Enhancing understanding of SARS-CoV-2 infection among individuals with Down syndrome: An integrative review

ABSTRACT BACKGROUND: Down syndrome (DS) is a non-rare genetic condition that affects approximately 1 in every 800 live births worldwide. Further, it is associated with comorbidities, anatomical alterations of the respiratory tract, and immunological dysfunctions that make individuals more susceptible to respiratory infections. OBJECTIVE: To systematize the current scientific knowledge about the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among individuals with DS. DESIGN AND SETTING: This integrative review was conducted at the Universidade Federal de São Carlos, São Paulo, Brazil. METHODS: This review was conducted in the following databases: the Virtual Health Library (Biblioteca Virtual em Saúde, BVS), PubMed, and Web of Science, using MeSH descriptors. The search included English or Portuguese studies published between January 1, 2020, and October 14, 2022. RESULTS: A total of 55 articles from 24 countries were selected, comprising 21 case-control or cohort studies, 23 case reports or series, and 11 narrative reviews or opinion studies. The articles were grouped into five categories: previous comorbidities, coronavirus disease 2019 (COVID-19) clinical features and evolution, cytokine storm and interleukins, living in institutions as a risk factor, and behavioral actions as a protective factor against SARS-CoV-2 infection. CONCLUSION: Individuals with DS are more susceptible to COVID-19 infection due to variables such as previous comorbidities, immunological factors, and their habitable environments. These aspects confer a higher risk of infection and an unfavorable clinical course. The precise pathways involved in the pathophysiology of COVID-19 in individuals with DS are not clear, thus requiring further studies. SYSTEMATIC REVIEW REGISTRATION: The Open Science Framework registered the research protocol (https://osf.io/jyb97/).

Different profiles of chemokines, cytokines and cell growth factors in plasma samples from patients with leprosy, leprosy reactions and households contacts

BACKGROUND Leprosy is a highly neglected disease that is considered a serious public health problem in many countries. This illness is characterised by a variety of clinical and histopathological manifestations that are related to the patient immune response. OBJECTIVES This work aimed evaluate the profile of circulating immune mediators in the plasma from patients classified clinically as paucibacillary (PB), multibacillary (MB), households contacts (HHC), type1 leprosy reaction (T1R), type2 leprosy reaction (T2R) and control individuals without medical history of leprosy (CTL). METHODS To assessment of the plasma immune mediators was used multiplex microbeads immunoassay "Luminex". FINDINGS The results showed that patients (PB) had a regulatory-biased profile, while MB revealed a pro-inflammatory trend of highly expressed biomarkers. HHC display conspicuously increased levels in the plasma of the chemokines (CCL2, CCL3, CCL4, CCL5 and CXCL8), pro-inflammatory cytokines (IFN-γ,TNF and IL-1β), modulating cytokines (IL-9 and IL-1Ra) and growth factors (PDGF, G-CSF and IL-2). Interestingly, HHC displayed superior production of IFN-γ as compared to other leprosy groups, indicating a putative protective role for this cytokine during chronic Mycobacterium leprae exposure. MAIN CONCLUSION Further investigations are currently underway to elucidate the potential of these mediators as biomarkers applicable to the diagnosis/prognosis of leprosy and also T1R and T2R leprosy reactions.

Targeted biotherapy for chronic obstructive pulmonary disease / 中国临床药理学与治疗学

Chronic obstructive pulmonary disease (COPD) is the most common chronic airway disease. The current status of treatment based mainly on bronchodilators and ICS is not sufficient for all of COPD patients. Various studies have attempted to use biologics targeting specific cytokines and their receptors in COPD patients to alleviate respiratory symptoms or reduce the risk of acute exacerbations. However, they failed to bring significant clinical benefits. More studies are needed to further determine the efficacy of targeted biotherapy for COPD.

Effectiveness of Tocilizumab in COVID-19 patients with pneumonia: A systematic review

Background and Objective@#COVID-19 contributes significantly to global morbidity and mortality. Age-related comorbidities elevate the risk of severe cases. Studies have recently demonstrated that widely available medications, including tocilizumab (TCZ), can manage severe symptoms. However, its effectiveness is unclear, particularly among the older population. Therefore, this review aimed to evaluate TCZ’s efficacy in managing severe pneumonia in individuals aged 50 and older.@*Methods@#We systematically search several databases and gray literature including Web of Science, CINAHL, Academic Search Complete, PsycINFO, PsycArticles, SocINDEX, CENTRAL/Cochrane Library, PubMed/MEDLINE for original research articles in English across several study designs published in the year 2020-2022. A narrative synthesis was conducted to summarize the evidence. We employed the NIH quality assessment tool for observational cohort studies to evaluate risk of bias. Additionally, we utilized GRADE to appraise the certainty of evidence.@*Results@#Among 539 screened articles, only five studies met the selection criteria. Tocilizumab's impact on severe COVID-19 pneumonia revealed a diverse effect on mortality rate, with 29% in the TCZ group, and 40% in the controls died within 30 days of intubation (OR 0.61; 95% CI, 0.27-1.36). It is also reported that TCZ was not associated with mortality, despite faster decline in pulmonary function and prolonged fever. Hospital mortality in the TCZ group was significantly lower than in the controls, and age over 60 was the only significant risk factor. Moreover, administering TCZ reduced mechanical ventilation needs, with 82% extubated compared to 53% in controls. However, 45% in TCZ group was associated with a higher ventilator-associated pneumonia rate than in the untreated group which was 20% (P < 0.001). Despite this, TCZ-treated patients had shorter hospital stays.@*Conclusions@#The effects of tocilizumab on reducing mortality risk and improving the survival rate of COVID-19 patients with pneumonia remained inconclusive. Yet, the majority of results suggested that giving tocilizumab leads to shorter hospital stays, lowers the requirement for mechanical ventilation, and decreases the likelihood of ICU transfer. Tocilizumab is linked to the incidence of secondary infections; hence, this medication should be closely monitored for side effects.

COVID-19 in the nervous system: physiopathology and neurological manifestations / Covid-19 no sistema nervoso: fisiopatologia e manifestações neurológicas

Abstract Background Coronavirus disease 2019 (COVID-19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although respiratory manifestations have received greater visibility during the pandemic caused by this virus, numerous neurological complaints related to coronavirus 2 infection have been documented in several countries. These records suggest that this pathogen presents neurotropism, and it can cause different neurological conditions of varying intensity. Objective To investigate the ability of coronavirus 2 to invade the central nervous system (CNS) and its neurological clinical outcomes. Methods The present study consists in a comprehensive literature review of the records available in the PubMed, SciELO, and Google Scholar databases. The descriptors COVID-19, brain and physiopathology, associated with the Boolean operator AND, were used in the search. Regarding the inclusion and exclusion criteria, we selected the papers published since 2020 with the highest number of citations. Results We selected 41 articles, most of them in English. The main clinical manifestation associated with COVID-19 patients was headache, but cases of anosmia, hyposmia, Guillain-Barré syndrome, and encephalopathies were also described with considerable frequency. Conclusion Coronavirus-2 presents neurotropism, and it can reach the CNS by hematogenous dissemination and by direct infection of the nerve endings. It causes brain injuries through several mechanisms, such as cytokine storm, microglial activation, and an increase in thrombotic factors.

Resumo Antecedentes A doença do coronavírus 2019 (coronavirus disease 2019, Covid-19, em inglês) é uma infecção viral provocada pelo coronavírus 2 da síndrome respiratória aguda grave (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, em inglês). Embora as manifestações respiratórias tenham recebido maior visibilidade ao longo da pandemia provocada por esse vírus, inúmeras queixas neurológicas relacionadas à infecção pelo coronavírus 2 foram documentadas em diversos países. Tais registros sugerem que esse patógeno apresenta neurotropismo, e é capaz de provocar quadros neurológicos diversos e de intensidade variáveis. Objetivo Investigar a capacidade de invasão do sistema nervoso central (SNC) pelo coronavírus 2 e seus principais desfechos clínicos neurológicos. Métodos O presente estudo consiste em uma ampla revisão de literatura a partir dos registros das bases de dados PubMed, SciELO e Google Acadêmico. Nesse contexto, os descritores COVID-19, cérebro e fisiopatologia, associados com o operador booleano AND, foram utilizados na busca. Quanto aos critérios de inclusão e exclusão, selecionou-se os trabalhos publicados a partir de 2020 com o maior número de citações. Resultados Foram selecionados 41 artigos, a maioria na língua inglesa. A principal manifestação clínica associada a pacientes acometidos pela COVID-19 foi a cefaleia, mas casos de anosmia, hiposmia, síndrome de Guillain-Barré e encefalopatias também foram descritos com frequência considerável. Conclusão O coronavírus 2 apresenta neurotropismo, e é capaz de alcançar o SNC por disseminação hematogênica e por infecção direta das terminações nervosas. Ele provoca injúria cerebral por meio de variados mecanismos, como tempestade de citocinas, ativação da micróglia e aumento dos fatores trombóticos.

The Role of Oxidative Stress and Cytokine Storm in the Pathogenesis, Oral Manifestation, Progression and Adverse Effects Related to SARS-Cov2 Infection- A Review

Introduction: COVID-19 pandemic has been the most challenging global health concern that the world has ever seen and is the focus of active research around the world. The interaction of the SARS CoV2 virus with the target cells, their action on the immune system and the subsequent reaction has all been linked to the inflammatory processes that are taking place in the human body mainly the oxidative stress. Objective: Through this article we aim to analyse the effect of oxidative stress in the pathogenesis of COVID-19, highlighting the role of the same in the oral manifestations that are being reported in literature and its subsequent impact in the transmission and propagation of SARS-CoV2. The role of antioxidants in the control of the SARS-CoV2 infection has also been explored. Materials and Methods: Four reviewers independently collected the data pertaining to the topic from case reports and review articles published in electronic databases like PubMed, Scopus, Science Direct and Research gate. Conclusion: Increased release of cytokines known as cytokine storm has been associated with disease progression, oral manifestation as well as adverse effects in patients with COVID 19. However, as this is an ongoing pandemic with new mu- tations occurring frequently, further clinical trials are required to evaluate the exact mechanisms that may be at play in the pathogenesis of SARS-CoV2 infection.

Inmunodeficiencias secundarias relacionadas con la presencia de autoanticuerpos anticitocinas / Secondary immunodeficiencies related to the presence of anti-cytokine autoantibodies

Resumen Los autoanticuerpos anticitocinas (ACAA) han sido reportados como causa importante de inmunodeficiencias secundarias. Altos títulos de autoanticuerpos neutralizantes pueden causar susceptibilidad a diferentes enfermedades infecciosas potencialmente mortales. Por ejemplo, se ha informado que autoanticuerpos neutralizantes contra IFNγ se correlacionan con susceptibilidad a infecciones micobacterianas y patógenos fúngicos intracelulares. Autoanticuerpos contra IL-6 se detectaron en pacientes con abscesos subcutáneos y celulitis estafilocócica recurrente; asimismo, pacientes con criptococosis, nocardiosis y proteinosis alveolar pulmonar fueron positivos a autoanticuerpos contra GM-CSF. También se ha establecido una relación entre los autoanticuerpos contra IL-17 e IL-22 y las infecciones crónicas por Candida en mucosas, que se han identificado en pacientes con poliendocrinopatía autoinmune tipo 1 o timoma. Recientemente se han reportado autoanticuerpos contra interferón tipo I durante el inicio de COVID-19 aguda. Estos ACAA se asemejan a defectos genéticos en citocinas o en sus rutas de señalización. Por ello, pueden considerarse fenocopias de inmunodeficiencias primarias. De esta forma, la detección de ACAA podría ser importante en el diagnóstico, particularmente en pacientes con enfermedades de aparición tardía, para decidir los tratamientos apropiados. Esta revisión presenta una descripción general de la comprensión actual de las inmunodeficiencias secundarias asociadas a ACAA.

Abstract Anti-cytokine autoantibodies (ACAA) have been reported to be an important cause of secondary immunodeficiencies. High titers of neutralizing autoantibodies may cause susceptibility to different life-threatening infectious diseases. For example, neutralizing autoantibodies against IFNγ have been reported to be correlated with susceptibility to mycobacterial infections and intracellular fungal pathogens. Autoantibodies against IL-6 were detected in patients with subcutaneous abscesses and recurrent staphylococcal cellulitis; on the other hand, patients with cryptococcosis, nocardiosis, and pulmonary alveolar proteinosis were positive for autoantibodies to GM-CSF. A relationship has also been established between autoantibodies against IL-17 and IL-22 and chronic mucosal Candida infections, which have been identified in patients with APECED or thymoma. Autoantibodies against type-I IFN have been recently reported during the onset of acute COVID-19. These ACAAs resemble genetic defects in cytokines or their signaling pathways. Therefore, they may be considered to be primary immunodeficiencies phenocopies. Consequently, the detection of ACAA could be important in the diagnosis of patients, particularly in the case of late-onset diseases, in order to decide appropriate treatments. This review presents an overview of current understanding of ACAA-associated secondary immunodeficiencies.

An elevated HScore is associated with poor clinical outcomes in COVID-19 / Un HScore elevado se asocia a mal pronóstico en pacientes con COVID-19

BACKGROUND: Patients with Coronavirus Disease 2019 (COVID-19) frequently experience a hyperinflammatory syndrome leading to unfavorable outcomes. This condition resembles Secondary Hemophagocytic Lymphohistiocytosis (sHLH) described in neoplastic, rheumatic and other infectious diseases. A scoring system (HScore) that evaluates underlying immunosuppression, temperature, organomegaly, cytopenias, ferritin, triglycerides, fibrinogen and AST was validated for sHLH, and recently proposed to evaluate hyperinflammation in COVID-19. AIM: To assess the presence of sHLH among patients with COVID-19 admitted for hospitalization and to evaluate Hscore as a prognostic tool for poor outcomes. MATERIAL AND METHODS: One hundred forty-three patients aged 21-100 years (64% males) admitted because of COVID-19 were enrolled in a prospective study. HScore was calculated within 72 hours admission. The incidence of sHLH during hospitalization was evaluated. Additionally, the relationship between a HScore ≥ 130 points and either the requirement of mechanical ventilation or 60-days mortality was explored. RESULTS: The median HScore was 96 (33-169). A SHLH was diagnosed in one patient (incidence 0.7%), whose HScore was 169. After adjusting for age, sex, comorbidities and obesity, HScore ≥ 130 was independently associated with the composite clinical outcome (Hazard rartio 2.13, p = 0.022). CONCLUSIONS: sHLH is not frequent among COVID-19 patients. HScore can be useful to predict the risk for poor outcomes.

ANTECEDENTES: Los pacientes con Enfermedad por Coronavirus 2019 (COVID-19), experimentan frecuentemente un síndrome hiperinflamatorio que lleva a resultados desfavorables. Esta situación se asemeja al Síndrome Hemofagocítico Secundario (sHLH) descrito en enfermedades neoplásicas, reumatológicas y por otros agentes infecciosos. Un sistema simple de puntaje (HScore) que evalúa inmunosupresión, temperatura organomegalia, citopenias, ferritina, triglicéridos, fibrinógeno y AST ha sido validado para el diagnóstico de sHLH y ha sido propuesto recientemente para evaluar la hiperinflamación en COVID-19. OBJETIVO: Medir la frecuencia de sHLH entre pacientes con COVID-19 hospitalizados, y evaluar a HScore como una herramienta pronóstica. MATERIAL Y MÉTODOS: Ciento cuarenta y tres pacientes de 21 a 100 años (64% hombres) fueron ingresados en este estudio de cohorte prospectivo, unicéntrico. Se calculó HScore dentro de las primeras 72 horas desde el ingreso, y se midió la incidencia de sHLH durante la hospitalización. Adicionalmente, se evaluó la relación entre HScore ≥ 130 puntos y un desenlace compuesto de ventilación mecánica o muerte a los 60 días. RESULTADOS: La mediana de HScore fue 96 (33-169) puntos. Un paciente fue diagnosticado con sHLH (incidencia 0,7%). Luego de ajustar por edad, sexo, comorbilidades y obesidad, un HScore ≥ 130 se asoció de manera independiente con el desenlace compuesto. CONCLUSIONES: El sHLH no es frecuente en los pacientes con COVID-19. El uso de HScore puede ser útil para predecir el riesgo de desenlaces clínicos desfavorables.

Targeting TLR-4 Signaling to Treat COVID-19-induced Acute Kidney Injury

The newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has turned into a potentially fatal pandemic illness. Numerous acute kidney injury (AKI) cases have been reported, although diffuse alveolar destruction and acute respiratory failure are the major symptoms of SARS-CoV-2 infection. The AKI, often known as a sudden loss of kidney function, carries a greater risk of mortality and morbidity. AKI was the second most frequent cause of death after acute respiratory distress syndrome (ARDS) in critically ill patients with coronavirus disease 2019 (COVID-19). While most patients with COVID-19 have moderate symptoms, some have severe symptoms, such as septic shock and ARDS. Also, it has been proven that some patients have severe symptoms, such as the failure of several organs. The kidneys are often affected either directly or indirectly. The major signs of kidney involvement are proteinuria and AKI. It is hypothesized that multiple mechanisms contribute to kidney injury in COVID-19. Direct infection of podocytes and proximal tubular cells in the kidneys may lead to acute tubular necrosis and collapsing glomerulopathy. SARS-CoV2 may also trigger a cascade of immunological responses that lead to AKI, including cytokine storm (CS), macrophage activation syndrome, and Toll-like receptor type 4 activation (TLR-4). Other proposed processes of AKI include interactions between organs, endothelial failure, hypercoagulability, rhabdomyolysis, and sepsis. Furthermore, ischemic damage to the kidney might result from the decreased oxygen supply. This article focuses on kidney injury’s epidemiology, etiology, and pathophysiological processes. Specifically, it focuses on the CS and the role of TLR-4 in this process. To effectively manage and treat acute kidney damage and AKI in COVID-19, it is crucial to understand the underlying molecular pathways and pathophysiology.

Cytokine hemoadsorption with CytoSorb® in patients with sepsis: a systematic review and meta-analysis / Hemoadsorção de citocinas com CytoSorb® em pacientes com sepse: revisão sistemática e metanálise

ABSTRACT Objective: To analyze the effect of CytoSorb® on mortality, interleukin levels, vasopressor use and adverse events in patients with sepsis. Methods: We searched MEDLINE®, Embase and the Cochrane Library for randomized controlled trials and cohort studies that reported the use of CytoSorb® among septic patients. The primary outcome was mortality, and secondary outcomes included the use of vasopressors, levels of inflammatory markers, predicted versus observed mortality, length of stay in the intensive care unit, and adverse events. Results: We included 6 studies enrolling 413 patients, and assessment for risk of bias indicated variations in study quality from high to moderate. The overall mortality rate was 45%, and no significant effect on mortality was found at 28 - 30 days (RR 0.98 [0.12 - 8.25] for the randomized clinical trial and RR 0.74 [0.49 - 1.13] for cohort studies). We did not perform a metanalysis for other outcomes due to the small number of studies found or the lack of data. Conclusion: Our study found very low certainty evidence, due to imprecision, risk of bias, and heterogeneity, thereby showing no benefit of CytoSorb® use in terms of mortality at 28 - 30 days. We cannot recommend the use of CytoSorb® in septic or septic shock patients outside clinical trials. Further high-quality randomized trials with a common intervention arm are needed to evaluate the influence of CytoSorb® in this population. PROSPERO register: CRD42021262219

RESUMO Objetivo: Analisar o efeito de CytoSorb® na mortalidade, nos níveis de interleucina, no uso de vasopressores e nos eventos adversos em pacientes com sepse. Métodos: Pesquisamos o MEDLINE®, o Embase e a Biblioteca Cochrane em busca de ensaios clínicos randomizados e estudos de coorte que relatassem o uso de CytoSorb® em pacientes com sepse. O desfecho primário foi a mortalidade, e os desfechos secundários incluíram uso de vasopressores, níveis de marcadores inflamatórios, mortalidade prevista versus observada, tempo de internação na unidade de terapia intensiva e eventos adversos. Resultados: Incluímos 6 estudos com 413 pacientes, e a avaliação do risco de viés indicou variações na qualidade do estudo de alta a moderada. A taxa de mortalidade geral foi de 45%, e não foi encontrado efeito significativo na mortalidade entre 28 e 30 dias (risco relativo de 0,98 [0,12 - 8,25] para o ensaio clínico randomizado e de 0,74 [0,49 - 1,13] para estudos de coorte). Não realizamos metanálise para outros desfechos, devido ao pequeno número de estudos encontrados ou à carência de dados. Conclusão: Nosso estudo encontrou evidências de certeza muito baixa, devido à imprecisão, ao risco de viés e à heterogeneidade, demonstrando nenhum benefício no uso de CytoSorb® em termos de mortalidade em 28 a 30 dias. Não podemos recomendar o uso de CytoSorb® em pacientes com sepse ou choque séptico fora dos estudos clínicos. São necessários mais estudos randomizados de alta qualidade com um braço de intervenção comum para avaliar a influência de CytoSorb® nessa população. Registro PROSPERO: CRD42021262219

Interferon-gamma gene diplotype (AA-rs2069716 / AG-rs2069727) may play an important role during secondary outcomes of severe dengue in Brazilian patients

ABSTRACT Dengue is a global and growing health threat, especially in Southeast Asia, West Pacific and South America. Infection by the dengue virus (DENV) results in dengue fever, which can evolve to severe forms. Cytokines, especially interferons, are involved in the immunopathogenesis of dengue fever, and so may influence the disease outcomes. The aim of this study was to investigate the association between severe forms of dengue and two single nucleotide polymorphisms (SNPs) in the interferon-gamma gene (IFNG): A256G (rs2069716) and A325G (rs2069727). We included 274 patients infected with DENV serotype 3: 119 cases of dengue without warning signs (DWoWS), and 155 with warning signs (DWWS) or severe dengue (SD). DNA was extracted, and genotyped with Illumina Genotyping Kit or real time PCR (TaqMan probes). We estimated the adjusted Odds Ratios (OR) by multivariate logistic regression models. When comparing with the ancestral AA/AA diplotype (A256G/A325G), we found a protective association of the AA/AG against DWWS/SD among patients with secondary dengue (OR 0.51; 95% IC 0.24-1.10, p = 0.085), adjusting for age and sex. The variant genotype at locus A325G of the IFNG, in combination with the ancestral genotype at locus A256G, can protect against severe clinical forms of secondary dengue in Brazilian DENV3-infected patients.

Efficacy and safety of Ixekizumab vs. low-dose IL-2 vs. Colchicine vs. standard of care in the treatment of patients hospitalized with moderate-to-critical COVID-19: A pilot randomized clinical trial (STRUCK: Survival Trial Using Cytokine Inhibitors)

ABSTRACT Background: Cases of coronavirus disease 2019 (COVID-19) requiring hospitalization continue to appear in vulnerable populations, highlighting the importance of novel treatments. The hyperinflammatory response underlies the severity of the disease, and targeting this pathway may be useful. Herein, we tested whether immunomodulation focusing on interleukin (IL)-6, IL-17, and IL-2, could improve the clinical outcomes of patients admitted with COVID-19. Methods: This multicenter, open-label, prospective, randomized controlled trial was conducted in Brazil. Sixty hospitalized patients with moderate-to-critical COVID-19 received in addition to standard of care (SOC): IL-17 inhibitor (ixekizumab 80 mg SC/week) 1 dose every 4 weeks; low-dose IL-2 (1.5 million IU per day) for 7 days or until discharge; or indirect IL-6 inhibitor (colchicine) orally (0.5 mg) every 8 hours for 3 days, followed by 4 weeks at 0.5 mg 2x/day; or SOC alone. The primary outcome was accessed in the "per protocol" population as the proportion of patients with clinical improvement, defined as a decrease greater or equal to two points on the World Health Organization's (WHO) seven-category ordinal scale by day 28. Results: All treatments were safe, and the efficacy outcomes did not differ significantly from those of SOC. Interestingly, in the colchicine group, all participants had an improvement of greater or equal to two points on the WHO seven-category ordinal scale and no deaths or patient deterioration were observed. Conclusions: Ixekizumab, colchicine, and IL-2 were demonstrated to be safe but ineffective for COVID-19 treatment. These results must be interpreted cautiously because of the limited sample size.

A Covid-19 e as citocinas: uma revisão de literatura / Covid-19 and cytokines: a literature review / Covid-19 y citocinas: una revisión de la literatura

A COVID-19 surgiu em dezembro de 2019 na China, o contágio se espalhou rapidamente pelo mundo e já em março de 2020 a Organização Mundial da Saúde (OMS) declarou o surto como pandemia. A infecção causada por SARS-COV-2 mostrou-se com sintomatologia variada. Enquanto alguns infectados não tinham sintomas, outros apresentavam sinais que variam dos semelhantes a uma gripe, até uma possível evolução para síndrome do desconforto respiratório. Evidências indicam que, durante o curso da COVID-19 a rápida progressão e mortalidade pode ter sido associada à mecanismo hiperinflamatórios, com descontrole regulatório da produção de citocinas pró- inflamatórias, tanto em nível local, quanto sistêmico. Sendo assim, neste artigo revisamos a literatura sobre a COVID-19, seus aspectos epidemiológicos e clínicos, bem como a o papel das citocinas no contexto da infecção por SARS-CoV-2, já que a busca pelo entendimento dos mecanismos imunológicos que envolvem a COVID-19 e outras doenças de caráter inflamatório é de suma importância para o tratamento e o manejo de tais enfermidades.

COVID-19 emerged in December 2019 in China, the contagion spread rapidly around the world, and already in March 2020 the World Health Organization (WHO) declared the outbreak a pandemic. The infection caused by SARS-COV-2 was shown to have varied symptomatology. While some infected people had no symptoms, others showed signs ranging from flu-like to a possible evolution to respiratory distress syndrome. Evidence indicates that during the course of COVID-19 the rapid progression and mortality may have been associated with hyperinflammatory mechanisms, with regulatory uncontrolled production of pro-inflammatory cytokines at both local and systemic levels. Therefore, in this article we review the literature on COVID-19, its epidemiological and clinical aspects, as well as the role of cytokines in the context of SARS-CoV-2 infection, since the search for understanding the immunological mechanisms surrounding COVID-19 and other inflammatory diseases is of paramount importance for the treatment and management of such diseases.

El COVID-19 surgió en diciembre de 2019 en China, el contagio se extendió rápidamente por todo el mundo y ya en marzo de 2020 la Organización Mundial de la Salud (OMS) declaró el brote como pandemia. Se demostró que la infección causada por el SARS-COV-2 presentaba una sintomatología variada. Mientras que algunos infectados no presentaban síntomas, otros mostraban signos que iban desde similares a los de la gripe hasta una posible evolución a síndrome de dificultad respiratoria. Las pruebas indican que durante el curso del COVID-19 la rápida progresión y la mortalidad pueden haber estado asociadas a mecanismos hiperinflamatorios, con una producción descontrolada reguladora de citocinas proinflamatorias tanto a nivel local como sistémico. Por lo tanto, en este artículo revisamos la literatura sobre la COVID-19, sus aspectos epidemiológicos y clínicos, así como el papel de las citocinas en el contexto de la infección por SARS-CoV-2, ya que la búsqueda de la comprensión de los mecanismos inmunológicos que rodean la COVID-19 y otras enfermedades inflamatorias es de suma importancia para el tratamiento y la gestión de dichas enfermedades.

Influence of blood hemodynamics on the treatment outcomes of limited fluid resuscitation in emergency patients with traumatic hemorrhagic shock

Abstract Objectives Traumatic hemorrhagic shock is a major death-related factor contributing to mortality in emergencies and can be effectively handled by the Limited Fluid Resuscitation (LFR) method. In the current investigation, the authors analyzed the influence of different administrating blood pressure on the treatment outcomes of LFR. Methods 276 participants were enrolled in the current study retrospectively from January 2016 to December 2021 and were divided into three groups based on the administrating blood pressure of LFR. The difference among the three groups regarding serum levels of cytokines as well as blood hemodynamics parameters was analyzed. Results The results showed after the T2 stage treatment, cytokine levels in the three groups were all significantly influenced by different LFR strategies with medium MAP showing the strongest effects on the expression of all cytokine genes. Moreover, the MAP value was in positive correlation with IL-6, IL-10, and TNF-α levels, but showed no clear relation with IL-4 level in all three groups. Regarding the effects on hemodynamics parameters, the levels of CVP, CO, and CI were slightly increased by the different LFR administrating strategies, and the effect of medium and high MAP was statistically stronger than that of low MAP. Conclusion The present results showed that LFR would influence serum inflammatory levels by improving blood hemodynamics parameters. Medium MAP showed the strongest improving effects with the least side effects, which can be employed as the optimal administrating strategy for LFR in the future.

Mechanism of Hedysari Radix Polysaccharide on Diabetic Nephropathy in db/db Mice Based on JAK2/STAT3 Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo observe the effect of Hedysari Radix polysaccharide （HRP） on the Janus kinase 2 （JAK2）/signal transducer and activator of transcription protein 3 （STAT3） signaling pathway in diabetic nephropathy db/db mice. MethodFifty db/db mice were randomly divided into model group， irbesartan group （irbesartan suspension， 22.75 mg·kg-1）， and high-， medium-， and low-dose HRP groups （HRP suspension， 200， 100， 50 mg·kg-1） according to the body weight， with 10 mice in each group. Another 10 C57BL/6 mice were assigned to the normal group. The mice were treated with corresponding drugs by gavage， while those in the normal group and the model group received distilled water at 5 mL·kg-1. The mice in the six groups were administered once a day by gavage for 12 consecutive weeks. The uric acid （UA）， triglycerides （TG）， and total cholesterol （TC） were detected. Periodic acid-Schiff （PAS） staining and Masson staining were used to observe the pathological changes in kidney tissues. Western blot and Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） were used to detect the protein and mRNA expression levels of JAK2， STAT3， suppressor of cytokine signaling 3 （SOCS3）， and tumor necrosis factor-α （TNF-α） in the kidney. ResultAfter 12 weeks of treatment， compared with the normal group， the model group showed significant pathological ultrastructural changes in kidney tissues and increased UA， TG， and TC levels （P<0.01）. Compared with the model group， the high- and medium-dose HRP groups and the irbesartan group showed improvement in pathological ultrastructure of kidney tissues and reduced UA， TG， and TC levels （P<0.05， P<0.01）. Compared with the normal group， the model group showed a decrease in SOCS3 protein and mRNA expression levels and an increase in JAK2， STAT3， and TNF-α protein and mRNA expression levels （P<0.01）. Compared with the model group， the high- and medium-dose HRP groups and the irbesartan group showed an increase in SOCS3 protein and mRNA expression levels and a decrease in JAK2， STAT3， and TNF-α protein and mRNA expression levels （P<0.05， P<0.01）. ConclusionHRP can alleviate renal damage in diabetic nephropathy to a certain extent， and its mechanism may be related to the inhibition of the activation of the JAK2/STAT3 signaling pathway.

Protective effects of WR-2721 combined with lentinan and cytokines against radiation damage / 中国辐射卫生

@#<b>Objective</b> To investigate the synergistic protective effects of WR-2721 combined with lentinan and cytokines against radiation damage in mice, and to provide a new treatment for acute radiation injury. <b>Methods</b> Seventy Institute of Cancer Research mice were divided into seven groups: a control group, a model group, WR-2721 group, Lentinan & cytokine group, WR-2721 & Lentinan group, WR-2721 & cytokine group and WR-2721 & Lentinan & cytokine group. All groups except the control group were irradiated with ⁶⁰Co γ-rays at a dose rate of 0.8 Gy/min and a cumulative dose of 5.0 Gy. The mice were sacrificed by cervical dislocation 14 d after irradiation to measure their spleen index, thymus index, and serum levels of superoxide dismutase (SOD), malondialdehyde (MDA), interleukin-11 (IL-11), and tumor necrosis factor-alpha (TNF-α). <b>Results</b> For the mice treated with WR-2721, lentinan, and cytokines, the spleen index was 7.33 ± 2.84, the thymus index was 1.70 ± 0.30, the serum SOD level was 114.0 ± 8.3, the MDA level was 7.33 ± 1.16, the IL-11 level was 155.8 ± 49.4, and the TNF-α level was 174.0 ± 37.8. All these indicators except the spleen index in the combination group significantly differed from those of the model group (<i>P</i> < 0.05 or 0.01), indicating the combined treatment promoted recovery from radiation damage. <b>Conclusion</b> WR-2721 combined with lentinan and cytokines has significant synergistic protective effects, which is a promising treatment for acute radiation injury.

Establishment of Poly （I∶C）-induced Cytokine Storm Model in Mice and Intervention Effect of Artesunate and Qingfei Paidu Decoction / 中国实验方剂学杂志

ObjectiveTo observe the intervention effect of artesunate （ART） and Qingfei Paidu decoction （QFPD） on the mouse model of cytokine storm （CS） induced by viral mimic Poly （I∶C）. MethodEighty-four SPF male BALB/c mice were randomly divided into seven groups， with 12 mice in each group. Mice， except for those in the blank group （n=12）， were subjected to CS model induction by tail vein injection of Poly （I∶C） at 15 mg·kg-1， followed by drug treatments of low-dose ART （ART-l， 10 mg·kg-1）， medium-dose ART （ART-m， 20 mg·kg-1）， high-dose ART （ART-h， 40 mg·kg-1）， Qingfei Paidu Decoction （QFPD， 2.4 g·kg-1）， and dexamethasone （DXM， 10 mg·kg-1）. After 6 hours， lung tissues， bronchoalveolar lavage fluid （BALF）， spleen， lung， and peripheral blood were collected. The lung and spleen indexes were calculated and the number of inflammatory cells in BALF was detected. The pathological changes in lung tissues were observed by hematoxylin-eosin （HE） staining and the levels of tumor necrosis factor-α （TNF-α）， interferon-γ （IFN-γ）， interleukin-1β （IL-1β）， and IL-6 in BALF were detected by enzyme-linked immunosorbent assay （ELISA）. The expression of immune cells in BALF and peripheral blood was detected by flow cytometry. ResultThe analysis of lung and spleen indexes showed that compared with the blank group， the model group showed increased lung and spleen indexes to varying degrees （P<0.05）. Compared with the model group， the ART groups showed reduced spleen index （P<0.05） and the ART-l group showed reduced lung index （P<0.05）. Additionally， the QFPD group showed reduced lung and spleen indexes （P<0.05）. ELISA results showed that except for TNF-α， the levels of IFN-γ， IL-1β， and IL-6 in the model group increased compared with those in the blank group （P<0.05）. Compared with the model group， the ART-l group and the QFPD group showed reduced content of TNF-α （P<0.05）， and all groups with drug intervention showed reduced content of IFN-γ， IL-1β， and IL-6 （P<0.05）. The number of inflammatory cells in BALF showed a downward trend in the model group， and the number of cells increased in the groups with drug intervention except for the DXM group （P<0.05）. Flow cytometry showed that compared with the blank group， the model group showed decreased number of CD3 in the peripheral blood （P<0.05）， increased Ly-6G and F4/80 （P<0.05）， decreased expression of CD45， CD3， and F4/80 in BALF （P<0.05）， and increased expressions of Ly-6G （P<0.05）. Compared with the model group， the ART groups and QFPD group showed increased CD45 content in peripheral blood （P<0.05）， decreased Ly-6G and F4/80 content （P<0.05）， increased CD45 and F4/80 content in BALF （P<0.05）， and decreased expression of Ly-6G （P<0.05）. ConclusionART and QFPD have a good protective effect on Poly （I∶C）-induced CS in mice， and the mechanism is related to the effective intervention in immune cell disorder.

Effect of Fangji Fulingtang on Macrophage Polarization and Oxidative Stress in Mouse Model of Myocardial Fibrosis / 中国实验方剂学杂志

ObjectiveTo investigate the effects of Fangji Fulingtang on macrophage polarization and oxidative stress in the mouse model of myocardial fibrosis. MethodThe mouse model of myocardial fibrosis was established by subcutaneous injection of isoproterenol （ISO， 5 mg·kg-1·d-1）. Fifty C57BL/6J mice were randomly assigned into control （0.9% NaCl）， model （0.9% NaCl）， low- and high-dose （3.315 g·kg-1·d-1 and 13.26 g·kg-1·d-1， respectively） Fangji Fulingtang （FFD-L and FFD-H， respectively）， and metoprolol tartrate （Meto， 15 mg·kg-1·d-1） groups， with 10 mice each group. After 2 weeks of treatment， the heart appearance， cardiac weight index （CWI）， heart weight （HW）/tibia length （TL） ratio， and myocardial histopathological alterations were observed. Meanwhile， the serum levels of creatine kinase-MB （CK-MB）， transforming growth factor-β1 （TGF-β1）， tumor necrosis factor-α （TNF-α）， interleukin （IL）-1β， IL-6， IL-10， malondialdehyde （MDA）， superoxide dismutase （SOD）， and glutathione （GSH） were measured by enzyme-linked immunosorbent assay （ELISA）. The expression levels of CD86 and CD206 were observed by immunohistochemical staining. ResultCompared with the model group， the FFD-L， FFD-H， and Meto groups showed improved heart appearance， decreased CWI and HW/TL ratio （P<0.01）， lowered serum levels of CK-MB， TGF-β1， TNF-α， IL-1β， and IL-6 （P<0.05， P<0.01）， and elevated IL-10 level （P<0.05）. Furthermore， the three groups showed reduced infiltration of inflammatory cells， myocardial injury， collagen deposition， and myocardial fibrosis， decreased CD86， SOD， and GSH （P<0.01）， and increased CD206 and MDA （P<0.01）. ConclusionFangji Fulingtang can mitigate ISO-induced myocardial fibrosis by regulating macrophage polarization and oxidative stress.

Dendrobium Polysaccharides Mitigate CSE-induced Inflammatory Damage of Human Bronchial Epithelial Cells via TLR4/NF-κB Pathway / 中国实验方剂学杂志

ObjectiveTo observe the effects of Dendrobium polysaccharides on the secretion of inflammatory cytokines and Toll-like receptor 4 （TLR4）/nuclear factor （NF）-κB pathway in 16HBE cells exposed to cigarette smoke extract （CSE）. MethodThe 16HBE cells were classified into the control， CSE， and CSE+ Dendrobium polysaccharides （100， 200， 400 mg·L-1） groups. The cell-counting kit-8 （CCK-8） assay was employed to measure the cell viability， and a microscope was used to observe the cell morphology. The enzyme-linked immunosorbent assay was employed to measure the levels of interleukin （IL）-8， IL-1β， IL-4， IL-13， and transforming growth factor （TGF）-β in cell culture supernatants. Real-time PCR was carried out to determine the mRNA levels of Toll-like receptor 4 （TLR4）， nuclear factor-κB （NF-κB）， and IL-4. Western blot was employed to determine the protein levels of interleukin-4 receptor （IL-4R）， TLR4， myeloid differentiation primary response protein 88 （MyD88）， NF-κB， phosphorylated nuclear factor-κB （p-NF-κB）， and nucleoproteins nuclear factor-κB （NEs-NF-κB）. The immunofluorescence assay was employed to measure the nuclear translocation of NF-κB. ResultCompared with the control group， the CSE group showed elevated levels of IL-8， IL-1β， IL-4， IL-13， and TGF-β in the cell culture supernatants （P<0.05， P<0.01）， up-regulated expression levels of TLR4， MyD88， NF-κB， p-NF-κB， NEs-NF-κB， and IL-4 （P<0.01）， and significant nuclear translocation of NF-κB. Compared with the CSE group， Dendrobium polysaccharides increased the cell survival rate， recovered the cell activity， lowered the levels of IL-8， IL-1β， IL-4， IL-13， and TGF-β， down-regulated the expression of TLR4， MyD88， NF-κB， p-NF-κB， NEs-NF-κB， and IL-4 （P<0.05， P<0.01）， and reduced the nuclear translocation of NF-κB. ConclusionDendrobium polysaccharides showed significant protective effects on the 16HBE cells exposed to CSE by inhibiting the TLR4/NF-κB signaling pathway.

Effects of overexpression of carbapenem OXA-48 on drug resistance,adaptability of bacterial strain and Toll-like receptor signaling pathway of host cell / 中国生物制品学杂志

@#Objective To investigate the effects of overexpression of OXA-48 on drug resistance,adaptability of bacterial strain and Toll-like receptor(TLR)signaling pathway of host cells. Methods The recombinant plasmid pET32a(+)-OXA-48was transformed into E.coli BL21(DE3),and the recombinant strain pET32a(+)-OXA-48-BL21(DE3)was identified by colony PCR and sequencing. Taking A_(600)(0. 3,0. 5 and 0. 7),IPTG final concentration(0. 4,0. 6 and 0. 8mmol/L)and induction time(2,4 and 6 h)as variables and mRNA transcription level as response value,an orthogonal experiment with three factors and three levels was designed to optimize the induced expression conditions of the plasmid. The drug resistance of recombinant strain pET32a(+)-OXA-48-BL21(DE3)to Imipenem(IPM),Meropenem(MEM),Ceftriaxone(CRO)and Cefepime(FEP)was detected by disk diffusion method;The adaptability was detected by biofilm formation test and serum resistance test. Mouse alveolar macrophages(MH-S)were infected with pET32a(+)-OXA-48-BL21(DE3),pET32a(+)-BL21(DE3)and E.coli BL21(DE3)strains,respectively. The mRNA transcription levels of TLR2,TLR4 and NF-кB(p65)genes were detected by qRT-PCR method,and the expressions of Interleukin-6(IL-6),IL-10,tumor necrosis factor-α(TNF-α)and transforming growth factor-β(TGF-β)were detected by ELISA. Results The recombinant strain pET32a(+)-OXA-48-BL21(DE3)was constructed correctly as identified by colony PCR and sequencing. The optimum induction conditions were as follows:A_(600)of 0. 3,IPTG final concentration of 0. 6 mmol/L and induction time of 2 h. Compared with pET32a(+)-BL21(DE3)strain,the resistance of recombinant strain pET32a(+)-OXA-48-BL21(DE3)to IPM,MEM,CRO and FEP significantly decreased(t = 7. 14～22. 32,P < 0. 05),the biofilm formed significantly increased(t = 15. 69,P < 0. 05),and the survival rate in serum significantly increased(t = 10. 60,P < 0. 05);The mRNA transcription level of TLR2 gene in MH-S cells infected with pET32a(+)-OXA-48-BL21(DE3)significantly increased 24 h after infection(t = 5. 77,P < 0. 05),while the mRNA transcription level of TLR4 and NF-кB(p65)genes(t = 3. 71～10. 06,P < 0. 05)and the expression level of IL-6 significantly increased 12 and 24 h after infection. Compared with the normal group,the expression of IL-6and TNF-α in MH-S cells infected with pET32a(+)-OXA-48-BL21(DE3)increased significantly at 6,12 and 24 h after infection(t = 7. 90 ～ 13. 44 and 5. 40～6. 32 respectively,each P < 0. 01),while the expression of IL-10 decreased significantly(t = 3. 15～4. 08,each P < 0. 05). There was no significant difference in the expression of TGF-β(t = 0. 013～1. 41,each P > 0. 05). The expression of IL-6 was significantly higher than that in pET32a(+)-BL21(DE3)group at 12 and 24 h after infection(t = 2. 92 and 3. 79 respectively,each P < 0.05) Conclusion Overexpression of OXA-48 can reduce bacterial drug resistance,improve bacterial adaptability and the transcription level of factors related to TLR signaling pathway in host cells,and affect the expression level of downstream cytokines in host cells.