Research progress of immunotherapies on correction of immunoparalysis in sepsis / 药学实践杂志

Immunoparalysis is the main cause of death in patients with intermediate and terminal sepsis. The correction of immunoparalysis is an important direction of sepsis treatment. In the pathological process of sepsis, a variety of factors contribute to the imbalanced secretion of cytokines, weakened function of antigen-presenting cells, apoptosis and depletion of lymphocytes, and ultimately lead to immunoparalysis, secondary infection, and even patient deaths. Cytokines such as GM-CSF, IFN-γ, IL-7, and IL-15, immune checkpoint-related therapies such as PD-1/PD-L1 antibodies, CTLA-4 antibodies, TIM-3 antibodies, and LAG-3 antibodies, and immunoreactive substances such as thymosin α1 and immunoglobulin might be beneficial to correct the immune paralysis of patients. the progress of immunotherapy to correct immune paralysis in sepsis were reviewed in this article.

Prognostic significance of immunoparesis in newly diagnosed multiple myeloma patients who achieved deep response / 中华内科杂志

Objective:To evaluate the effect of immune status on disease progression in patients with newly diagnosed multiple myeloma (NDMM) achieving deep response.Methods:Clinical data of 125 NDMM patients at Beijing Chaoyang Hospital from August 2015 to February 2020 were retrospectively analyzed who achieved very good partial response (VGPR) or better after front-line treatment. The immune status and its influence on progression-free survival (PFS) were analyzed.Results:(1) All patients received novel drug regimens, and 50.4% (63/125) patients followed by autologous stem cell transplantation (ASCT). The rate of complete response (CR) as best efficacy was 89.6%, in which 66.4% achieved CR and MRD negativity tested by second generation flow cytometry. (2) Cox multivariate analysis suggested that persistent severe immunoparesis 3 months and 6 months since the best response was an independent poor prognostic factor for PFS. (3) The 3-year PFS rate in the severe immunoparesis group was significantly lower than that in the control group (41.3% vs. 64.4%, P=0.021). (4) The 3-year PFS rates in patients with persistent severe immunoparesis at 3 months or 6 months were significantly lower (30.0% vs. 63.5%, P<0.001; 16.4% vs. 63.8%, P<0.001 respectively). (5) Even in those achieving CR and negative MRD, the 3-year PFS rate when severe immunoparesis lasted 6 months was significantly lower (22.2% vs. 83.2%, P=0.005). Conclusion:The immune status in NDMM patients achieving deep response is closely related to survival. Persistent severe immunoparesis indicates early progression of the disease.

Immunosuppression of sepsis / 国际儿科学杂志

Sepsis is an infectious disease that affects immune function by various inflammatory factors and is the main cause of death in ICU patients. As a syndrome caused by uncontrollable inflammation,sepsis not only contains a large number of continuous inflammatory reactions,but also has a long-term immunosuppressive state,which increases the probability of secondary nosocomial infection in patients with sepsis. The immune sta-tus of patients with sepsis will change with the progression of the disease,and different biomarkers help to ex-plain the immune stage of patients. Immune-enhancing therapy is expected to reduce the mortality rate of sepsis patients in the stage of immunoparalysis.

Lymphocyte count as a sign of immunoparalysis and its correlation with nutritional status in pediatric intensive care patients with sepsis: A pilot study

OBJECTIVES: Developing malnutrition during hospitalization is well recognized worldwide, and children are at a relatively higher risk for malnutrition than adults. Malnutrition can lead to immune dysfunction, which is associated with a higher mortality rate due to sepsis, the most frequent cause of death in pediatric intensive care units (PICUs). The aim of this study was to investigate whether malnourished patients are more likely to have relative or absolute lymphopenia and, consequently, worse prognoses. METHODS: We enrolled 14 consecutive patients with sepsis whose legal representatives provided written informed consent. Patients were classified as normal or malnourished based on anthropometric measurements. As an additional evaluation of nutritional status, serum albumin and zinc were measured on the 1st and 7th days of hospitalization. Lymphocyte count was also measured on the 1st and 7th days. Clinicaltrials.gov: NCT02698683. RESULTS: Malnutrition prevalence rates were 33.3% and 42.8% based on weight and height, respectively. Laboratory analyses revealed a reduction of serum albumin in 100% of patients and reduction of zinc in 93.3% of patients. A total of 35% of patients had fewer than 500 lymphocytes/mm3 on their first day in the PICU. Lymphocyte counts and zinc concentrations significantly increased during hospitalization. CONCLUSIONS: Nutritional evaluations, including anthropometric measurements, were not correlated with lymphocyte counts. Lymphocyte counts concomitantly increased with zinc levels, suggesting that micronutrient supplementation benefits patients with sepsis.

"Reproduction of a model of ""two-hit"" sepsis model with complication of pneumonia in rat" / 中华危重病急救医学

ObjectiveTo reproduce a clinically relevant two-hit model of sepsis complicated by pneumonia and to explore the correlation between two-hit and immune state.Methods Eighty-one male Sprague-Dawley ( SD ) rats were divided into groups according to the random number table. Forty-five male rats were assigned respectively to sepsis-alone group, pneumonia 4 days and 7 days after sepsis groups, respectively. Survival rate of each group was observed. Another group of 36 male rats were divided into normal control group, sepsis-alone for 1, 4 and 7 days groups, and sepsis complicated by pneumonia for 4 days and 7 days after sepsis groups, each group consisted of 6 rats. Cecal ligation and puncture (CLP) was done in rats, andStreptococcus pneumoniae suspension (bacteria count 1×1010 cfu/mL) was injected via the nose on the 4th day or 7th day after CLP. Rats were sacrificed at corresponding time points, and 1 day after challenge ofStreptococcus pneumoniae on the 4 days or 7 days post CLP for the collection of blood and tissue samples to make bacterial count of the blood, splenocyte count, biochemical indices, cytokines concentration, pathological changes in spleen and apoptotic cells.Results① Compared with the rats of sepsis-alone group, the rats in pneumonia 4 days after CLP group had poor survival rate (4 vs. 11,χ2 = 6.533,P = 0.011), while no difference was found between pneumonia 7 days after CLP group and sepsis-alone group (9 vs. 11,χ2 = 0.600,P = 0.439).② The blood bacterial count and all the biochemical indexes were sharply increased on 1 day post-CLP in the rats of sepsis-alone group, and then they gradually lowered. Compared with the rats of 1 day post-CLP, the proportion of splenocytes were decreased on the 4th day post-CLP [dendritic cells (DC): (0.69±0.09)% vs. (0.87±0.31)%, CD4+T cells: (21.05±2.89)% vs. (24.84±4.59)%, CD8+ T cells: (10.62±1.79)% vs. (13.40±1.31)%, allP 0.05). The same trend of changes, with slight reduction in splenocytes and biochemical indices were found between the groups of sepsis followed by pneumonia and sepsis-alone, but no significant difference was found. The level of HMGB1 in the 4-day group of sepsis with complication of pneumonia was further decreased compared with sepsis-alone group (μg/L:1.17±0.74 vs. 1.76±0.71,P 0.05).Conclusions The mortality of this two-hit model with complication of pneumonia 4 days after CLP was significantly higher than that of single sepsis model. The ability of bacteria clearance was decreased, and immunocyte apoptosis was exacerbated. These findings may be with the result of the occurrence of immunoparalysis in the mid stage of sepsis. The two-hit model reproduced on 7 days after CLP might suggest reconstruction of host immune function, and maybe associated with the recovery of immune response.

Shock séptico en la Unidad de Cuidados Intensivos: terapéutica avanzada, inmunoparálisis y genómica. Estado del arte / Septic shock in ICU: Advanced therapeutics, immunoparalysis and genomics. State of the art

En las últimas décadas, se han incorporado nuevos y trascendentes conceptos para el tratamiento avanzado del paciente en shock séptico. Se debe considerar el uso de terapia inmune en grupos seleccionados de pacientes. Las terapias de sustitución renal de carácter continuo son bien toleradas y su empleo precoz evita sobrecargas de fluidos. El uso de hemofiltración de alto volumen puede jugar un papel en el paciente séptico hiperdinámico. La plasmaféresis es útil en el paciente con disfunción multiorgánica. El empleo de soporte extracorpóreo se debe considerar en quienes presentan shock séptico refractario. La inmunoparálisis se ha asociado con infecciones nosocomiales y mortalidad tardía. La información obtenida de los marcadores genéticos puede permitir la búsqueda de una medicina basada en la genómica

New and important concepts have emerged for the advanced management of the child with septic shock in the recent decades. Attending physicians in the Pediatric intensive care unit must be fully aware of them to improve patient care in the critical care unit. It should be considered the use of immune therapy only in selected groups of patients. Continuous renal replacement therapies are well tolerated and their early use prevents deleterious fluid overload. Removal of inflammatory mediators by using high volume hemofiltration may play a role in hyperdynamic septic patients. The use of plasmapheresis is recommended in patients with thrombocytopenia-associated multiple organ failure. Extracorporeal support use should be considered in those with refractory septic shock despite goals directed therapy. The immunoparalysis has been associated with nosocomial infections and late mortality. The information from genetic markers may allow early intervention and preventive genomics-based medicine

Epidemiologia, diagnóstico, marcadores de imunocompetência e prognóstico da sepse / Epidemiology, diagnosis, markers of immunocompetence and prognosis of sepsis

Apesar de uma diversidade de estudos científicos, em que dezenas de milhares de pacientes foram analisados e tratados, a sepse continua sendo um grande desafio para a medicina contemporânea. Investigações bem conduzidas levaram a uma reavaliação do modelo clássico da sepse, tradicionalmente vista como um processo descontrolado de hiperinflamação sistêmica, uma vez que observou-se a existência de uma atividade antiinflamatória ao longo do seu curso evolutivo. Nesse contexto, o comportamento do sistema imune inato se assemelha ao de indivíduos idosos submetidos ao fenômeno da imunossenescência, interseção ainda mais relevante ao considerarmos o crescente incremento na faixa etária média dos pacientes internados em UTI. O presente estudo visou a estabelecer a epidemiologia da sepse em um hospital público de um país de renda media, como é o caso do Brasil. Ademais, através de citometria de fluxo, buscamos definir a cinética da expressão monocitária de moléculas HLA-DR e CD64 ao longo do processo de envelhecimento humano. Comparamos essas observações com o comprometimento do sistema imune inato visto na sepse visando discriminar as alterações da senescência do sistema imune associada ao envelhecimento daquelas associadas ao fenômeno da imunoparalisia da sepse. Na investigação epidemiológica, nós encontramos uma taxa de ocorrência de 5,9 casos de sepse por 100 pacientes e uma densidade de incidência de 6,4 casos por 1000 pacientes-dia. Documentamos ainda sua associação com uma elevada incidência de sepse e documentamos sua associação com uma elevada taxa de comorbidades crônicas. A sepse foi diagnosticada tardiamente (72% dos casos após 12 horas de evolução) e em estágio avançado como atestado pelos elevados escores de gravidade de doença e de disfunção orgânica. O presente estudo identificou vários obstáculos à efetiva implementação das recomendações da Surviving Sepsis Campaign. No segundo estudo, observamos correlações negativas significativas entre idade...