IL-6R complex responses. Recombinant soluble gp130 protein is a molecular tool to discriminate between gp130 responses via membrane bound and soluble IL-6R responses. Neutralizing monoclonal antibodies for global blockade of IL-6 signaling and the sgp130Fc protein for selective blockade of IL-6 trans-signaling have been used in several animal models of human diseases. Using the sgp130Fc protein or sgp130Fc transgenic mice we demonstrate in models of inflammatory bowel disease, peritonitis, rheumatoid arthritis, atherosclerosis pancreatitis, colon cancer, ovarian cancer and pancreatic cancer, that IL-6 trans-signaling via the soluble IL-6R is the crucial step in the development and the progression of the disease. Therefore, sgp130Fc is a novel therapeutic agent for the treatment of chronic inflammatory diseases and cancer and it undergoes phase I clinical trials as an anti-inflammatory drug since June 2013.
Tocilizumab (TCZ) is a biological agent used for the treatment of moderate to severe rheumatoid arthritis (RA). In the present systematic literature review and meta-analysis, we provide an update on the efficacy and safety of TCZ and our clinical comments for the treatment of RA.
We searched PubMed for randomized, double-blind, placebo-controlled clinical trials investigating the effects of TCZ on RA. The initial search included articles from 1966 to December 2011. The search was subsequently updated in April 2013. Studies had to report clinical efficacy using American College of Rheumatology (ACR) 20, 50, and 70 disease measures. The studies included participants who were 18 years of age and who met the ACR 1987 revised criteria for RA for 6 months or longer. Two reviewers independently abstracted the data, and disagreement was resolved by discussion with a third reviewer. Outcome measures were analyzed as odds ratio using the Mantel-Haenszel estimator under a random effects model to account for heterogeneity in intervention effects between trials. Descriptive statistics were used to compare adverse events.
After reviewing and culling, 8 randomized, controlled, double-blind studies were included in the efficacy meta-analysis. TCZ 8mg/kg was statistically favored over TCZ 4mg/kg or placebo regarding ACR responses. Clinically significant adverse events that occurred with TCZ treatment included infections, lipid and liver function test abnormalities, and gastrointestinal side effects, all of which were more common with TCZ.
This meta-analysis supports the use of TCZ as an appropriate treatment for moderate to severe RA as monotherapy and combination therapy. Close monitoring for significant adverse events is required when treating patients with TCZ. Future long-term trials should focus further on safety of this agent.
Chimeric antigen receptor-modified T cells with specificity for CD19 have shown promise in the treatment of chronic lymphocytic leukemia (CLL). It remains to be established whether chimeric antigen receptor T cells have clinical activity in acute lymphoblastic leukemia (ALL). Two children with relapsed and refractory pre-B-cell ALL received infusions of T cells transduced with anti-CD19 antibody and a T-cell signaling molecule (CTL019 chimeric antigen receptor T cells), at a dose of 1.4×10(6) to 1.2×10(7) CTL019 cells per kilogram of body weight. In both patients, CTL019 T cells expanded to a level that was more than 1000 times as high as the initial engraftment level, and the cells were identified in bone marrow. In addition, the chimeric antigen receptor T cells were observed in the cerebrospinal fluid (CSF), where they persisted at high levels for at least 6 months. Eight grade 3 or 4 adverse events were noted. The cytokine-release syndrome and B-cell aplasia developed in both patients. In one child, the cytokine-release syndrome was severe; cytokine blockade with etanercept and tocilizumab was effective in reversing the syndrome and did not prevent expansion of chimeric antigen receptor T cells or reduce antileukemic efficacy. Complete remission was observed in both patients and is ongoing in one patient at 11 months after treatment. The other patient had a relapse, with blast cells that no longer expressed CD19, approximately 2 months after treatment. Chimeric antigen receptor-modified T cells are capable of killing even aggressive, treatment-refractory acute leukemia cells in vivo. The emergence of tumor cells that no longer express the target indicates a need to target other molecules in addition to CD19 in some patients with ALL.
The key role of interleukin-17 (IL-17) and T helper 17 (T(H)17) cells in tissue inflammation, autoimmunity and host defence led to the experimental targeting of these molecules in mouse models of diseases as well as in clinical settings. Moreover, the demonstration that IL-17 and T(H)17 cells contribute to local and systemic aspects of disease pathogenesis, as well as the finding that the IL-17-T(H)17 cell pathway is regulated by IL-23, prompted the identification of inhibitors. These inhibitors include biotechnology products that target IL-23 as well as the leading member of the IL-17 family, IL-17A, and one of its receptors, IL-17 receptor A. Several clinical trials of these inhibitors are underway, and positive results have been obtained in psoriasis, rheumatoid arthritis and ankylosing spondylitis. This Review focuses on the current knowledge of the IL-17-T(H)17 cell pathway to better understand the positive as well as potential negative consequences of targeting them.
Adult T-cell leukemia (ATL) is a heterogeneous tumor that is resistant to chemotherapy. Telomerase activity plays a critical role in tumorigenesis and is associated with the prognosis of ATL patients. Interleukin (IL)-2 commonly promotes tumor growth in chronic ATL cells. The signaling pathways involved in IL-2-regulated telomerase activation were studied in ATL cells derived from chronic ATL patients. IL-2 challenge enhanced tyrosine phosphorylation of Janus-activated kinase (JAK)1-3 and STAT5, and induced JAK1 and JAK2 to associate with STAT5 in IL-2-dependent ATL cells. Chromatin immunoprecipitation assays revealed that STAT5 directly bound to the human telomerase reverse transcriptase (hTERT) promoter. STAT5 short interfering RNA inhibited hTERT transcription in IL-2-stimulated ATL cells. Inhibitors of PI3K, HSP90, and mTOR reduced IL-2-induced hTERT mRNA, protein expression, and telomerase activity. AKT, HSP90, mTOR, S6 kinase, and hTERT immunoprecipitate from IL-2-stimulated cells contained telomerase activity, suggesting that hTERT directly interacts with, and is regulated by, these proteins. Binding of the p85 regulatory subunit of PI3K to JAK2 was enhanced in an IL-2-dependent manner, indicating that JAK2 propagates activation signals from the IL-2 receptor and links hTERT activation to both the STAT5 and PI3K pathways. Finally, IL-2-induced activation of telomerase and STAT5 was observed in primary leukemic cells. These results indicate that IL-2 stimulation induces hTERT activation through the JAK/STAT pathway and the JAK/PI3K/AKT/HSP90/mTORC1 pathway in IL-2-responsive ATL cells. These signaling proteins represent novel and promising molecular therapeutic targets for IL-2-dependent ATL.
Interleukin-6 (IL-6/BSF-2/IFN beta 2) is a multifunctional cytokine that regulates the growth and differentiation of various
tissues, and is known particularly for its role in the immune response and acute phase reactions. A complementary DNA encoding
the human IL-6 receptor (IL-6-R) has now been isolated. The IL-6-R consists of 468 amino acids, including a signal peptide
of approximately 19 amino acids and a domain of approximately 90 amino acids that is similar to a domain in the immunoglobulin
(Ig) superfamily. The cytoplasmic domain of approximately 82 amino acids lacks a tyrosine/kinase domain, unlike other growth
factor receptors.
Eleven patients with relapsed fludarabine-resistant B-cell chronic lymphocytic leukemia (CLL) or leukemic variants of low-grade B-cell non-Hodgkin's lymphoma (NHL) were treated with the chimeric monoclonal anti-CD20 antibody rituximab (IDEC-C2B8). Peripheral lymphocyte counts at baseline varied from 0.2 to 294.3 x 10(9)/L. During the first rituximab infusion, patients with lymphocyte counts exceeding 50.0 x 10(9)/L experienced a severe cytokine-release syndrome. Ninety minutes after onset of the infusion, serum levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) peaked in all patients. Elevated cytokine levels during treatment were associated with clinical symptoms, including fever, chills, nausea, vomiting, hypotension, and dyspnea. Lymphocyte and platelet counts dropped to 50% to 75% of baseline values within 12 hours after the onset of the infusion. Simultaneously, there was a 5-fold to 10-fold increase of liver enzymes, d-dimers, and lactate dehydrogenase (LDH), as well as a prolongation of the prothrombin time. Frequency and severity of first-dose adverse events were dependent on the number of circulating tumor cells at baseline: patients with lymphocyte counts greater than 50.0 x 10(9)/L experienced significantly more adverse events of National Cancer Institute (NCI) grade III/IV toxicity than patients with less than 50.0 x 10(9)/L peripheral tumor cells (P = .0017). Due to massive side effects in the first patient treated with 375 mg/m(2) in 1 day, a fractionated dosing schedule was used in all subsequent patients with application of 50 mg rituximab on day 1, 150 mg on day 2, and the rest of the 375 mg/m(2) dose on day 3. While the patient with the leukemic variant of the mantle-cell NHL achieved a complete remission (9 months+) after treatment with 4 x 375 mg/m(2) rituximab, efficacy in patients with relapsed fludarabine-resistant B-CLL was poor: 1 partial remission, 7 cases of stable disease, and 1 progressive disease were observed in 9 evaluable patients with CLL. On the basis of these data, different infusion schedules and/or combination regimens with chemotherapeutic drugs to reduce tumor burden before treatment with rituximab will have to be evaluated.
Interleukin-6 (IL-6) regulates immune response and inflammation. We carried out a pilot placebo-controlled study to investigate the efficacy, pharmacokinetics, and safety of MRA, a humanized monoclonal antibody to IL-6 receptor, in patients with active Crohn's disease.
Thirty-six patients with active Crohn's disease (Crohn's Disease Activity Index [CDAI] > or =150) were randomly assigned to receive biweekly intravenous infusion of either placebo, MRA, or MRA/placebo alternately for 12 weeks at a dose of 8 mg/kg. The study's primary end point was a clinical response rate that was defined as a reduction of CDAI > or =70.
At the final evaluation, 80% of the patients (8 of 10) given biweekly MRA had a clinical response as compared with 31% of the placebo-treated patients (4 of 13; P = 0.019). Twenty percent of the patients (2 of 10) on this regimen went into remission (CDAI <150), as compared with 0% of the placebo-treated patients (0 of 13). The clinical response rate of the every-4-week regimen was 42% (5 of 12). The serum concentrations of MRA were detected at 2 weeks after every infusion, at which time acute phase responses were completely suppressed; however, they were not suppressed at 4 weeks. Endoscopic and histologic examination showed no difference between MRA and placebo groups. The incidence of adverse events was similar in all the groups.
This is the first clinical trial of humanized anti-IL-6 receptor monoclonal antibody in Crohn's disease. A biweekly 8 mg/kg infusion of MRA was well tolerated, normalized the acute-phase responses, and suggests a clinical effect in active Crohn's disease.
To investigate the safety and efficacy of a recombinant human anti-interleukin-6 (anti-IL-6) receptor monoclonal antibody (MRA) that indirectly inhibits the effects of IL-6 in children with systemic-onset juvenile idiopathic arthritis (JIA) refractory to high-dose, long-term corticosteroids.
An individual escalating-dose trial was conducted in 11 children with active systemic-onset JIA who met the inclusion criteria. All were first administered an intravenous dose of 2 mg/kg MRA. Each child without active inflammation was given a second identical dose 2 weeks later and a third identical dose 2 weeks after the second dose. Children with disease flares according to laboratory marker values received a 4-mg/kg dose. Those without disease flares at this dose received a second 4-mg/kg dose 2 weeks later and a third 4-mg/kg dose 2 weeks after the second dose, while those with active inflammation received an additional 3 doses of 8 mg/kg MRA. Efficacy was evaluated every 2 weeks according to responses on the JIA core set of improvement criteria and the results of laboratory tests.
MRA abruptly reduced disease activity in 10 of the 11 children, as assessed by the occurrence of febrile episodes, active arthritis, scores on the Childhood Health Assessment Questionnaire, and levels of acute-phase reactants. However, levels of inflammatory reactants fluctuated until the proper MRA dose for each child was reached. Two weeks after the third fixed dose of MRA, 90.9% of all patients had a 30% improvement response, 90.9% had a 50% improvement response, and 63.6% had a 70% improvement response.
MRA treatment of children with active systemic disease results in clinical improvement and in normalized levels of acute-phase reactants. MRA was safe and well tolerated and provided greater clinical benefit than conventional corticosteroids, considering the ill effects of IL-6 and adverse events.
Severe acute respiratory syndrome (SARS) caused by a novel human coronavirus (CoV), designated SARS-CoV, is a highly contagious respiratory disease with the lungs as a major target. Although the exact mechanism of SARS-CoV pathogenesis remains unknown, an intense, ill-regulated local inflammatory response has been suggested as partially responsible for the devastating lung pathology. We investigated the interaction of SARS-CoV with human macrophages (Mphi) and dendritic cells (DC), two key innate immune cells of the host immune system, by focusing on their susceptibility to viral infection and subsequent responses (e.g., phenotypic maturation, T cell-priming activity, phagocytosis, and cytokine production). We found neither cell to be permissive for SARS-CoV replication. However, incubation of Mphi and DC with live, but not gamma irradiation-inactivated, viruses appeared to better sustain their viability. Also, exposure to infectious SARS-CoV led to the phenotypic and functional maturation of DC, with regard to MHC class II and costimulatory molecule expression, T cell-stimulatory capacity, and cytokine production, respectively. Cytokine production was also observed for Mphi, which were refractory to cell surface phenotypic changes. Strikingly, live SARS-CoV could further prime cell types to respond to a suboptimal dose of bacterial LPS (100 ng/ml), resulting in massive release of IL-6 and IL-12. However, the endocytic capacity (e.g., Ag capture) of Mphi was significantly compromised upon exposure to infectious SARS-CoV. This study is the first demonstration that although SARS-CoV does not productively infect human Mphi or DC, it appears to exert differential effects on Mphi and DC maturation and functions, which might contribute to SARS pathogenesis.
Multicentric Castleman disease (MCD) is an atypical lymphoproliferative disorder characterized by systemic lymphadenopathy and constitutional inflammatory symptoms. Dysregulated overproduction of interleukin-6 is responsible for the clinical abnormalities. This multicenter prospective study was undertaken to evaluate the safety and efficacy of a humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody (MRA) in patients with MCD. We report here results of the first 60 weeks of the study enrolling 28 patients. The initial dosing period consisted of 8 infusions of 8 mg/kg MRA administered biweekly. Adjustments in the dose and treatment interval were allowed for each patient in an extension phase after 16 weeks. Within 16 weeks, treatment with MRA consistently alleviated lymphadenopathy and all the inflammatory parameters. Hemoglobin, albumin, and total cholesterol levels, high-density lipoprotein cholesterol values, and body mass index all increased significantly. In addition, fatigue diminished. Chronic inflammatory symptoms were successfully managed over 60 weeks. In 8 (28.6%) patients, the MRA dose was decreased or the treatment interval was extended without exacerbation. Eleven (73.3%) of 15 patients who had received oral corticosteroids before study entry were able to do well on a reduced corticosteroid dose. Most adverse events were mild to moderate in severity. MRA was tolerated well and significantly alleviated chronic inflammatory symptoms and wasting in patients with MCD.
Background:
Severe acute respiratory syndrome (SARS) is an emerging infection caused by a novel coronavirus known as SARS-CoV, characterized by an over-exuberant immune response with lung lymphomononuclear cells infiltration and proliferation that may account for tissue damage more than the direct effect of viral replication. This study is aimed at investigating the capability of SARS-CoV to activate IFN-alpha and -gamma expression in lymphomonocytes (PBMC) from healthy donors, evaluating whether viral replication is necessary for this activation.
Results:
SARS-CoV virus is able to induce both IFN-alpha and -gamma mRNA accumulation and protein release in a dose-dependent manner, MOI 10 being the most effective. The time course curve indicated that IFN-alpha mRNA induction peaked at 24 h.p.i,. whereas IFN-gamma mRNA was still increasing at 48 h.p.i. Released IFN (both types) reached a plateau after 24-48 h.p.i. and remained rather stable over a 5-day period. A transient peak of negative strand viral RNA was detected after 1-2 days of infection, but neither infectious virus progeny yield nor newly produced viral genomic RNA could be evidenced in infected cultures, even after prolonged observation time (up to 13 days). Cocultivation of PBMC with fixed SARS-CoV-infected Vero cells was even more efficient than exposure to live virus in eliciting IFN-alpha and -gamma induction. A combination of IFN-alpha and -gamma strongly inhibited SARS-CoV replication in Vero cells, while the single cytokines were much less effective.
Conclusions:
This study provides evidence that SARS-CoV is able to induce in normal PBMC a coordinate induction of IFN-alpha and -gamma gene expression. Virus replication is not necessary for IFN induction since efficient IFN expression could be obtained also by the cocultivation of normal PBMC with fixed SARS-CoV-infected cells. Concomitant activation of IFN-alpha and -gamma gene expression by SARS-CoV in vivo may be relevant for the pathogenesis of the disease, both for the possible involvement in immunomediated damage of the tissues and for the strong inhibition of SARS-CoV replication as a result of combined cytokine action.