ArticleLiterature Review

Interleukin-6 use in COVID-19 pneumonia related macrophage activation syndrome

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Abstract

Severe COVID-19 associated pneumonia patients may exhibit features of systemic hyper-inflammation designated under the umbrella term of macrophage activation syndrome (MAS) or cytokine storm, also known as secondary haemophagocytic lymphohistocytosis (sHLH). This is distinct from HLH associated with immunodeficiency states termed primary HLH -with radically different therapy strategies in both situations. COVID-19 infection with MAS typically occurs in subjects with adult respiratory distress syndrome (ARDS) and historically, non-survival in ARDS was linked to sustained IL-6 and IL-1 elevation. We provide a model for the classification of MAS to stratify the MAS-like presentation in COVID-19 pneumonia and explore the complexities of discerning ARDS from MAS. We describe the potential impact of viral load and therapy timing towards improving the outcome of IL-6 antagonism and other immunomodulatory therapies.

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... progression, leading to severe conditions like CSS and macrophage activation syndrome (McGonagle;Sharif;O'Regan;Bridgewood, 2020;Kermali;. ...
... progression, leading to severe conditions like CSS and macrophage activation syndrome (McGonagle;Sharif;O'Regan;Bridgewood, 2020;Kermali;. ...
... progression, leading to severe conditions like CSS and macrophage activation syndrome (McGonagle;Sharif;O'Regan;Bridgewood, 2020;Kermali;. ...
Article
Interleukin 6 (IL-6) plays an important role in the progression of COVID-19, reinforcing the possible efficacy of treatment with Tocilizumab (TCZ). However, there is no scientific confirmation that proves the real effectiveness of TCZ on mortality or length of hospital stay in patients with SARS-CoV-2. To update the evidence on TCZ treatment in patients with COVID-19 based on a systematic review and meta-analysis. We carried out searches based on the acronym PICOS in 5 databases (PubMed, Scopus, EMBASE, Cochrane and Web of Science). The assessment of methodological quality was carried out using the Cochrane Collaboration’s tool Risk of Bias 2 (RoB-2). The certainty of the evidence was assessed by the Grading of Recommendations Assessment Development and Evaluation (GRADE approach). The quantitative analysis was conducted using the software Review Manager 5.4. Of the 327 articles identified, 12 were included. Mortality was not influenced by treatment with TCZ compared to placebo or standard treatment (RR: 0.92; 95% CI: 0.82-1.04; p=0.17; I2=0%, p=0.63), and the certainty of the evidence was low. Five studies were considered for length of hospital stay (mean difference: -2.61; 95% CI from -5.41 to 0.19; p=0.07; I2=99%, p<0.001), the cumulative evidence it was very low. The risk of bias was low in 10 included studies. TCZ was not efficient in reducing mortality in patients with COVID-19 during hospital admission, but the true effect may be substantially different from the estimated effect. For length of hospital stay, the use of TCZ in patients with COVID-19 did not show a significant reduction in length of stay.
... Esto se debe a una mayor susceptibilidad a la infección por el SARS-CoV-2, debido a la disminución en la actividad de las vías inmunes provocado por deficiencia de insulina e hiperglucemia (6). Esto, a su vez, provoca la inhibición del reclutamiento de leucocitos, hipoactividad en leucocitos, macrófagos y sistema del complemento (7). Como consecuencia, este grupo poblacional tiene un riesgo de 2.75 veces para desarrollar patología grave y de 1.90 veces para fallecer (8). ...
... La cohorte recopilada demostró una alta carga comórbida, lo que pudo haber generado la hospitalización de estos pacientes. En las primeras investigaciones los pacientes que más ingresaron a hospitalización y fallecieron tenían un mayor número de antecedentes patológicos, lo que se puede explicar por alteraciones inmunes, microvasculares y menor reserva fisiológica (7,20). La hipertensión arterial (HTA) fue una de las patologías crónicas más prevalentes en la cohorte, hallazgo similar a los registros de EU, en donde 49.7% de los pacientes hospitalizados sufrían hipertensión (21). ...
... El mayor riesgo asociado a un mal control glicémico reflejado en una HbA1c por fuera de metas se explica por el desbalance inmunológico que presentan los pacientes con DM y niveles elevados de HbA1c; donde la inhibición del reclutamiento de leucocitos, hipoactividad en leucocitos, macrófagos y sistema del complemento llevan a un estado protrombótico lleva a un mayor riesgo de eventos trombóticos y SDRA (7). ...
Article
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Objetivo: establecer la relación entre los niveles de hemoglobina glicada elevada con enfermedad grave y mortalidad por COVID-19 en pacientes hospitalizados por la enfermedad producida por SARS-CoV-2 en la Clínica Universitaria Colombia entre junio de 2020 y diciembre de 2021. Material y método: estudio observacional, analítico de cohorte retrospectivo. Se incluyeron pacientes mayores de 18 años ingresados con diagnóstico de COVID-19 confirmado por prueba de antígeno o PCR. Se buscó la asociación entre los niveles de hemoglobina glicada (HbA1c) con los desenlaces de enfermedad grave y mortalidad. Se realizó un análisis univariado para describir la población, un análisis bivariado para establecer las asociaciones y un análisis multivariado predictivo, todo con una significancia de estadística de 5%. La recolección de la información se realizó a partir de historias clínicas electrónicas de la clínica universitaria Colombia hospitalizados por COVID-19 entre junio de 2020 y diciembre del 2021. Se tomaron variables sociodemográficas, antecedentes, uso de medicamentos, para clínicos intrahospitalarios y curso hospitalario. La variable hemoglobina glicada fue categorizada en rangos menores a 7%, entre 7 y 10% y mayores 10% con el fin de evaluar su relación con enfermedad grave, definida como aquellos pacientes que ingresaron a la unidad de cuidados intensivos o requirieron intubación orotraqueal (IOT). Resultados: la cohorte fue conformada por 329 pacientes. La media de edad fue de 62.1 años (DE=14 años). Las comorbilidades más frecuentes registradas en los pacientes fueron hipertensión arterial, diabetes mellitus y enfermedad cardiovascular. El promedio de hemoglobina glicada tomada al ingreso o en los tres meses previos a la hospitalización fue 7.08 ±1.86%. La HbA1c 7% y 10% tenían 1.90 veces riesgo para fallecer (IC95%1.03-3.50) comparado con aquellos que tuvieron la HbA1c menor a 7%. También, tenían entre 1.63 y 1.78 veces riesgo de ingresar a UCI o requerir IOT. Conclusiones: encontramos una cohorte de pacientes con una alta carga de comorbilidades. La proporción de pacientes con HbA1c por fuera de metas fue elevada. La HbA1c se comportó como factor de riesgo para enfermedad grave y mortalidad.
... Ураження ендотеліоцитів спричиняє масивне вивільнення фактора Віллебранда, який є продуктом нормальних клітин інтими і головним кофактором для приєднання тромбоцита до матриксу. Фізичне ушкодження ендотелію призводить до підвищеної адгезії тромбоцитів [8]. Ушкоджений ендотелій зумовлює запалення, результатом якого є активація каскаду арахідонової кислоти та вивільнення тромбоксану А 2 , який також спричиняє адгезію тромбоцитів. ...
... Ушкоджений ендотелій зумовлює запалення, результатом якого є активація каскаду арахідонової кислоти та вивільнення тромбоксану А 2 , який також спричиняє адгезію тромбоцитів. Все це призводить до місцевого виснаження запасів PgI 2 , який діє на противагу тромбоксану та підсилює антикоагуляцію [8]. Запалення індукує вивільнення клітинами прозапального медіатора інтерлейкіну-6, який відіграє провідну роль у розвитку такого тяжкого ускладнення, як цитокіновий шторм [8,9]. ...
... Все це призводить до місцевого виснаження запасів PgI 2 , який діє на противагу тромбоксану та підсилює антикоагуляцію [8]. Запалення індукує вивільнення клітинами прозапального медіатора інтерлейкіну-6, який відіграє провідну роль у розвитку такого тяжкого ускладнення, як цитокіновий шторм [8,9]. У відповідь на це гемостатична система збільшує свій потенціал у бік гіперкоагуляції та інгібує фібринолітичну систему [10]. ...
Article
A well-known and dangerous complication of COVID-19 infection is the development of hypercoagulation, which leads to thrombosis of various localization. Therefore, the problem of anticoagulant therapy was widely discussed during the first months of the pandemic and continues to be relevant. At the same time, concomitant cardiac pathology is associated with a more severe course of COVID-19 and higher risks of complications and mortality. Therefore, patients who underwent cardiac surgery require special attention. Individuals with prosthetic metal heart valves must constantly receive anticoagulant therapy, however, the literature describes cases of intracardiac thrombotic complications despite anticoagulation during COVID-19 infection. Currently, there are no randomized studies on this issue, and only individual clinical cases provide this information. The aim of the work was to describe a clinical case of thrombosis at the left ventricular apex during COVID-19 infection in a patient with a prosthetic aortic valve who received adequate warfarin therapy and to compare the tactics of patient management and therapeutic outcomes with other clinical cases. Materials and methods. The patient was followed-up after aortic valve replacement for 2 years. During the visits, a general clinical examination, laboratory examinations – clinical blood test, blood glucose, urea, creatinine, bilirubin, INR, NT-proBNP, echocardiography were performed. Results. The patient with a congenital heart defect, a condition after aortic valve replacement, mitral and tricuspid valve annuloplasty (15.03.2022) due to bicuspid aortic valve, combined aortic defect with predominance of stage III-IV regurgitation; stage III secondary arterial hypertension; chronic heart failure IIA, functional class III, stage C, reduced systolic left ventricular function; a two-chamber pacemaker due to complete AV blockade; paroxysmal atrial flutter presented to a cardiologist with worsening shortness of breath and weakness one month after a moderate COVID-19 infection. The patient received bisoprolol 5 mg, amiodarone 200 mg, spironolactone 50 mg, perindopril 8 mg, warfarin 5 mg, INR was carefully controlled, at presentation – 3.7. Echocardiography revealed a left ventricular apex thrombus, a decrease in left ventricular ejection fraction (LVEF) from 46 % to 38 %. Aspirin 75 mg/day, torasemide 10 mg/day, dapagliflozin 10 mg/day, and metabolic therapy were added to the treatment. After 1 month, the patient’s condition improved, no thrombus was detected in the left ventricular cavity, LVEF increased to 46 %. Conclusions. This case demonstrates the problem of careful cardiovascular system state monitoring in patients with prosthetic valves during and after COVID-19, since symptoms of heart cavity or valve thrombosis, worsening heart failure can be mistakenly considered as signs of a viral infection or respiratory failure.
... The overlapping profiles between severe COVID-19 and MAS have led to the hypothesis that the latter may be involved in COVID-19 pathogenesis and may drive some of its serious complications including ARDS [28]. Due to a temporary virus-induced immunodeficiency state which is associated with lymphopenia and NK cell abnormalities, the underlying mechanism of MAS in COVID-19 may resemble a pHLH-like phenotype. ...
... Due to a temporary virus-induced immunodeficiency state which is associated with lymphopenia and NK cell abnormalities, the underlying mechanism of MAS in COVID-19 may resemble a pHLH-like phenotype. In contrast, a more typical MAS/sHLH presentation could be the result of an exaggerated immune response that clears the virus but induces pulmonary tissue damage and ARDS [28]. Of importance, the role of macrophages in severe COVID-19 cases is pivotal as the development of ARDS largely depends on a dysregulated macrophage activation pattern and the accumulation of activated macrophages in the lung [29,30]. ...
... In addition, the coagulation profile of COVID-19 patients differs from those with typical MAS, as indicated by the normal circulatory fibrinogen with elevated d-Dimers. Hence, these parameters may point towards pulmonary intravascular coagulopathy rather than diffuse intravascular coagulation (DIC) which is a feature of typical MAS [28,34]. ...
Article
Full-text available
Macrophage activation syndrome (MAS) is a life-threatening systemic hyperinflammatory syndrome triggered by various infections, particularly viral infections, autoimmune disorders, and malignancy. The condition is characterized by an increased production of proinflammatory cytokines resulting in a cytokine storm and has been associated with poor clinical outcomes. During the COVID-19 pandemic, patients with severe manifestations developed features similar to those of MAS, although these characteristics remained well defined within the lung. Additionally, other viral infections including EBV, the herpes family of viruses, hepatitis viruses, influenza, HIV, and hemorrhagic fevers can be complicated by MAS. The diagnosis and management of the condition remain challenging due to the lack of consensus on specific guidelines, especially among the adult population. Currently, therapeutic options primarily rely on medications that are typically used to treat primary hemophagocytic lymphohistiocytosis, such as corticosteroids and etoposide. In addition, cytokine-targeted therapies present promising treatment options. The objective of this review is to discuss the emergence of MAS in the context of viral infections including, but not limited to, its occurrence in COVID-19.
... During the study period, there were 349 children hospitalized with COVID-19 i tions. The median age of them was 8 years (IQR [3][4][5][6][7][8][9][10][11][12][13][14]. Of the hospitalized children (51.86%) were boys. ...
... During the study period, there were 349 children hospitalized with COVID-19 infections. The median age of them was 8 years (IQR [3][4][5][6][7][8][9][10][11][12][13][14]. Of the hospitalized children, 181 (51.86%) were boys. ...
... Previous studies have established significant associations between monocytes and COVID-19 severity. For instance, monocytes and macrophages have been implicated in the hyperactivation and overproduction of pro-inflammatory cytokines in severe COVID-19 cases, leading to cytokine storms and severe outcomes, including acute respiratory distress syndrome (ARDS) [12]. In addition, monocytes are recognized for their ability to infiltrate the lungs, thereby contributing to tissue damage and fibrosis. ...
Article
Full-text available
The COVID-19 pandemic, caused by SARS-CoV-2, has posed significant health challenges worldwide. While children generally experience less severe illness compared to adults, pneumonia remains a substantial risk, particularly for those under five years old. This study examines the clinical characteristics and treatment outcomes of pediatric COVID-19 pneumonia patients treated with favipiravir in Thailand, aiming to identify associated factors for pneumonia. A retrospective review was performed on pediatric patients aged 1 month to 18 years hospitalized with COVID-19 at Srinagarind Hospital, Khon Kaen University, from 13 January 2020 to 15 November 2021. Data on demographics, clinical symptoms, treatment, and outcomes were collected, and logistic regression analysis was used to identify factors associated with pneumonia. Among 349 hospitalized children, the median age was 8 years, with 51.9% being male. Symptoms included a fever (100%), a cough (74.2%), and a rash (24.9%). COVID-19 pneumonia was diagnosed in 54.7% of the children. Favipiravir was administered as the standard treatment, showing mild adverse effects, including a rash (4.3%) and nausea (2.8%). Monocytosis was significantly associated with COVID-19 pneumonia (aOR 30.85, 95% CI: 9.03–105.41, p < 0.001), with an ROC curve area of 0.77 (95% CI: 0.71–0.83). Pediatric COVID-19 patients typically exhibit mild-to-moderate symptoms, with pneumonia being common in the early pandemic phase. Monocytosis is a significant factor associated with COVID-19 pneumonia. Favipiravir demonstrated mild adverse effects. Further studies are needed to validate these findings across different settings and phases of the pandemic.
... COVID-19 is also characterized by a cytokine storm, and patients with severe COVID-19 exhibit drastically elevated levels of proinflammatory cytokines such as IL-6, IL-1 beta (IL-1β), IL-17, and TNF-α [58]. Cytokine storms may lead to extensive pulmonary pathology and numerous complications, such as shock and tissue damage in vital organs, as well as multiple organ failure [8,47]. ...
... This leads to an increase in TNF-α and IL-6, which can be attributed to the promotion of translation and stability of their mRNAs [99]. IL-6 is a critical proinflammatory factor that causes cytokine storms in COVID-19 [58,90]. It is also upregulated to recruit neutrophils through enzymatic activation, subsequently activating the NF-κB signaling pathway in inflammatory diseases [100]. ...
Article
Full-text available
Background Coronavirus disease 2019 (COVID‐19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), is a major concern due to its astonishing prevalence and high fatality rate, especially among elderly people. Patients suffering from COVID‐19 may exhibit immunosuppression in the initial stage of infection, while a cytokine storm can occur when the disease progresses to a severe stage. This inopportune immune rhythm not only makes patients more susceptible to the virus but also leads to numerous complications resulting from the excessive production of inflammatory factors. A20, which is widely accepted as a pivotal regulator of inflammation, has been shown to be implicated in the processes of antiviral responses and immunosuppression. Thus, A20 may participate in regulating the pathological processes of COVID‐19. Methods This narrative literature review summarizes recent evidence on the mechanisms of A20 in regulating the pathological processes of COVID‐19. We also downloaded single‐cell RNA‐seq data sets from healthy individuals and patients with varying severities of COVID‐19 from the NCBI GEO database to further dissect A20's regulatory mechanisms of these intricate cytokine pathways that are closely associated with SARS‐CoV‐2 infection. Results A20 might be one of the most critical anti‐infectious and anti‐inflammatory factors involved in the pathogenesis of COVID‐19. It effectively suppresses the immune damage and inflammatory storm caused by viral infection. Conclusions Understanding the relationship between A20‐regulated signaling pathways and pathological processes of COVID‐19 can provide insight into potential targets for intervention. Precise regulation of A20 to induce antiviral activity and an anti‐inflammatory response could mediate the pathogenesis of COVID‐19 and could become an effective treatment.
... Before initiating therapy, a range of markers characterising the patients' condition were assessed: ferritin levels (by quantitative immunoturbidimetric method) [12], interleukin-6 (IL-6) (by electrochemiluminescent immunoassay) [13], and C-reactive protein (CRP) (by solid-phase immunometric analysis) [14]. The levels of D-dimer [15] and procalcitonin (by immunochemical method with electrochemiluminescent detection) [16] were also measured. ...
... Although the risk of death in the first group was lower, the use of thrombolysis in the second group offset this difference. Thrombi in one of the right chambers of the heart, combined with PE, were found in 489% of PE patients (45 patients), which is 2.7 times higher than the prevalence of right heart thrombi in non-COV-ID-related PE cases [13]. This is likely attributable to the presence of COVID-19. ...
Article
Full-text available
Current research provides insufficient data on the use of thrombolytic therapy in the treatment of pulmonary embolism in patients with COVID-19. Existing studies present data on the efficacy of thrombolytic drug therapy for thrombotic complications in severe COVID-19. However, these studies either involve a very small number of observations or remain incomplete. This article aimed to assess systemic thrombolysis’s effectiveness in intravenous alteplase administration in this pathology. The medical records of 92 patients were analysed. Patients were divided into four groups depending on the therapy administered. Patients in the first group had complications in the form of pulmonary embolism but did not require thrombolytic therapy. Treatment of patients in the first group consisted of prescribing low-molecular-weight heparin at a therapeutic dose. Patients in the second and third groups had pulmonary embolism in the context of COVID-19 and required thrombolytic therapy. The third group differed from the second in the presence of a thrombus in the right heart. Patients in the fourth group had complications in the form of pulmonary embolism, and required thrombolytic therapy, but did not receive it due to a lack of funds. Patients in the second and third groups were immediately treated with unfractionated heparin and alteplase. Thrombolysis was not performed in the fourth group. Mortality rates were studied according to the assigned group. It was established that the risk of death increased (p<0.001) with increasing levels of D-dimer and decreased with increasing PaO2/FiO2 (p < 0.001). In the presence of a thrombus in the right heart chambers, the risk of death increased (p = 0.002), OR = 3.97 (95% CI 1.66-9.49). A trend towards reducing death risk with thrombolytic therapy was observed (p = 0.052). Data were summarised regarding the increased (p = 0.009) risk of death when thrombolytic therapy was delayed. Mortality in the fourth group was 100%. The obtained data indicate the significant effectiveness of thrombolytic therapy in the treatment of this pathology
... CRP and IL -6 were increased in this hyper-inflammatory state which are associated with ARDS and death . (6) IL-6 usually increases the permeability of pulmonary vasculature with developing pulmonary edema and ARDS and also initiate the coagulation cascade with developing micro-thrombi in pulmonary vasulature with developing pulmonary embolism which may be massive. (6) The level of IL-6 > 12.6 pg/mL at medical presentation had excellent sensitivity and good specificity and usually predicted the occurence of hypoxia demanding hospital admission better in ICU . ...
... (6) IL-6 usually increases the permeability of pulmonary vasculature with developing pulmonary edema and ARDS and also initiate the coagulation cascade with developing micro-thrombi in pulmonary vasulature with developing pulmonary embolism which may be massive. (6) The level of IL-6 > 12.6 pg/mL at medical presentation had excellent sensitivity and good specificity and usually predicted the occurence of hypoxia demanding hospital admission better in ICU . so , IL-6 is an important factor for the occurrence of the severe pulmonary infection that needs immediate early intervention for saving lives. ...
... Treatment modalities for MALS encompass immunosuppressive pharmacological agents, cytokine targeted therapy, blood exchange, among others [64][65][66][67][68]. Can the treatment methods used for MALS in other diseases be applied to sepsis patients with MALS in order to enhance their prognosis? ...
... Given the potentially grave consequences associated with this disease, timely identification assumes paramount significance. The diagnostic scoring criteria for MALS were established based on various clinical manifestations, such as fever, hepatosplenomegaly, hyperferritinemia, hepatopathy, coagulopathy, thrombocytopenia, hypertriglyceridemia, decrease in erythrocyte sedimentation rate and bone marrow hemophagocytosis [67,82]. The widely acknowledged diagnostic and identification standards for sHLH/ MALS encompass the HLH-2004 criteria, published by the Histiocyte Society in 2007 [83], and the HScore, proposed by Laurence Fardet et al. in 2014 [84]. ...
Article
Full-text available
Background Sepsis represents a significant global health and hygiene challenge. Excessive activation of macrophages in sepsis can result in certain patients displaying characteristics akin to those observed in Macrophage Activation Syndrome (MAS). MAS represents a grave immune system disorder characterized by persistent and severe inflammation within the body. In the context of sepsis, MAS presents atypically, leading some researchers to refer to it as Macrophage Activation-Like Syndrome (MALS). However, there are currently no effective treatment measures for this situation. The purpose of this article is to explore potential treatment methods for sepsis-associated MALS. Objective The objective of this review is to synthesize the specific pathophysiological mechanisms and treatment strategies of MAS to investigate potential therapeutic approaches for sepsis-associated MALS. Method We searched major databases (including PubMed, Web of Science, and Google Scholar etc.) for literature encompassing macrophage activation syndrome and sepsis up to Mar 2024 and combined with studies found in the reference lists of the included studies. Conclusion We have synthesized the underlying pathophysiological mechanism of MALS in sepsis, and then summarized the diagnostic criteria and the effects of various treatment modalities utilized in patients with MAS or MALS. In both scenarios, heterogeneous treatment responses resulting from identical treatment approaches were observed. The determination of whether the patient is genuinely experiencing MALS significantly impacts the ultimate outcomes of therapeutic efficacy. In order to tackle this concern, additional clinical trials and research endeavors are imperative.
... COVID-19 has been recognised to cause a cytokine cause storm from an imbalance between T helper (Th)1 and Th2 cells resulting in increased levels of interferon gamma and cytokine release such as ILs (1-b, 2, 6, and 7) [20]. It has been postulated that this cytokine storm dysregulates the ryanodine receptors, disrupting the transfer of calcium into cardiomyocytes, thus creating a proarrhythmic environment [21]. ...
... It has been postulated that this cytokine storm dysregulates the ryanodine receptors, disrupting the transfer of calcium into cardiomyocytes, thus creating a proarrhythmic environment [21]. Inflammatory cytokines known to be upregulated in COVID-19, such as TNF-alpha, IL-1, and IL-6, have been demonstrated to exhibit arrhythmogenic effects through complex interactions between potassium and calcium channels [20]. IL-6 induces structural remodelling, which can result in QTc prolongation, thus increasing the risk of sudden cardiac death [18,22]. ...
... Patients with severe and fatal COVID-19-associated pneumonia may show disproportionately high signs of systemic hyper-inflammation with cytokine storm, also known as hemophagocytic lymphohistiocytosis (HLH) [1][2][3][4]. In principle, HLH is a hyperinflammatory condition divided into a primary (familial) or secondary variant (sHLH) when associated with triggers including viral infections, certain chemotherapies or malignancies [5]. ...
... Typically, in the severe course of the disease, there is pronounced activation and dysregulation of the immune system with significantly increased levels of pro-inflammatory cytokines with inhomogeneous behavior of leukocytes, with an increase in the number of neutrophil granulocytes and a decrease in lymphocytes. The hyperferritinemia observed in SARS-CoV-2 with a pronounced increase in IL-6 is considered as a reliable indicator of uncontrolled activation of macrophages and the manifestation of sHLH [2]. ...
Article
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In systemic hyper-inflammation, as in severe COVID-19 disease, there are pronounced disorders of the hematological and lymphatic systems with prognostically relevant hemophagocytosis of the bone marrow. The current work aimed to address the importance of hemophagocytosis in the lymph nodes of patients with severe COVID-19 disease. From 28 patients who died of severe COVID-19 infection, samples of the vertebral bone marrow and lymph nodes from the cervical, hilar, para-aortic, mesenteric and inguinal locations were morphologically and immunohistologically (CD163, CD68, CD61, CD71, CD3, CD20, CD138) examined for the possible presence of hemophagocytosis. In the single-center study at the University Hospital Jena, a total of 191 hemophagocytes were found in the bone marrow and a total of 780 hemophagocytes in the lymph nodes in a standardized area of 21,924 mm2 per tissue sample. With 370 hemophagocytes, hilar lymph nodes were most frequently affected (370/780; 47.44%; 95%-CI: [43.94, 50.95]), followed by cervical lymph nodes (206/780; 26.41%; 95%-CI: [23.41, 29.59]), para-aortic lymph nodes (125/780; 16.03%; 95%-CI: [13.58, 18.73]) and inguinal/mesenteric lymph nodes (79/780; 10.13%; 95%-CI: [8.155, 12.4]). Based on the standard area (21,924 mm2), the difference in the number of hemophagocytes in the bone marrow and in the hilar lymph nodes was statistically significant (p < 0.05), while this did not apply to the lymph nodes from the other locations. In fatal COVID-19 disease, hemophagocytosis is particularly found in the hilar lymph nodes and is therefore a better indicator of the severity of the disease than hemophagocytosis in the bone marrow. The findings provide some evidence for the concept of compartmentalized human host responses to life-threatening infections.
... Given the fact that IL-6 is a key mediator of the ʺcytokine stormʺ that leads to acute respiratory distress syndrome (ARDS) and multi-organ dysfunction in severe COVID-19 [14], it is assumable that such distribution of tRF types may be due the condition the patient underwent. Other cell types did not exhibit any significant alterations in tRF composition. ...
... 14 and types of these molecules in main blood cell populations. We additionally observed a significant change in the profile of tRFs in the erythrocytes, monocytes and lymphocytes of patients infected with SARS-CoV-2. ...
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tRNA-derived fragments function as markers additionally to playing the role key of signalling molecules in a number of disorders. It is known that the repertoire of these molecules differs greatly in different cell types and varies depending on the physiological condition. The aim of our research was to compare the pattern of tRF expression in the main blood cell types and to determine how the composition of these molecules changes during COVID-19-induced cytokine storm. Erythrocytes, monocytes, lymphocytes, neutrophils, basophils, and eosinophils from control donors and patients with severe COVID-19 were obtained by fluorescence sorting. We extracted RNA from FACS sorted cells and performed NGS of short RNAs. The composition of tRNA-derived fragments was analysed applying a semi-custom bioinformatic pipeline. In this study, we assessed the length and type distribution of TRFs and reported the 150 most prevalent TRF sequences across all cell types. Additionally we demonstrate a significant (p<0.05, fold change>16) change in the pattern of tRFs in erythrocytes (21 downregulated, 12 upregulated), monocytes (53 downregulated, 38 upregulated) and lymphocytes (49 upregulated) in patients with severe COVID-19. Thus, different blood cell types exhibit a significant variety of TRFs and react to cytokine storm by dramatically changing their differential expression patterns. We suppose that the observed phenomenon occurs due to the regulation of nucleotide modifications and alterations in activity of various Rnases.
... Known virally induced hypercoagulable states are characterized by microvascular and macrovascular thrombotic angiopathies 2,4,5 . In severe cases of infection, the association of systemic hyperinflammation and proinflammatory cytokines have been found as contributory toward the elevated risk of developing intravascular coagulopathy 6,7 . With thrombotic occlusion, a decrease in peripheral perfusion can threaten viability and compromise arterial integrity 5,8,9 . ...
Article
Case: We present a 42-year-old man who developed extensive left lower extremity arterial thrombosis following COVID-19 pneumonia. Despite multiple revascularization attempts and a below-knee amputation, he faced wound necrosis and insufficient soft tissue coverage. An innovative approach using a pedicled flap and sequential flow-through free flaps was used for limb salvage. Further interventions included through-knee amputation and targeted muscle reinnervation vs. nerve capping to address phantom limb pain. Conclusion: This case demonstrates the potential of sequential flow-through free flaps in complex limb salvage when traditional revascularization is unfeasible, emphasizing early intervention and vigilant complication management.
... Indeed, cytokine storm is strongly connected with pulmonary inflammation and multiple organ failure in COVID-19 infection [59][60][61]. Indeed, IL-6 has been frequently documented to be a central mediator of COVID-19-induced cytokine storm [60,62,63]. Notably, IL-6 has also been reported to be dramatically high in people with COPD [64], where it is shown to be a significant predictor of acute exacerbation of COPD [65]. ...
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Purpose of the Review Mounting evidence indicates that individuals with chronic obstructive pulmonary disease (COPD) face a heightened risk of severe outcomes upon contracting coronavirus disease 2019 (COVID-19). Current medications for COVID-19 often carry side effects, necessitating alternative therapies with improved tolerance. This review explores the biological mechanisms rendering COPD patients more susceptible to severe COVID-19 and investigates the potential of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in mitigating the severity of COVID-19 in COPD patients. Recent Findings Current evidence indicates that COPD patients are at an increased risk of severe COVID-19 due to factors including compromised pulmonary function, dysregulated inflammation, weakened immune response, increased oxidative stress, elevated expression of angiotensin-converting enzyme (ACE2) receptors in the lungs, and genetic predispositions. Remarkably, n-3 PUFAs exhibit the potential in ameliorating the clinical outcomes of COPD patients with COVID-19 by modulating inflammation, reinforcing the body's antioxidant defenses, reducing viral entry and replication, and enhancing immunity. Summary N-3 PUFAs hold potential for improving COVID-19 outcomes in patients with COPD. However, there has been limited investigation into the therapeutic effects of n-3 PUFAs in enhancing clinical outcomes for COPD patients. Rigorous clinical studies are essential to evaluate the impact of n-3 PUFAs on COPD patients with concurrent COVID-19 infection.
... hIL-6 transmits signals within cells by binding to either its specific receptor, IL-6Rα, or a natural soluble form of this receptor, sIL-6Rα to form a binary complex that binds to the ubiquitously expressed glycoprotein coreceptor gp130, also referred to as IL-6R [1,2]. Signal in severe instances of COVID-19, where it is a vital mediator of the cytokine storm syndrome that can lead to adult respiratory distress syndrome (ARDS) [11]. Thus, hIL-6 has been implicated in the pathophysiology of multiple diseases and this makes it an important therapeutic target. ...
Preprint
Human Interleukin-6 (hIL-6) is a pro inflammatory cytokine that binds to its receptor, IL-6Rα followed by binding to gp130 and subsequent dimerization to form a hexamer signaling complex. A critical inflammation mediator, hIL-6 is associated with a diverse range of diseases and monoclonal antibodies are in clinical use that either target IL-6Rα or hIL-6 to inhibit signaling. Here, we perform high throughput structure-based computational screening using ensemble docking for small molecule antagonists for which the target conformations were taken from 600 ns long molecular dynamics simulations of the apo protein. Prior knowledge of the contact sites from binary complex studies and experimental work was incorporated into the docking studies. The top 20 scored ligands from the in silico studies after post analysis were subjected to in vitro functional assays. Among these compounds, the ligand with second-highest calculated binding affinity showed experimentally ~84% inhibitory effect on IL6-induced STAT3 reporter activity at 10-5 molar concentration. This finding may pave the way for designing small molecule inhibitors of hIL-6 of therapeutic significance.
... 5 6 This finding suggests that fatal COVID-19 may involve a cytokine release syndrome triggered by a cytokine storm, with IL-6 playing a critical role. [7][8][9] There remains an ongoing debate about the reliability of serum IL-6 levels in accurately assessing the severity of COVID-19 and predicting mortality risk. [10][11][12][13][14][15][16] According to a previous study, the initial level of serum IL-6 can effectively predict the risk of death in the hospital for patients with COVID-19. ...
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Objectives To investigate the serum IL-6 levels and their rate of change in predicting the mortality of critically ill patients with COVID-19 in Vietnam. Design A single-centre, cross-sectional study. Setting An Intensive Care Centre for the Treatment of Critically Ill Patients with COVID-19 in Ho Chi Minh City, Vietnam. Participants We included patients aged 18 years or older who were critically ill with COVID-19 and presented to the study centre from 30 July 2021 to 15 October 2021. We excluded patients who did not have serum IL-6 measurements between admission and the end of the first day. Primary outcome measures The primary outcome was hospital all-cause mortality. Results Of 90 patients, 41.1% were men, the median age was 60.5 years (Q1–Q3: 52.0–71.0), and 76.7% of patients died in the hospital. Elevated IL-6 levels were observed on admission (41.79 pg/mL; Q1–Q3: 20.68–106.27) and on the third day after admission (72.00 pg/mL; Q1–Q3: 26.98–186.50), along with a significant rate of change in IL-6 during that period (839.5%; SD: 2753.2). While admission IL-6 level (areas under the receiver operator characteristic curve (AUROC): 0.610 (95% CI: 0.459 to 0.761); cut-off value ≥15.8 pg/mL) and rate of change in IL-6 on the third day of admission (AUROC: 0.586 (95% CI: 0.420 to 0.751); cut-off value ≥−58.7%) demonstrated poor discriminatory ability in predicting hospital mortality, the third day IL-6 rate of change from admission ≥−58.7% (adjusted OR: 12.812; 95% CI: 2.104 to 78.005) emerged as an independent predictor of hospital mortality. Conclusions This study focused on a highly selected cohort of critically ill COVID-19 patients with a high IL-6 level and mortality rate. Despite the poor discriminatory value of admission IL-6 levels, the rate of change in IL-6 proved valuable in predicting mortality. To identify critically ill COVID-19 patients with the highest risk for mortality, monitoring the serial serum IL-6 measurements and observing the rate of change in serum IL-6 levels over time are needed.
... Interestingly, our models posit that GROa, IL-1R antagonist, and IL-6 may contribute agedependent effects, and this is supported by prior studies as older age modulates expression of these cytokines (74,75). This is compatible with high inflammatory markers, cytotoxic immune cells, and macrophages as key players in the second week of illness during severe COVID-19 (23,73,76). ...
Article
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Introduction Dysregulated host cytokine responses to SARS-CoV-2 infection are a primary cause of progression to severe disease, whereas early neutralizing antibody responses are considered protective. However, there are gaps in understanding the early temporal dynamics of these immune responses, and the profile of productive immune responses generated by non-hospitalized people with mild infections in the community. Methods Here we conducted a prospective cohort study of people with suspected infections/exposures in the US state of North Carolina, before vaccine availability. We recruited participants not only in hospitals/clinics, but also in their homes. With serial sampling, we compared virologic and immunologic factors in 258 community cases versus 114 hospital cases of COVID-19 to define factors associated with severity. Results We found that high early neutralizing antibodies were associated with lower nasal viral load, but not protection from hospitalization. Cytokine responses were evaluated in 125 cases, with subsets at first versus second week of illness to assess for time-dependent trajectories. The hospital group demonstrated a higher magnitude of serum IL-6, IL-1R antagonist, IP-10, and MIG; prolonged upregulation of IL-17; and lesser downregulation of GROα, IL-1R antagonist, and MCP1, in comparison to the community group suggesting that these factors may contribute to immunopathology. In the second week of illness, 2-fold increases in IL-6, IL-1R antagonist, and IP-10 were associated with 2.2, 1.8, and 10-fold higher odds of hospitalization respectively, whereas a 2-fold increase in IL-10 was associated with 63% reduction in odds of hospitalization (p<0.05). Moreover, antibody responses at 3-6 months post mild SARS-CoV-2 infections in the community revealed long-lasting antiviral IgM and IgA antibodies as well as a stable set point of neutralizing antibodies that were not waning. Discussion Our data provide valuable temporal cytokine benchmarks to track the progression of immunopathology in COVID-19 patients and guide improvements in immunotherapies.
... Although the exact mechanisms by which IL-6 contributes to liver injury are not fully understood, it is believed that the cytokine storm, systemic inflammation, and viral load directly affect hepatocytes. Monitoring IL-6, in conjunction with liver enzymes, can help assess liver involvement and predict patient prognosis [21][22]. ...
... Te recent analysis reported excessive certain cytokines production, including IL-6, can develop into the primary cause of infammatory response. Terefore, antiinfammatory therapy may be a promising intervention for COVID-19-related pneumonia [3,11]. ...
Article
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Coronavirus disease-19 (COVID-19) is correlated to a severe condition caused by a cytokine storm during which numerous proinflammatory cytokines, including interleukin-6 (IL-6) are released. IL-6 is a critical driver in the COVID-19 inflammatory state, and the inhibition is considered a potential treatment approach to prevent serious complications. Meanwhile, Melaleuca cajuputi is a plant with antibacterial, antiviral, anti-inflammatory, and antioxidant activities. Therefore, this aimed to investigate the anti-inflammatory potential of M. cajuputi in silico. Extraction of leaves was conducted by using 96% ethanol, followed by fractionation to obtain active compounds. Subsequently, LC/MS and GC/MS analyses were performed to obtain active compound profiling. Protein-protein interaction (PPI), as well as molecular docking and dynamic analyses, were performed to examine interaction of active compounds of M. cajuputi with IL-6. The results showed that 30 protein nodes played a significant role in COVID-19 cytokine storm and eight active compounds had interactions with IL-6. Among the active compounds, pinostrobin chalcone had the best delta G interaction with IL-6. In conclusion, M. cajuputi has potential activity as an anti-inflammatory agent against COVID-19.
... [6][7][8] Microvascular thrombosis leading to multiorgan dysfunction is presumed to be a major driver of mortality, as evidenced by disproportionately elevated D-dimer in nonsurvivors. [9] However, larger studies comprehensively evaluating the clinical, laboratory, and management factors affecting mortality are needed. ...
Article
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A BSTRACT Background Older age and comorbidities are associated with adverse outcomes in patients with coronavirus disease 2019 (COVID-19); however, comprehensive identification of mortality risk factors can further guide disease management. We aimed to analyze predictors of in-hospital mortality in hospitalized COVID-19 patients. Methods This retrospective cohort study included 400 COVID-19 patients admitted between March and December 2020. Demographics, vital signs, medical history, presenting symptoms, laboratory findings, treatments, and outcomes were extracted from the patient’s electronic medical records. Patients were stratified into survivor (n = 300) and nonsurvivor (n = 100) groups. Univariate and multivariate logistic regressions were used to analyze associations between variables and mortality. Results Nonsurvivors were older (mean age 65 vs 45 years) and had more hypertension (60% vs 33%), diabetes (40% vs 20%), chronic obstructive pulmonary disease (20% vs 5%), and chronic kidney disease (15% vs 3%). Shorter symptom onset to admission (7 vs 4 days), lower oxygen saturation (92% vs 96%), lymphopenia, and elevated inflammatory and coagulation markers were also associated with mortality (all P < 0.001). Mechanical ventilation (60% vs 3%) and therapeutic anticoagulation were more common in nonsurvivors (all P < 0.001). Age over 75 years (adjusted odds ratio 5.2), chronic medical conditions, elevated D-dimer, and mechanical ventilation had the strongest independent associations with mortality ( P < 0.001). Conclusions Older age, comorbidities such as chronic pulmonary and renal disease, disease severity parameters such as dysregulated inflammatory and coagulation markers, and the need for aggressive interventions predict increased mortality risk in hospitalized COVID-19 patients.
... Given the fact that IL-6 is a key mediator of the "cytokine storm" that leads to acute respiratory distress syndrome (ARDS) and multi-organ dysfunction in severe COVID-19 [14], it can be assumed that such a distribution of tRF types may be due to the condition the patient underwent. Other cell types did not exhibit any significant alterations in tRF composition. ...
Article
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tRNA-derived fragments function as markers in addition to playing the key role of signalling molecules in a number of disorders. It is known that the repertoire of these molecules differs greatly in different cell types and varies depending on the physiological condition. The aim of our research was to compare the pattern of tRF expression in the main blood cell types and to determine how the composition of these molecules changes during COVID-19-induced cytokine storms. Erythrocytes, monocytes, lymphocytes, neutrophils, basophils and eosinophils from control donors and patients with severe COVID-19 were obtained by fluorescence sorting. We extracted RNA from FACS-sorted cells and performed NGS of short RNAs. The composition of tRNA-derived fragments was analysed by applying a semi-custom bioinformatic pipeline. In this study, we assessed the length and type distribution of tRFs and reported the 150 most prevalent tRF sequences across all cell types. Additionally, we demonstrated a significant (p < 0.05, fold change >16) change in the pattern of tRFs in erythrocytes (21 downregulated, 12 upregulated), monocytes (53 downregulated, 38 upregulated) and lymphocytes (49 upregulated) in patients with severe COVID-19. Thus, different blood cell types exhibit a significant variety of tRFs and react to the cytokine storm by dramatically changing their differential expression patterns. We suppose that the observed phenomenon occurs due to the regulation of nucleotide modifications and alterations in activity of various Rnases.
... The first is related to virus replication, which leads to pyroptosis, a highly inflammatory form of lytic-programmed cell death (apoptosis). In patients with COVID-19, pyroptosis triggers the release of proinflammatory cytokines and affects macrophage and lymphocyte functions, causing peripheral lymphopenia (McGonagle et al. 2020;Tavakolpour et al. 2020). ...
Article
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The cytokine storm has been identified as one of the leading causes of the severe course and, in some cases, the fatal outcome of COVID-19 infection. Other factors aggravating the course of the disease are accompanying disorders such as cardiovascular diseases, diabetes mellitus, diseases of the respiratory system, and oncological diseases. In this article, we present the course of the coronavirus infection in patients with an accompanying malignant disease, chronic lymphocytic leukemia (CLL), namely. The study included 8 patients with proven PCR-positive tests for SARS-CoV2 and confirmed chronic lymphocytic leukemia as a comorbidity. The course of the coronavirus infection in the CLL group was compared with that in the control group of 100 patients. In both groups, we compared subjective complaints such as tiredness, fatigue, and joint and muscle pain with objective criteria such as temperature, laboratory markers of inflammation, X-ray imaging, and frequency of necessary intubation. Despite the expected poor prognosis in patients with concomitant oncological disease, in the case of chronic lymphocytic leukemia, our results showed a quite different milder coronavirus infection course. Obviously, patients with CLL cannot develop a pronounced cytokine storm, most probably due to certain immunosuppression related to the pathogenesis and drug treatment options for the comorbidity of CLL.
... These logics serve as an institutional basis for organizations, guiding or offering standards for the decision-making process and providing meaning about organizational reality (Chen et al., 2020;McGonagle et al., 2020). ...
Article
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Objective: The objective of this study is to investigate the impact of the COVID-19 pandemic on religious tourism in Aparecida do Norte, aiming to understand the challenges and opportunities generated by the crisis and propose strategies for the sector's recovery and adaptation. Theoretical Framework: The theory of institutional logics is highlighted, providing a solid foundation for understanding the social and institutional dynamics that permeate religious tourism. Method: The methodology adopted for this research includes a qualitative approach, comprising a local technical visit, semi-structured interviews with key actors, and document analysis. Data collection was carried out through direct observation, interviews, and the gathering of official documents. Results and Discussion: The results revealed the existence of conflicting institutional logics among the main agents involved in religious tourism in Aparecida do Norte. In the discussion section, these results are contextualized in light of the theory of institutional logics, highlighting the need for institutional reconfiguration to ensure the sector's sustainability and resilience. Research Implications: The practical and theoretical implications of this research are discussed, providing insights on how the results can be applied to revitalize the local economy, strengthen institutional articulation, and promote sustainable tourism in Aparecida do Norte. These implications encompass social, economic, and management areas. Originality/Value: This study contributes to the literature by using the theory of institutional logics to analyze the impact of the pandemic on religious tourism. The relevance and value of this research are evidenced by offering a theoretical proposition that supports the construction of strategies aimed at the sustainability of the local tourism ecosystem in the post-pandemic context.
... Overall, SIAD has been described as one of the main causes of hyponatremia in COVID-19 infection. Nonosmotically induced AVP secretion appears to be stimulated by pro-inflammatory cytokines released by monocytes and macrophages from infected patients [37][38][39]. Among these, IL-6 is a known factor that can induce AVP secretion, thus causing SIAD [40,41]. ...
Article
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Hyponatremia is the most frequent electrolyte alteration among hospitalized patients and it has been reported in 20–40% of patients with SARS-CoV-2 (COVID-19) infection. Multiple causes of hyponatremia have been hypothesized in these patients. The syndrome of inappropriate antidiuresis (SIAD) has been considered one of the main reasons leading to hyponatremia in this condition. SIAD can be secondary to cytokines release, in particular IL-6. Positive pressure ventilation can be another cause of hyponatremia due to SIAD. Other possible etiologies of hyponatremia in COVID-19 patients can be related to secondary hypocortisolism, nausea, vomiting, heart and kidney damage. Similar to many other clinical conditions, there is strong evidence that hyponatremia is associated with a worse prognosis also in patients with COVID-19 infection. In particular, hyponatremia has been identified as an independent risk of ICU transfer, need of non-invasive ventilation and death. Hyponatremia in COVID-19 patients is in principle acute and symptomatic and should be treated as such, according to the published guidelines. Therefore, patients should be initially treated with i.v. hypertonic saline (3% NaCl) infusion and serum [Na⁺] should be frequently monitored, in order to remain within a safe rate of correction. There is evidence showing that serum [Na⁺] correction is associated with a better outcome in different pathologies, including COVID-19 infection.
... In the case of COVID-19 patients with a critical disease course, it must be taken into account that some of them show signs of cytokine release syndrome (CRS) or macrophage activation syndrome (MAS) [51,52]. A secondary effect of CAP treatment is the release of pro-inflammatory cytokines, which could exacerbate CRS and MAS. ...
Article
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Cold atmospheric plasma (CAP) devices generate reactive oxygen and nitrogen species, have antimicrobial and antiviral properties, but also affect the molecular and cellular mechanisms of eukaryotic cells. The aim of this study is to investigate CAP treatment in the upper respiratory tract (URT) to reduce the incidence of ventilator-associated bacterial pneumonia (especially superinfections with multi-resistant pathogens) or viral infections (e.g., COVID-19). For this purpose, the surface-microdischarge-based plasma intensive care (PIC) device was developed by terraplasma medical GmbH. This study analyzes the safety aspects using in vitro assays and molecular characterization of human oral keratinocytes (hOK), human bronchial–tracheal epithelial cells (hBTE), and human lung fibroblasts (hLF). A 5 min CAP treatment with the PIC device at the “throat” and “subglottis” positions in the URT model did not show any significant differences from the untreated control (ctrl.) and the corresponding pressurized air (PA) treatment in terms of cell morphology, viability, apoptosis, DNA damage, and migration. However, pro-inflammatory cytokines (MCP-1, IL-6, and TNFα) were induced in hBTE and hOK cells and profibrotic molecules (collagen-I, FKBP10, and αSMA) in hLF at the mRNA level. The use of CAP in the oropharynx may make an important contribution to the recovery of intensive care patients. The results indicate that a 5 min CAP treatment in the URT with the PIC device does not cause any cell damage. The extent to which immune cell activation is induced and whether it has long-term effects on the organism need to be carefully examined in follow-up studies in vivo.
... T cells can act through CD4+ cells, helping in the development of immune response and tissue repair, or through CD8+ T cells that kill infected cells. B cells produce antibodies that attempt to counteract the virulent potential of the pathogen [3][4][5]. Dysregulation in immune response leads to cytokine release syndrome (CRS). Scientific data imply that patients with comorbidities, particularly obesity, defined as body mass index (BMI) ≥ 30 kg/m 2 , are at a greater risk of severe course of the disease and lethal complications [6][7][8]. ...
Article
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Objective: The COVID-19 pandemic has posed significant global health challenges. Despite extensive research efforts, the inflammatory response triggered by SARS-CoV-2 remains to be further explored and understood. Our study aims to examine the changes in serum concentrations of pro-inflammatory adipokines—visfatin and leptin—in COVID-19 patients in relation to a healthy control group. Patients/Materials/Subjects and Methods: The study consisted of forty COVID-19 patients and twenty-four healthy patients in the control group. Two serum samples were collected: upon admission and on the seventh day of hospitalization. Concentrations of visfatin and leptin in the serum, alongside routine biochemical parameters, were measured using enzyme immunoassay or enzyme-linked immunosorbent assay kits. The Shapiro–Wilk test was used to assess normality. Differences between independent groups were compared using the Mann–Whitney U test and Kruskal–Wallis ANOVA. Correlations were evaluated with Spearman’s rank correlation coefficient. Results: Our findings revealed significantly lower visfatin levels in COVID-19 patients compared to the control group upon admission (4.29 ng/mL, (3.0–6.88 ng/mL) vs. 37.16 ng/mL (24.74–50.12 ng/mL), p < 0.001 for visfatin 1 and 52.05 ng/mL, (31.2–69.66 ng/mL) vs. 37.16 ng/mL (24.74–50.12 ng/mL), p = 0.048 for visfatin 2). The visfatin level of COVID-19 patients returned to the normal levels, established in the control group. However, there was no significant difference in leptin levels between the two groups (p = 0.270 for leptin 1 and p = 0.129 for leptin 2). There was a positive correlation between BMI and leptin concentration (r = 0.66 and p = 0.00). Moreover, it was discovered that COVID-19 independently reduces visfatin levels during the first day of illness. Conclusions: The results of our research suggest that the onset of COVID-19 infection is correlated to visfatin levels. Association with leptin levels remains inconclusive. Further research is imperative to elucidate the intricate role of visfatin and leptin in SARS-CoV-2 infection and their potential as biomarkers for COVID-19 severity and prognosis.
... problem of respiratory failure in pneumonia caused by COVID-19 and to preserve the maximum volume of lung tissue. Hence the conclusion of specialists: to save seriously ill patients, it is necessary (in accordance with approved treatment protocols) to use various combinations of medications, with constant monitoring of the level of oxygen in blood (saturation), in the case of oxygen starvation of the body, connect the patient to oxygen supply devices [24]. In the fight against COVID-19 infection, all possible treatment methods must be considered based on the complex pathophysiology of this viral infection. ...
Article
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... [4,5,[8][9][10] This likely reflects excess inflammation and a cytokine storm triggered by SARS-CoV-2 infection, more pronounced in severe disease. [11] Notably, we identified an elevated neutrophil-to-lymphocyte ratio (NLR) as an independent predictor of fever status. NLR >4 was associated with a 4-fold higher odds of fever. ...
Article
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A BSTRACT Background Laboratory markers like lymphopenia, thrombocytopenia, elevated D-dimer, and C-reactive protein (CRP) predict worse outcomes in coronavirus disease 2019 (COVID-19). However, a comprehensive analysis of hematologic and coagulation parameter alterations based on fever status is lacking. Methods This retrospective study analyzed 300 COVID-19 patients hospitalized from March to December 2020. Demographic, clinical, and laboratory data were extracted from electronic medical records. Patients were stratified into fever (n = 200) and no fever (n = 100) groups. Hematologic, coagulation, and inflammatory markers were compared between groups using appropriate statistical tests. Multivariate regression identified independent predictors of fever. Results Fever was associated with leukocytosis, neutrophilia, lymphopenia, thrombocytopenia, elevated CRP, D-dimer, procalcitonin, interleukin-6, neutrophil to lymphocyte ratio (NLR), and ferritin compared to no fever (all P < 0.05). D-dimer (r = 0.42), CRP (r = 0.52), NLR (r = 0.48), and interleukin-6 (r = 0.46) demonstrated the strongest correlation with fever ( P < 0.001). High D-dimer >1000 ng/mL (adjusted odds ratio 2.7), CRP >100 mg/L (3.1), lymphopenia <1.0 × 109/L (2.8), NLR >4 (2.9), and thrombocytopenia <150 × 109/L (2.7) were significant independent predictors of fever status ( P < 0.005). These parameters had moderate sensitivity (40–60%) and high specificity (74–88%) for discriminating febrile patients with AUC of 0.85. Conclusions Marked alterations in hematologic, coagulation, and inflammatory markers occur in COVID-19 based on fever. Routine laboratory parameters can facilitate diagnosis and risk stratification.
... INF-1 является жизненно важным фактором репликации вируса и стимулирования адаптивной иммунной системы. COVID-19 влияет на врожденный иммунный ответ хозяина и ослабляет функцию INF-1 в ответ на инфекцию [37,38]. После заражения вирусом макрофаги, дендритные клетки и нейтрофилы запускают иммунный ответ в качестве первой линии защиты организма. ...
Article
The presented literature review presents studies, including our own, on the characteristics of the course of coronavirus infection in patients with acute myeloid leukemia in the older age group. Patients with acute leukemia, myelodysplastic syndrome are often over 65 years of age and have a burdened comorbid background and have profound immunodeficiency due to the underlying disease and the antitumor treatment received, and delaying treatment is often impossible due to the urgent need to start antitumor therapy. Management of this cohort of patients with concomitant COVID-19 is a challenge for hematologists around the world and requires interdisciplinary collaboration between hematologists and infectious disease specialists, clinical pharmacologists. There is a need to develop criteria to determine clear indications for starting antitumor treatment against the background of COVID-19 and the optimal timing for resuming the next course of chemotherapy after a coronavirus infection. The analysis of the literature and our own experience showed high hospital mortality taking into account the state of deep immunodeficiency of patients, despite the treatment of COVID-19, secondary bacterial and fungal infections and demonstrated the need to develop, first of all, preventive strategies in elderly patients with acute leukemia.
... In a metaanalysis with 27 trials, IL-6 antagonists were associated with lower 28-day all-cause mortality and no difference in secondary infections [23]. On the other hand, in less severely ill patients, IL-6 blockade did not prove benefit in intubation rate, extracorporeal membrane oxygenation or death in several trials using IL-6 blockade [23][24][25][26][27][28][29]. Moreover, in the interpretation of IL-6, the dual effect as proinflammatory as well as anti-inflammatory cytokine has to be considered. ...
... This is in line with the high levels of IL-18 found to be associated with disease severity and poor clinical outcome in COVID-19 patients (10,12,38,75,76). The COVID-19 pandemic has brought attention to a virally induced hyperinflammatory lung injury, sometimes evolving to ARDS, the most severe form of acute lung injury, that is characterized by a cytokine storm syndrome, multiple-organ failure and in most cases leads to death (77)(78)(79)(80)(81). This finding also mirrors what has been observed in MAS (82)(83)(84). ...
Article
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Introduction Interleukin-18 (IL-18), a pro-inflammatory cytokine belonging to the IL-1 Family, is a key mediator ofautoinflammatory diseases associated with the development of macrophage activation syndrome (MAS).High levels of IL-18 correlate with MAS and COVID-19 severity and mortality, particularly in COVID-19patients with MAS. As an inflammation inducer, IL-18 binds its receptor IL-1 Receptor 5 (IL-1R5), leadingto the recruitment of the co-receptor, IL-1 Receptor 7 (IL-1R7). This heterotrimeric complex subsequentlyinitiates downstream signaling, resulting in local and systemic inflammation. Methods We reported earlier the development of a novel humanized monoclonal anti-human IL-1R7 antibody whichspecifically blocks the activity of human IL-18 and its inflammatory signaling in human cell and wholeblood cultures. In the current study, we further explored the strategy of blocking IL-1R7 inhyperinflammation in vivo using animal models. Results We first identified an anti-mouse IL-1R7 antibody that significantly suppressed mouse IL-18 andlipopolysaccharide (LPS)-induced IFNg production in mouse splenocyte and peritoneal cell cultures. Whenapplied in vivo, the antibody reduced Propionibacterium acnes and LPS-induced liver injury and protectedmice from tissue and systemic hyperinflammation. Importantly, anti-IL-1R7 significantly inhibited plasma,liver cell and spleen cell IFNg production. Also, anti-IL-1R7 downregulated plasma TNFa, IL-6, IL-1b,MIP-2 production and the production of the liver enzyme ALT. In parallel, anti-IL-1R7 suppressed LPSinducedinflammatory cell infiltration in lungs and inhibited the subsequent IFNg production andinflammation in mice when assessed using an acute lung injury model. Discussion Altogether, our data suggest that blocking IL-1R7 represents a potential therapeutic strategy to specificallymodulate IL-18-mediated hyperinflammation, warranting further investigation of its clinical application intreating IL-18-mediated diseases, including MAS and COVID-19.
... In addition, acute SAR-CoV-2 infection of the surfactantreleasing, immunomodulatory Type II cells (ATII), results in the secretion of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) [30], interleukin (IL)-6 [31], and interferon-gamma (IFN-γ) [32], which recruit and activate macrophages, neutrophils, and lymphocytes. As a result, immune cells further increase cytokine production and generate a cytokine storm that causes severe inflammation and coagulation [33]. ...
Article
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Purpose of Review Long COVID affects approximately 5 million people in Africa. This disease is characterized by persistent symptoms or new onset of symptoms after an acute SARS-CoV-2 infection. Specifically, the most common symptoms include a range of cardiovascular problems such as chest pain, orthostatic intolerance, tachycardia, syncope, and uncontrolled hypertension. Importantly, these conditions appear to have endothelial dysfunction as the common denominator, which is often due to impaired nitric oxide (NO) mechanisms. This review discusses the role of mechanisms contributing to endothelial dysfunction in Long COVID, particularly in people living with HIV. Recent Findings Recent studies have reported that increased inflammation and oxidative stress, frequently observed in Long COVID, may contribute to NO dysfunction, ultimately leading to decreased vascular reactivity. These mechanisms have also been reported in people living with HIV. In regions like Africa, where HIV infection is still a major public health challenge with a prevalence of approximately 26 million people in 2022. Specifically, endothelial dysfunction has been reported as a major mechanism that appears to contribute to cardiovascular diseases and the intersection with Long COVID mechanisms is of particular concern. Further, it is well established that this population is more likely to develop Long COVID following infection with SARS-CoV-2. Therefore, concomitant infection with SARS-CoV-2 may lead to accelerated cardiovascular disease. Summary We outline the details of the worsening health problems caused by Long COVID, which exacerbate pre-existing conditions such as endothelial dysfunction. The overlapping mechanisms of HIV and SARS-CoV-2, particularly the prolonged inflammatory response and chronic hypoxia, may increase susceptibility to Long COVID. Addressing these overlapping health issues is critical as it provides clinical entry points for interventions that could improve and enhance outcomes and quality of life for those affected by both HIV and Long COVID in the region.
... Recent evidence suggests that severe COVID-19 is a consequence of immune dysregulation, often characterized by cytokine storms, which are believed to be the primary cause of mortality in affected patients [13,14]. ...
Article
Introduction Bruton’s Tyrosine Kinase (BTK), an important element for the pro-duction of several inflammatory cytokines, may play a role in the pathogenesis of COVID-19. This study aimed to assess BTK gene expression levels in COVID-19 cases based on disease severity and outcome. Methods In this study, 33 hospitalized patients with COVID-19 were recruited and divided into two groups based on the severity of the disease: "mild to moderate" and "severe to critical". A blood sample was taken from each patient, peripheral blood mononuclear cells (PBMCs) were extracted, and BTK gene expression was measured. The level of BTK gene expression was compared based on the demographic data, laboratory results, and the severity and outcome of the disease. Results Among 33 patients, 22 (66.7%) were male. Nearly half of the cases had at least one underlying disease. According to the severity of the disease, 12 patients were in the "mild to moderate" group, and 21 were in the "severe to critical" group; eight (24.2%) eventually died. Age, weight, and BMI had no significant relationship with BTK expression. BTK expression was significantly lower in "severe to critical" and ICU-admitted cases and in subjects with low O2 saturation. There was no significant difference in BTK expression between cured and dead patients (p=0.117). Conclusion BTK gene expression in PBMCs had an inverse relationship with the severity of the disease of COVID-19. However, no correlation between BTK expression and disease outcome was observed.
... can cause the non-osmotic release of ADH and increase the occurrence of hyponatremia. McGonagle et al. found that increased IL-6 and TNF-a were associated with decreased FT3 levels in patients with severe COVID-19 (45). In patients with SARS-CoV-2 infection, elevated IL-6 is associated with subacute thyroiditis, Graves' disease, and Hashimoto's thyroiditis (46), while abnormalities of the hypothalamic-pituitary-thyroid axis can cause a series of changes in TSH and thyroid hormones. ...
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Purpose Chest computed tomography (CT) is used to determine the severity of COVID-19 pneumonia, and pneumonia is associated with hyponatremia. This study aims to explore the predictive value of the semi-quantitative CT visual score for hyponatremia in patients with COVID-19 to provide a reference for clinical practice. Methods In this cross-sectional study, 343 patients with RT-PCR confirmed COVID-19, all patients underwent CT, and the severity of lung lesions was scored by radiologists using the semi-quantitative CT visual score. The risk factors of hyponatremia in COVID-19 patients were analyzed and combined with laboratory tests. The thyroid function changes caused by SARS-CoV-2 infection and their interaction with hyponatremia were also analyzed. Results In patients with SARS-CoV-2 infection, the total severity score (TSS) of hyponatremia was higher [M(range), 3.5(2.5–5.5) vs 3.0(2.0–4.5) scores, P=0.001], implying that patients with hyponatremia had more severe lung lesions. The risk factors of hyponatremia in the multivariate regression model included age, vomiting, neutrophils, platelet, and total severity score. SARS-CoV-2 infection impacted thyroid function, and patients with hyponatremia showed a lower free triiodothyronine (3.1 ± 0.9 vs 3.7 ± 0.9, P=0.001) and thyroid stimulating hormone level [1.4(0.8–2.4) vs 2.2(1.2–3.4), P=0.038]. Conclusion Semi-quantitative CT score can be used as a risk factor for hyponatremia in patients with COVID-19. There is a weak positive correlation between serum sodium and free triiodothyronine in patients with SARS-CoV-2 infection.
... These pro-inflammatory cytokines play important roles in the acute phase of inflammation. IL-6 promotes the production of several acute-phase proteins, priming inflammatory responses (McGonagle et al., 2020a). GM-CSF links T-cell-driven acute pulmonary inflammation with an autocrine, self-amplifying cytokine loop, leading to monocyte and macrophage activation (Mortaz et al., 2020). ...
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Glomerulonephritis (GN) is an important cause of renal inflammation resulting from kidney‐targeted adaptive and innate immune responses and consequent glomerular damage. Given the lack of autoantibodies, immune complexes, or the infiltrating immune cells in some forms of GN, for example, focal segmental glomerulosclerosis and minimal change disease, along with paraneoplastic syndrome and a special form of renal involvement in some viral infections, the likeliest causative scenario would be secreted factors, mainly cytokine(s). Since cytokines can modulate the inflammatory mechanisms, severity, and clinical outcomes of GN, it is rational to consider the umbrella term of cytokine GN as a new outlook to reclassify a group of previously known GN. We focus here, particularly, on cytokines that have the central “canonical effect” in the development of GN.
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In December 2019, a novel coronavirus (2019-nCoV) caused an outbreak in Wuhan, China, and soon spread to other parts of the world. It was believed that 2019-nCoV was transmitted through respiratory tract and then induced pneumonia, thus molecular diagnosis based on oral swabs was used for confirmation of this disease. Likewise, patient will be released upon two times of negative detection from oral swabs. However, many coronaviruses can also be transmitted through oral–fecal route by infecting intestines. Whether 2019-nCoV infected patients also carry virus in other organs like intestine need to be tested. We conducted investigation on patients in a local hospital who were infected with this virus. We found the presence of 2019-nCoV in anal swabs and blood as well, and more anal swab positives than oral swab positives in a later stage of infection, suggesting shedding and thereby transmitted through oral–fecal route. We also showed serology test can improve detection positive rate thus should be used in future epidemiology. Our report provides a cautionary warning that 2019-nCoV may be shed through multiple routes.
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Systemic juvenile idiopathic arthritis and adult-onset Still's disease are rare autoinflammatory disorders with common features, supporting the recognition of these being one disease-Still's disease-with different ages of onset. Anakinra was recently approved by the European Medicines Agency for Still's disease. In this review we discuss the reasoning for considering Still's disease as one disease and present anakinra efficacy and safety based on the available literature. The analysis of 27 studies showed that response to anakinra in Still's disease was remarkable, with clinically inactive disease or the equivalent reported for 23-100% of patients. Glucocorticoid reduction and/or stoppage was reported universally across the studies. In studies on paediatric patients where anakinra was used early or as first-line treatment, clinically inactive disease and successful anakinra tapering/stopping occurred in >50% of patients. Overall, current data support targeted therapy with anakinra in Still's disease since it improves clinical outcome, especially if initiated early in the disease course.
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Acute lung injury (ALI) and acute kidney injury (AKI) are major causes of sepsis-induced mortality. The objective of the study is to evaluate the effect of tocilizumab (TCZ), an IL-6 receptor inhibitor, in sepsis-induced ALI and AKI using the cecal ligation and puncture (CLP) rat model of sepsis. Clinical and experimental studies have demonstrated the importance of IL-6 in sepsis; however, the role of TCZ has not been investigated. Rats subjected to CLP developed histological evidence of ALI and AKI at 24 h. We found that TCZ alleviated sepsis-induced ALI and AKI as evidenced by improvements in various pathological changes, a significant reduction in the lung wet/dry weight ratio and total protein content in bronchoalveolar lavage fluid (BALF), and a significant decrease in the elevated serum level of creatinine (CR) and blood urea nitrogen (BUN). TCZ induced an increase in the survival rate of treated rats. Additionally, TCZ markedly inhibited sepsis-induced pulmonary and renal inflammatory responses. Moreover, we found that treatment with TCZ inhibited oxidative stress and apoptosis in lung and kidney tissue. TCZ treatment significantly inhibited NF-κB activation, attenuating JNK signaling pathway and significantly up-regulated P-glycoprotein (P-gp) expression in pulmonary as well as in renal tissues. Our data provide novel evidence that TCZ has a protective effect against sepsis-induced ALI and AKI by blocking IL-6 receptor signaling. This could provide a molecular basis for a new medical treatment for sepsis-induced ALI and AKI.
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Objective Systemic juvenile idiopathic arthritis (JIA) is associated with a recently recognized, albeit poorly defined and characterized, lung disease (LD). The objective of this study was to describe the clinical characteristics, risk factors, and histopathologic and immunologic features of this novel inflammatory LD associated with systemic JIA (designated SJIA‐LD). Methods Clinical data collected since 2010 were abstracted from the medical records of patients with systemic JIA from the Cincinnati Children's Hospital Medical Center. Epidemiologic, cellular, biochemical, genomic, and transcriptional profiling analyses were performed. Results Eighteen patients with SJIA‐LD were identified. Radiographic findings included diffuse ground‐glass opacities, subpleural reticulation, interlobular septal thickening, and lymphadenopathy. Pathologic findings included patchy, but extensive, lymphoplasmacytic infiltrates and mixed features of pulmonary alveolar proteinosis (PAP) and endogenous lipoid pneumonia. Compared to systemic JIA patients without LD, those with SJIA‐LD were younger at the diagnosis of systemic JIA (odds ratio [OR] 6.5, P = 0.007), more often had prior episodes of macrophage activation syndrome (MAS) (OR 14.5, P < 0.001), had a greater frequency of adverse reactions to biologic therapy (OR 13.6, P < 0.001), and had higher serum levels of interleukin‐18 (IL‐18) (median 27,612 pg/ml versus 5,413 pg/ml; P = 0.047). Patients with SJIA‐LD lacked genetic, serologic, or functional evidence of granulocyte–macrophage colony‐stimulating factor pathway dysfunction, a feature that is typical of familial or autoimmune PAP. Moreover, bronchoalveolar lavage (BAL) fluid from patients with SJIA‐LD rarely demonstrated proteinaceous material and had less lipid‐laden macrophages than that seen in patients with primary PAP (mean 10.5% in patients with SJIA‐LD versus 66.1% in patients with primary PAP; P < 0.001). BAL fluid from patients with SJIA‐LD contained elevated levels of IL‐18 and the interferon‐γ–induced chemokines CXCL9 and CXCL10. Transcriptional profiling of the lung tissue from patients with SJIA‐LD identified up‐regulated type II interferon and T cell activation networks. This signature was also present in SJIA‐LD human lung tissue sections that lacked substantial histopathologic findings, suggesting that this activation signature may precede and drive the lung pathology in SJIA‐LD. Conclusion Pulmonary disease is increasingly detected in children with systemic JIA, particularly in association with MAS. This entity has distinct clinical and immunologic features and represents an uncharacterized inflammatory LD.
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Our recently published research on the characterization of vesicular stomatitis virus (VSV) pathogenesis in swine, identified a systemic upregulation of interleukin 6 (IL-6) during the acute phase of infection (Velazquez-Salinas et al., 2018). This upregulation was observed during infection with a highly virulent VSV strain, suggesting a potential association between IL-6 levels and virus virulence in pigs. In this opinion note we would like to explore in more detail the biological functions of IL-6 in different virus models, and present our perspective regarding the debatable role of IL-6 during viral infections. While several studies show the essential role of IL-6 to mount a proper immune response during some viral infections, others link this cytokine with exacerbation of viral disease. These latter findings lend support to the hypothesis that upregulation of IL-6 during certain viral infections may promote virus survival and/or exacerbation of clinical disease. Copyright © 2019 Velazquez-Salinas, Verdugo-Rodriguez, Rodriguez and Borca. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
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Synonymous with secondary hemophagocytic lymphohistiocytosis, macrophage activation syndrome (MAS) is a term used by rheumatologists to describe a potentially life-threatening complication of systemic inflammatory disorders, most commonly systemic juvenile idiopathic arthritis (sJIA) and systemic lupus erythematosus (SLE). Clinical and laboratory features of MAS include sustained fever, hyperferritinemia, pancytopenia, fibrinolytic coagulopathy, and liver dysfunction. Soluble interleukin-2 receptor alpha chain (sCD25) and sCD163 may be elevated, and histopathology often reveals characteristic increased hemophagocytic activity in the bone marrow (and other tissues), with positive CD163 (histiocyte) staining. A common hypothesis as to the pathophysiology of many cases of MAS proposes a defect in lymphocyte cytolytic activity. Specific heterozygous gene mutations in familial HLH-associated cytolytic pathway genes (e.g., PRF1, UNC13D) have been linked to a substantial subset of MAS patients. In addition, the pro-inflammatory cytokine environment, particularly IL-6, has been shown to decrease NK cell cytolytic function. The inability of NK cells and cytolytic CD8 T cells to lyse infected and otherwise activated antigen presenting cells results in prolonged cell-to-cell (innate and adaptive immune cells) interactions and amplification of a pro-inflammatory cytokine cascade. The cytokine storm results in activation of macrophages, causing hemophagocytosis, as well as contributing to multi-organ dysfunction. In addition to macrophages, dendritic cells likely play a critical role in antigen presentation to cytolytic lymphocytes, as well as contributing to cytokine expression. Several cytokines, including tumor necrosis factor, interferon-gamma, and numerous interleukins (i.e., IL-1, IL-6, IL-18, IL-33), have been implicated in the cytokine cascade. In addition to broadly immunosuppressive therapies, novel cytokine targeted treatments are being explored to dampen the overly active immune response that is responsible for much of the pathology seen in MAS.
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Haemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome, which if not promptly treated, can lead rapidly to critical illness and death. HLH is termed macrophage activation syndrome (MAS) when associated with rheumatic disease (where it is best characterized in systemic JIA) and secondary HLH (sHLH) when associated with other triggers including malignancy and infection. MAS/sHLH is rare and coupled with its mimicry of other conditions, is underrecognized. These inherent challenges can lead to diagnostic and management challenges in multiple medical specialties including haematology, infectious diseases, critical care and rheumatology. In this review we highlight the pathogenesis of MAS/sHLH including its underlying triggers, key clinical features and diagnostic challenges, prognostic factors and current treatments in adults.
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Background Interleukin 6 (IL-6) is a predictive factor of poor prognosis in patients with acute respiratory distress syndrome (ARDS). However, its acute pulmonary hemodynamic effects and role in lung injury have not been investigated in a clinically relevant murine model of ARDS. Methods We used adult C57Bl6 wild-type (WT) and IL-6 knock-out (IL-6KO) mice. The animals received intravenous recombinant human IL-6 (rHuIL-6) or vehicle followed by intratracheal lipopolysaccharide (LPS) or saline before undergoing low tidal volume mechanical ventilation (MV) for 5 h. Before sacrifice, right ventricular systolic pressure and cardiac output were measured and total pulmonary resistance was calculated. After sacrifice, lung inflammation, edema and injury were assessed with bronchoalveolar lavage (BAL) and histology. In other experiments, right ventricular systolic pressure was recorded during hypoxic challenges in uninjured WT mice pretreated with rHuIL-6 or rHuIL-6 + non-selective nitric oxide synthase inhibitor L-NAME or vehicle. ResultsIL-6KO(LPS+MV) mice showed a faster deterioration of lung elastic properties and more severe bronchoalveolar cellular inflammation as compared to WT(LPS+MV). Treatment with rHuIL-6 partially prevented this lung deterioration. Total pulmonary resistance was higher in IL-6KO(LPS+MV) mice and this increase was abolished in rHuIL-6-treated IL-6KO mice. Finally, rHuIL-6 reduced hypoxic pulmonary vasoconstriction in uninjured WT mice, an effect that was abolished by co-treatment with L-NAME. Conclusions In a double-hit murine model of ARDS, IL-6 deficient mice experienced more severe bronchoalveolar cellular inflammation as compared to wild-type littermates. Furthermore, IL-6 deficiency caused marked acute pulmonary hypertension, which may be, at least partially, due to vasoactive mechanisms. A dysregulation of nitric oxide synthase may account for this observation, a hypothesis that will need to be investigated in future studies.
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Interleukin 6 (IL-6) is involved in innate and adaptive immune responses to defend against pathogens. It also participates in the process of influenza infection by affecting viral clearance and immune cell responses. However, whether IL-6 impacts lung repair in influenza pathogenesis remains unclear. Here, we studied the role of IL-6 in acute influenza infection in mice. IL-6-deficient mice infected with influenza virus exhibited higher lethality, lost more body weight and had higher fibroblast accumulation and lower extracellular matrix (ECM) turnover in the lung than their wild-type counterparts. Deficiency in IL-6 enhanced proliferation, migration and survival of lung fibroblasts, as well as increased virus-induced apoptosis of lung epithelial cells. IL-6-deficient lung fibroblasts produced elevated levels of TGF-β, which may contribute to their survival. Furthermore, macrophage recruitment to the lung and phagocytic activities of macrophages during influenza infection were reduced in IL-6-deficient mice. Collectively, our results indicate that IL-6 is crucial for lung repair after influenza-induced lung injury through reducing fibroblast accumulation, promoting epithelial cell survival, increasing macrophage recruitment to the lung and enhancing phagocytosis of viruses by macrophages. This study suggests that IL-6 may be exploited for lung repair during influenza infection.
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