Contribution of Dendritic Cell Responses to Sepsis-Induced Immunosuppression and to Susceptibility to Secondary Pneumonia.
Bouras Marwan,Asehnoune Karim,Roquilly Antoine
Frontiers in immunology
Dendritic cells (DCs) are bone marrow derived cells which continuously seed in peripheral tissue. During infection, DCs play an essential interface between innate and adaptive immunity. Pneumonia is a lung inflammation triggered by pathogens and is characterized by excessive release of inflammatory cytokines that activate innate and acquired immunity. Pneumonia induces a rapid and protracted state of susceptibility to secondary infection, a state so-called sepsis-induced immunosuppression. In this review, we focus on the role of DCs in the development of this state of immunosuppression. Early during inflammation, activated DCs are characterized by decreased capacity of antigen (cross)- presentation of newly encountered antigens and decreased production of immunogenic cytokines, and sepsis-induced immunosuppression is mainly explained by a depletion of immature DCs which had all become mature. At a later stage, newly formed respiratory immature DCs are locally programmed by an immunological scare left-over by inflammation to induce tolerance. Tolerogenic Blimp1+ DCs produce suppressive cytokines such as tumor growth factor-B and participate to the maintenance of a local tolerogenic environment notably characterized by accumulation of Treg cells. In mice, the restoration of the immunogenic functions of DCs restores the mucosal immune response to pathogens. In humans, the modulation of inflammation by glucocorticoid during sepsis or trauma preserves DC immunogenic functions and is associated with resistance to secondary pneumonia. Finally, we propose that the alterations of DCs during and after inflammation can be used as biomarkers of susceptibility to secondary pneumonia and are promising therapeutic targets to enhance outcomes of patients with secondary pneumonia.
10.3389/fimmu.2018.02590
Incidence, Risk Factors, and Attributable Mortality of Secondary Infections in the Intensive Care Unit After Admission for Sepsis.
van Vught Lonneke A,Klein Klouwenberg Peter M C,Spitoni Cristian,Scicluna Brendon P,Wiewel Maryse A,Horn Janneke,Schultz Marcus J,Nürnberg Peter,Bonten Marc J M,Cremer Olaf L,van der Poll Tom,
JAMA
IMPORTANCE:Sepsis is considered to induce immune suppression, leading to increased susceptibility to secondary infections with associated late mortality. OBJECTIVE:To determine the clinical and host genomic characteristics, incidence, and attributable mortality of intensive care unit (ICU)-acquired infections in patients admitted to the ICU with or without sepsis. DESIGN, SETTING, AND PARTICIPANTS:Prospective observational study comprising consecutive admissions of more than 48 hours in 2 ICUs in the Netherlands from January 2011 to July 2013 stratified according to admission diagnosis (sepsis or noninfectious). MAIN OUTCOMES AND MEASURES:The primary outcome was ICU-acquired infection (onset >48 hours). Attributable mortality risk (fraction of mortality that can be prevented by elimination of the risk factor, acquired infection) was determined using time-to-event models accounting for competing risk. In a subset of sepsis admissions (n = 461), blood gene expression (whole-genome transcriptome in leukocytes) was analyzed at baseline and at onset of ICU-acquired infectious (n = 19) and noninfectious (n = 9) events. RESULTS:The primary cohort included 1719 sepsis admissions (1504 patients; median age, 62 years; interquartile range [IQR], 51-71 years]; 924 men [61.4%]). A comparative cohort included 1921 admissions (1825 patients, median age, 62 years; IQR, 49-71 years; 1128 men [61.8%] in whom infection was not present in the first 48 hours. Intensive care unit-acquired infections occurred in 13.5% of sepsis ICU admissions (n = 232) and 15.1% of nonsepsis ICU admissions (n = 291). Patients with sepsis who developed an ICU-acquired infection had higher disease severity scores on admission than patients with sepsis who did not develop an ICU-acquired infection (Acute Physiology and Chronic Health Evaluation IV [APACHE IV] median score, 90 [IQR, 72-107] vs 79 [IQR, 62-98]; P < .001) and throughout their ICU stay but did not have differences in baseline gene expression. The population attributable mortality fraction of ICU-acquired infections in patients with sepsis was 10.9% (95% CI, 0.9%-20.6%) by day 60; the estimated difference between mortality in all patients with a sepsis admission diagnosis and mortality in those without ICU-acquired infection was 2.0% (95% CI, 0.2%-3.8%; P = .03) by day 60. Among nonsepsis ICU admissions, ICU-acquired infections had a population attributable mortality fraction of 21.1% (95% CI, 0.6%-41.7%) by day 60. Compared with baseline, blood gene expression at the onset of ICU-acquired infections showed reduced expression of genes involved in gluconeogenesis and glycolysis. CONCLUSIONS AND RELEVANCE:Intensive care unit-acquired infections occurred more commonly in patients with sepsis with higher disease severity, but such infections contributed only modestly to overall mortality. The genomic response of patients with sepsis was consistent with immune suppression at the onset of secondary infection.
10.1001/jama.2016.2691
Recurrent Sepsis Exacerbates CD4 T Cell Exhaustion and Decreases Antiviral Immune Responses.
He Wanxue,Xiao Kun,Xu Jiaruo,Guan Wei,Xie Sheling,Wang Kaifei,Yan Peng,Fang Min,Xie Lixin
Frontiers in immunology
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to an infection. It is a disease with a high incidence, mortality, and recurrence rate and frequently results in its survivors requiring readmission into hospitals. The readmission is mainly due to recurrent sepsis. Patients with recurrent sepsis are more susceptible to secondary infections partly due to immune dysfunction, leading to a higher mortality in the long term. However, there remains a gap in the understanding of immunological characteristics and underlying mechanisms of recurrent sepsis. In this study, we used mouse models of acute and recurrent sepsis to investigate their different immunological characteristics. And then we subjected the two mouse models to a secondary influenza A virus (H1N1) infection and characterized the different immune responses. Here, we demonstrated that CD4 T cells present an exacerbated exhaustion phenotype in response to recurrent sepsis as illustrated by the decreased frequency of CD4 T cells, reduced co-stimulatory CD28 and increased inhibitory PD-1 and Tim-3 expression on CD4 T cells, increased frequency of regulatory T cells, and reduced MHC-II expression on antigen-presenting cells. Moreover, we showed that antiviral immune responses decrease in the recurrent sepsis mouse model subjected to a secondary infection as illustrated by the reduced pathogen clearance and inflammatory response. This may be a consequence of the exacerbated CD4 T cell exhaustion. In summary, recurrent sepsis exacerbates CD4 T cell exhaustion and decreases antiviral immune responses, contributing to significant morbidity, increased late mortality, and increased health care burden in recurrent sepsis patients.
10.3389/fimmu.2021.627435
Sepsis induces early alterations in innate immunity that impact mortality to secondary infection.
Delano Matthew J,Thayer Terri,Gabrilovich Sonia,Kelly-Scumpia Kindra M,Winfield Robert D,Scumpia Philip O,Cuenca Alex G,Warner Elizabeth,Wallet Shannon M,Wallet Mark A,O'Malley Kerri A,Ramphal Reuben,Clare-Salzer Michael,Efron Philip A,Mathews Clayton E,Moldawer Lyle L
Journal of immunology (Baltimore, Md. : 1950)
Sepsis, the systemic inflammatory response to microbial infection, induces changes in both innate and adaptive immunity that presumably lead to increased susceptibility to secondary infections, multiorgan failure, and death. Using a model of murine polymicrobial sepsis whose severity approximates human sepsis, we examined outcomes and defined requirements for survival after secondary Pseudomonas aeruginosa pneumonia or disseminated Listeria monocytogenes infection. We demonstrate that early after sepsis neutrophil numbers and function are decreased, whereas monocyte recruitment through the CCR2/MCP-1 pathway and function are enhanced. Consequently, lethality to Pseudomonas pneumonia is increased early but not late after induction of sepsis. In contrast, lethality to listeriosis, whose eradication is dependent upon monocyte/macrophage phagocytosis, is actually decreased both early and late after sepsis. Adaptive immunity plays little role in these secondary infectious responses. This study demonstrates that sepsis promotes selective early, impaired innate immune responses, primarily in neutrophils, that lead to a pathogen-specific, increased susceptibility to secondary infections.
10.4049/jimmunol.1002104
Reduced Immunocompetent B Cells and Increased Secondary Infection in Elderly Patients With Severe Sepsis.
Suzuki Kodai,Inoue Shigeaki,Kametani Yoshie,Komori Yukako,Chiba Sayuri,Sato Takehito,Inokuchi Sadaki,Ogura Shinji
Shock (Augusta, Ga.)
Lymphocyte exhaustion was recently recognized as a mechanism of immunosuppression in sepsis. While B cells are known to play pivotal roles in bacterial infection and sepsis, changes in B-cell-mediated humoral immunity have not been evaluated in critically ill septic patients. We aimed to investigate changes in humoral immunity caused by defective B-cell function during severe sepsis. Thirty-three severe sepsis patients and 44 healthy subjects were prospectively enrolled. Blood was collected from patients within 72 h of and 8 to 11 h after sepsis onset to measure B-cell subtypes, serum immunoglobulin M concentration, and CpG-B oligodeoxynucleotide-induced immunoglobulin M (IgM) production ex vivo. Participants were divided into two age groups: adults (18-64 years) and elderly (≥65 years). The fraction of CD21 exhausted B cells in acute sepsis patients (3.18%) was higher than that observed in healthy donors (0.77%, respectively, P <0.01). Significantly, serum IgM in elderly septic patients (≥65 years) was negatively correlated with acute physiology and chronic health evaluation II score (r = -0.57, P <0.05). Consistently, in B cells stimulated ex vivo, both aging and sepsis induced significant reductions in supernatant IgM (P <0.01). This finding was clinically relevant, as elderly patients with decreased IgM production might be more susceptible to infection by Gram-negative bacteria and fungi. Reduced immunocompetent B cells may be related to increased secondary infection after sepsis, especially in the elderly. Finally, impaired humoral immunity with increased CD21 exhausted B cells and insufficient immunoglobulin M production may be a critical immunological change in sepsis.
10.1097/SHK.0000000000000619
The Host Response in Patients with Sepsis Developing Intensive Care Unit-acquired Secondary Infections.
van Vught Lonneke A,Wiewel Maryse A,Hoogendijk Arie J,Frencken Jos F,Scicluna Brendon P,Klein Klouwenberg Peter M C,Zwinderman Aeilko H,Lutter Rene,Horn Janneke,Schultz Marcus J,Bonten Marc M J,Cremer Olaf L,van der Poll Tom
American journal of respiratory and critical care medicine
RATIONALE:Sepsis can be complicated by secondary infections. We explored the possibility that patients with sepsis developing a secondary infection while in the intensive care unit (ICU) display sustained inflammatory, vascular, and procoagulant responses. OBJECTIVES:To compare systemic proinflammatory host responses in patients with sepsis who acquire a new infection with those who do not. METHODS:Consecutive patients with sepsis with a length of ICU stay greater than 48 hours were prospectively analyzed for the development of ICU-acquired infections. Twenty host response biomarkers reflective of key pathways implicated in sepsis pathogenesis were measured during the first 4 days after ICU admission and at the day of an ICU-acquired infection or noninfectious complication. MEASUREMENTS AND MAIN RESULTS:Of 1,237 admissions for sepsis (1,089 patients), 178 (14.4%) admissions were complicated by ICU-acquired infections (at Day 10 [6-13], median with interquartile range). Patients who developed a secondary infection showed higher disease severity scores and higher mortality up to 1 year than those who did not. Analyses of biomarkers in patients who later went on to develop secondary infections revealed a more dysregulated host response during the first 4 days after admission, as reflected by enhanced inflammation, stronger endothelial cell activation, a more disturbed vascular integrity, and evidence for enhanced coagulation activation. Host response reactions were similar at the time of ICU-acquired infectious or noninfectious complications. CONCLUSIONS:Patients with sepsis who developed an ICU-acquired infection showed a more dysregulated proinflammatory and vascular host response during the first 4 days of ICU admission than those who did not develop a secondary infection.
10.1164/rccm.201606-1225OC
Incidence, risk factors and impact on outcomes of secondary infection in patients with septic shock: an 8-year retrospective study.
Zhao Guang-Ju,Li Dong,Zhao Qian,Song Jia-Xing,Chen Xiao-Rong,Hong Guang-Liang,Li Meng-Fang,Wu Bing,Lu Zhong-Qiu
Scientific reports
Secondary infection in septic patients has received widespread attention, although clinical data are still lacking. The present study was performed on 476 patients with septic shock. Time trends for mortality were analyzed using Spearman's rank correlation test. Risk factors for secondary infection were investigated by binary logistic regression. The extended Cox model with time-varying covariates and hazard ratios (HR) was performed to determine the impact of secondary infection on mortality. Differences in hospital length of stay (LOS) between patients with and without secondary infection were calculated using a multistate model. Thirty-nine percent of septic shock patients who survived the early phase of the disease developed secondary infection. There was a statistically significant increased odds ratio for secondary infection in older patients and patients with a longer LOS in the intensive care unit (ICU), a higher Sequential Organ Failure Assessment (SOFA) score, and endotracheal intubation. Secondary infection significantly reduced the rate of discharge (HR 5.607; CI 3.612-8.704; P < 0.001) and was associated with an increased hospital LOS of 5.46 days. The present findings represent a direct description of secondary infection in septic shock patients and highlight the influence of this condition on septic shock outcomes.
10.1038/srep38361
The pathogens of secondary infection in septic patients share a similar genotype to those that predominate in the gut.
Mu Sucheng,Xiang Hao,Wang Yuezhu,Wei Wei,Long Xiangyu,Han Yi,Kuang Zhongshu,Yang Yilin,Xu Feixiang,Xue Mingming,Dong Zhimin,Tong Chaoyang,Zheng Huajun,Song Zhenju
Critical care (London, England)
BACKGROUND:Secondary nosocomial infections, which are commonly caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) and vancomycin-resistant Enterococcus faecium (VRE), often develop in septic patients. This study aimed to identify the origin of secondary systemic pathogens and reveal the underlying mechanism of infection. METHODS:In this prospective, observational case-control study, a total of 34 septic patients, 33 non-septic intensive care unit (ICU) patients and 10 healthy individuals serving as controls were enrolled. Three hundred and twelve fecal samples were collected and subjected to 16S rRNA gene amplicon sequencing. Metagenome sequencing was performed to identify the homology between dominant CRKP or VRE in the intestine and pathogens isolated from secondary infectious sites. C57/BL mice were established as pseudo germ-free animal model by pretreatment with broad-spectrum antibiotics for two weeks. RESULTS:The abundance and diversity of the gut microbiota in septic patients was drastically decreased one week after ICU admission, potentially leading to the enrichment of antibiotic-resistant bacteria, such as CRKP. Furthermore, secondary bloodstream and abdominal infections caused by CRKP or VRE in septic patients occurred after intestinal colonization with the predominant bacterial species. Genomic analysis showed that bacteria isolated from secondary infection had high homology with the corresponding predominant intestinal opportunistic pathogens. In addition, animal model experiments validated the hypothesis that the administration of antibiotics caused the enrichment of CRKP and VRE among the intestinal microbiota, increasing the likelihood of permeation of other tissues and potentially causing subsequent systemic infection in pseudo germ-free mice. CONCLUSION:Our study indicated that the pathogens causing secondary infection in septic patients might originate from the intestinal colonization of pathogens following broad-spectrum antibiotic treatment.
10.1186/s13054-022-03943-z
The underlying changes and predicting role of peripheral blood inflammatory cells in severe COVID-19 patients: A sentinel?
Sun Da-Wei,Zhang Dong,Tian Run-Hui,Li Yang,Wang Yu-Shi,Cao Jie,Tang Ying,Zhang Nan,Zan Tao,Gao Lan,Huang Yan-Zhu,Cui Chang-Lei,Wang Dong-Xuan,Zheng Yang,Lv Guo-Yue
Clinica chimica acta; international journal of clinical chemistry
BACKGROUND:The underlying changes of peripheral blood inflammatory cells (PBICs) in COVID-19 patients are little known. Moreover, the risk factors for the underlying changes of PBICs and their predicting role in severe COVID-19 patients remain uncertain. MATERIAL AND METHODS:This retrospective study including two cohorts: the main cohort enrolling 45 patients of severe type serving as study group, and the secondary cohort enrolling 12 patients of no-severe type serving as control group. The PBICs analysis was based on blood routine and lymphocyte subsets. The inflammatory cell levels were compared among patients according to clinical classifications, disease-associated phases, as well as one-month outcomes. RESULTS:Compared with patients of non-severe type, the patients of severe type suffered from significantly decreased counts of lymphocytes, eosinophils, basophils, but increased counts of neutrophils. These PBICs alterations got improved in recovery phase, but persisted or got worse in aggravated phase. Compared with patients in discharged group, the patients in un-discharged/died group suffered from decreased counts of total T lymphocytes, CD4 + T lymphocytes, CD8 + T lymphocytes, as well as NK cells at 2 weeks after treatment. Clinical classification-critically severe was the independently risk factor for lymphopenia (OR = 7.701, 95%CI:1.265-46.893, P = 0.027), eosinopenia (OR = 5.595, 95%CI:1.008-31.054, P = 0.049), and worse one-month outcome (OR = 8.984; 95%CI:1.021-79.061, P = 0.048). CONCLUSION:Lymphopenia and eosinopenia may serve as predictors of disease severity and disease progression in COVID-19 patients, and enhancing the cellular immunity may contribute to COVID-19 treatment. Thus, PBICs might become a sentinel of COVID-19, and it deserves attention during COVID-19 treatment.
10.1016/j.cca.2020.05.027
Lymphocyte subset (CD4+, CD8+) counts reflect the severity of infection and predict the clinical outcomes in patients with COVID-19.
Liu Zeming,Long Wei,Tu Mengqi,Chen Sichao,Huang Yihui,Wang Shipei,Zhou Wei,Chen Danyang,Zhou Ling,Wang Min,Wu Meng,Huang Qi,Xu Haibo,Zeng Wen,Guo Liang
The Journal of infection
10.1016/j.jinf.2020.03.054
Neutrophil to CD4+ lymphocyte ratio as a potential biomarker in predicting virus negative conversion time in COVID-19.
International immunopharmacology
BACKGROUND:Since December 2019, novel coronavirus (SARS-CoV-2)-infected pneumonia (COVID-19) occurred in Wuhan, and rapidly spread throughout China. Our study aimed to evaluate the robustness of neutrophil to CD4+ lymphocyte ratio (NCD4LR) in predicting the negative conversion time (NCT) of SARS-CoV-2 in COVID-19 patients. METHODS:Univariate and multivariate analysis were conducted to evaluate the independency of NCD4LR in predicting NCT. Receiver operating characteristic (ROC) curve analysis and area under the curve (AUC) were used to assess the diagnostic accuracy. RESULTS:Compared with low NCD4LR patients, patients with high NCD4LR had an older age; higher incidence of fever, fatigue, chest distress/breath shortness, severer disease assessment on admission; higher levels of inflammatory indicators; low levels of lymphocyte subsets, and a longer NCT. Multivariate analysis also identified NCD4LR as an independent risk factor for delayed NCT. ROC analysis showed that NCD4LR had a better performance than neutrophil to lymphocyte ratio in predicting the virus negative conversion within 2 weeks (AUC = 0.772), 3 weeks (AUC = 0.710), 4 weeks (AUC = 0.728), or 5 weeks (AUC = 0.815). CONCLUSION:This study suggests that NCD4LR is a potential and useful biomarker for predicting the virus negative conversion time in COVID-19 patients. Furthermore, due to the NCDLR value is easily calculated, it can be widely used as a clinical biomarker for disease progression and clinical outcomes in COVID-19 patients.
10.1016/j.intimp.2020.106683
Reduced Counts of Various Subsets of Peripheral Blood T Lymphocytes in Patients with Severe Course of COVID-19.
Bulletin of experimental biology and medicine
This study was intended to define T lymphocyte subsets in different clinical groups of COVID-19-infected patients to explore the interaction between T cell-mediated immune response and the severity of COVID-19 course. Lymphopenia in patients with severe COVID-19 was found. In patients with severe COVID-19 course, the absolute counts of CD3, CD4, and CD8 T lymphocytes at admission were lower than on day 14 after discharge. Further analysis showed that the older were the patients with COVID-19, the more likely they developed severe infection. The results confirmed the significance of T lymphocytes in the clearance of the COVID-19.
10.1007/s10517-022-05464-9
Lymphocyte Subset Alteration and Monocyte CD4 Expression Reduction in Patients with Severe COVID-19.
Kazancioglu Sumeyye,Yilmaz Fatma Meric,Bastug Aliye,Sakallı Arzu,Ozbay Bahadır Orkun,Buyuktarakci Cansu,Bodur Hurrem,Yilmaz Gulsen
Viral immunology
The spectrum of coronavirus disease 2019 (COVID-19) severity, related to cellular immune functions, has not been fully clarified yet. Therefore, this study aimed to investigate the alteration of peripheral blood cells in patients with COVID-19. The flow cytometric characterization of immune cell subset was performed on 69 COVID-19 patients and 21 healthy controls. These data were evaluated based on the disease severity. A total of 69 patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were classified as asymptomatic infection ( = 14), nonsevere ( = 39), and severe ( = 16) groups. Decreased lymphocytes and increased CD14 + 4- monocytes are found in patients with severe COVID-19. Decreased CD4 expression level was observed in the monocytes of patients with severe COVID-19. The total lymphocytes, B and T lymphocytes, CD4+ cells and CD8+ cells, and natural killer (NK) and natural killer T (NKT) cells were found to be decreased in patients with severe COVID-19. The CD4+/CD8+ ratio was not significantly different between patients with COVID-19 and healthy controls. The percentage of activated T cells (CD3+HLA-DR+) and B cells (CD19+CD38+) was lower in patients with severe COVID-19. Age and CD4- monocytes were independent predictors of disease severity. The SARS-CoV-2 infection may affect lymphocyte subsets, resulting in decreased T and B cells, monocytes, and NK and NKT cells. Decreased CD4 expression level by monocytes was significantly correlated with disease severity. Further studies on the host immune response to SARS-CoV-2 infection are necessary to predict the disease severity and protect against the virus.
10.1089/vim.2020.0166
Characteristics of Peripheral Lymphocyte Subset Alteration in COVID-19 Pneumonia.
Wang Fan,Nie Jiayan,Wang Haizhou,Zhao Qiu,Xiong Yong,Deng Liping,Song Shihui,Ma Zhiyong,Mo Pingzheng,Zhang Yongxi
The Journal of infectious diseases
BACKGROUND:In December 2019, novel coronavirus (SARS-CoV-2) pneumonia (COVID-19) was reported in Wuhan and has since rapidly spread throughout China. We aimed to clarify the characteristics and clinical significance of peripheral lymphocyte subset alteration in COVID-19. METHODS:The levels of peripheral lymphocyte subsets were measured by flow cytometry in 60 hospitalized COVID-19 patients before and after treatment, and their association with clinical characteristics and treatment efficacy was analyzed. RESULTS:Total lymphocytes, CD4+ T cells, CD8+ T cells, B cells, and natural killer (NK) cells decreased in COVID-19 patients, and severe cases had a lower level than mild cases. The subsets showed a significant association with inflammatory status in COVID-19, especially CD8+ T cells and CD4+/CD8+ ratio. After treatment, 37 patients (67%) showed clinical response, with an increase in CD8+ T cells and B cells. No significant change in any subset was detected in nonresponsive cases. In multivariate analysis, posttreatment decrease in CD8+ T cells and B cells and increase in CD4+/CD8+ ratio were indicated as independent predictors of poor efficacy. CONCLUSIONS:Peripheral lymphocyte subset alteration was associated with clinical characteristics and treatment efficacy of COVID-19. CD8+ T cells tended to be an independent predictor for COVID-19 severity and treatment efficacy.
10.1093/infdis/jiaa150
Clinical Outcome Prediction in COVID-19 Patients by Lymphocyte Subsets Analysis and Monocytes' iTNF-α Expression.
Biology
In December 2019, a novel coronavirus, "SARS-CoV-2", was recognized as the cause of coronavirus disease 2019 (COVID-19). Several studies have explored the changes and the role of inflammatory cells and cytokines in the immunopathogenesis of the disease, but until today, the results have been controversial. Based on these premises, we conducted a retrospective assessment of monocyte intracellular TNF-α expression (iTNF-α) and on the frequencies of lymphocyte sub-populations in twenty-five patients with moderate/severe COVID-19. We found lymphopenia in all COVID-19 infected subjects compared to healthy subjects. On initial observation, in patients with favorable outcomes, we detected a high absolute eosinophil count and a high CD4+/CD8+ T lymphocytes ratio, while in the Exitus Group, we observed high neutrophil and CD8+ T lymphocyte counts. During infection, in patients with favorable outcomes, we observed a rise in the lymphocyte count, in the monocyte and in Treg lymphocyte counts, and in the CD4+ and in CD8+ T lymphocytes count but a reduction in the CD4+/CD8+ T lymphocyte ratio. Instead, in the Exitus Group, we observed a reduction in the Treg lymphocyte counts and a decrease in iTNF-α expression. Our preliminary findings point to a modulation of the different cellular mediators of the immune system, which probably play a key role in the outcomes of COVID-19.
10.3390/biology10080735
Monitoring peripheral neutrophil and T-lymphocyte subsets could assist in differentiating the severity and disease progression of coronavirus disease 2019.
Aging
Helper T cells (CD3+CD4+ T cells) and cytotoxic T cells (CD3+CD8+ T cells) play direct and indirect antiviral roles. This study retrospectively explored the clinical significance of peripheral lymphocytes, especially the dynamic analysis of T-cell subsets, in determining coronavirus disease 2019 (COVID-19) severity and progression. Seventy-nine patients with COVID-19 in the Public Health Clinical Center of Chengdu from January to February 2020 were included, 59 of which were analyzed for dynamic peripheral T-cell subsets expression. The neutrophil to CD4+ T lymphocyte ratio (N4R) and neutrophil to CD3+ T lymphocyte ratio (N3R) showed clinical significance in differentiating severe or critically-severe COVID-19, with area under receiver operating characteristic curves (AUCs) of 0.933 and 0.900, respectively (P < 0.05). COVID-19 patients with more baseline peripheral lymphocytes or NK cells were prone to test negative to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after therapy (P < 0.05), and the AUC of NK cells for predicting negative results of SARS-CoV-2 RNA detection after therapy was 0.800. When the number of peripheral CD3+CD4+ and CD3+CD8+ T cells in COVID-19 patients continuously increased 6-9 days after baseline, the period of disease exacerbation could be delayed for more than 2 weeks after admission. Baseline N4R and N3R could be potential biomarkers for assisting in differentiating COVID-19 severity, and dynamically monitoring peripheral CD3+CD4+ and CD3+CD8+ T cells 6-9 days after baseline could help clinicians to evaluate disease progression in COVID-19 patients.
10.18632/aging.202701
[Analysis of the correlation between lymphocyte subsets and severity of corona virus disease 19].
Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences
OBJECTIVE:To understand the differences in lymphocyte subsets in patients with different clinical classifications of corona virus disease 19 (COVID-19). METHODS:Eighty-one patients with COVID-19 who were admitted to the isolation ward under the responsibility of three medical aid teams in the Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, from February 8, 2020 to March 28, 2020, were selected to collect clinical data. According to the relevant diagnostic criteria, the disease status of the patients was classified into moderate cases (=35), severe cases (=39) and critical cases (=7) when lymphocyte subset testing was performed. Their blood routine tests, lymphocyte subsets and other indicators were tested to compare whether there were differences in each indicator between the patients of different clinical classification groups. RESULTS:The differences in the absolute count of total lymphocytes, T-lymphocytes, CD4T-lymphocytes, CD8T-lymphocytes and natural killer (NK) cells among the three groups of patients were all statistically significant ( < 0.05), and the critical cases were significantly lower than the moderate and severe cases in the above indicators, and the indicators showed a decreasing trend with the severity of the disease. In 22 patients, the six indicators of the absolute count of T-lymphocytes, B-lymphocytes, CD4T-lymphocytes, CD8T-lymphocytes and NK cells, CD4/CD8 ratio were all within the normal reference range in the first test, and 59 patients had abnormalities of the above indicators, with the absolute count of NK cells and CD8 T lymphocytes decreasing most frequently (61%, 56%). The patients with the absolute count of NK cells and CD8 T lymphocytes below the normal reference range were one group, and the remaining abnormal patients were the other group. There were more critical cases in the former group (moderate : severe : critical cases were 4 : 8 : 7 . 19 : 21 : 0, respectively, =0.001), and all the deaths were in this group (6 cases . 0 case, =0.001). The absolute B lymphocyte count was below the normal reference range in 15 patients, and the remaining 64 cases were within the normal range. The ratio of moderate, severe and critical cases in the reduced group was 4 : 7 : 4, and the ratio of critical cases was more in normal group which was 30 : 31 : 3, and the difference between the two groups was statistically significant (=0.043). CONCLUSION:The more critical the clinical subtype of patients with COVID-19, the lower the absolute count of each subset of lymphocytes.
Dynamics of cytokines and lymphocyte subsets associated with the poor prognosis of severe COVID-19.
Li Q,Xu W,Li W-X,Huang C-L,Chen L
European review for medical and pharmacological sciences
OBJECTIVE:We aimed to study the dynamics of cytokines and lymphocyte subsets and their correlation with the prognosis of patients with severe COVID-19. PATIENTS AND METHODS:The lymphocyte subsets and cytokines of 31 patients with severe COVID-19 (7 deaths and 24 survivals) were longitudinally analyzed. RESULTS:The mean age of enrolled patients was 64 years, 24 (77.4%) patients were men, and 23 (74.2%) patients had comorbidities. Compared with survival group, the death group showed significant and sustained increases in the levels of IL-6, IL-8, and IL-10 from baseline to 28 days after admission (all p<0.05). No significant differences were observed in the levels of TNF-α, IL-1b, IL-2, IL-4, IL-5, IL-12P70, IL-17, IFN-α, and IFN-γ between the death group and survival group during the follow-up (all p>0.05). The absolute counts of CD3+ T cells, CD4+ T cells, CD8+ T cells, and CD45+ T cells were lower in both survival group and death group patients from hospital admission to 3 days after admission, and gradually recovered in 4 to 35 days in the survival group, but continually stayed at low levels in the death group during the follow-up. CONCLUSIONS:The kinetic changes of cytokines and lymphocyte subsets are related with the prognosis of patients with severe COVID-19.
10.26355/eurrev_202012_24051
Relationships among lymphocyte subsets, cytokines, and the pulmonary inflammation index in coronavirus (COVID-19) infected patients.
Wan Suxin,Yi Qingjie,Fan Shibing,Lv Jinglong,Zhang Xianxiang,Guo Lian,Lang Chunhui,Xiao Qing,Xiao Kaihu,Yi Zhengjun,Qiang Mao,Xiang Jianglin,Zhang Bangshuo,Chen Yongping,Gao Cailiang
British journal of haematology
We explored the relationships between lymphocyte subsets, cytokines, pulmonary inflammation index (PII) and disease evolution in patients with (corona virus disease 2019) COVID-19. A total of 123 patients with COVID-19 were divided into mild and severe groups. Lymphocyte subsets and cytokines were detected on the first day of hospital admission and lung computed tomography results were quantified by PII. Difference analysis and correlation analysis were performed on the two groups. A total of 102 mild and 21 severe patients were included in the analysis. There were significant differences in cluster of differentiation 4 (CD4 T), cluster of differentiation 8 (CD8 T), interleukin 6 (IL-6), interleukin 10 (IL-10) and PII between the two groups. There were significant positive correlations between CD4 T and CD8 T, IL-6 and IL-10 in the mild group (r = 0·694, r = 0·633, respectively; P < 0·01). After 'five-in-one' treatment, all patients were discharged with the exception of the four who died. Higher survival rates occurred in the mild group and in those with IL-6 within normal values. CD4 T, CD8 T, IL-6, IL-10 and PII can be used as indicators of disease evolution, and the PII can be used as an independent indicator for disease progression of COVID-19.
10.1111/bjh.16659
The predictive role of lymphocyte subsets and laboratory measurements in COVID-19 disease: a retrospective study.
Wang Lin,Chen Jun,Zhao Jun,Li Feng,Lu Shuihua,Liu Ping,Liu Xu-Hui,Huang Qin,Wang He,Xu Qing Nian,Liu Xiaomin,Yu Shijun,Liu Li,Lu Hongzhou
Therapeutic advances in respiratory disease
AIM:The aim of this study was to investigate the predictive role of lymphocyte subsets and other laboratory measurements in patients with COVID-19. METHODS:Electronic medical records of adult patients with confirmed diagnosis of COVID-19 from the Shanghai Public Health Clinical Center were reviewed retrospectively to obtain relevant data. RESULTS:The mean age of patients was 40.98 ± 15.95 years, with 58% of the patients being males. The cutoff values at the intensive care unit (ICU) admission, mechanical ventilation, and mortality were CD4+ cells (267, 198, and 405), CD8+ cells (263, 203, and 182), and CD4+ /CD8+ cells (1.4, 1.8, and 1.4). The cutoffs below these values indicate the higher chances of disease progression. Higher CD4+ cell count led to lesser chances for ICU admission [odds ratio (OR) (95% confidence interval (CI): 0.994 (0.991, 0.997); = 0.0002] and mortality [OR (95% CI): 0.988 (0.979, 0.99); = 0.001], higher CD8+ count was an independent risk factor for ICU admission. T-cell count positively correlated with total lymphocyte count and platelets, while negatively correlated with D-dimer and lactate dehydrogenase (LDH). Among patients with non-severe COVID-19, median CD8+ T cell, CD4+ T cell, total lymphocyte count, and platelets were 570, 362, 1.45, and 211, respectively, while median values decreased to 149, 106, 0.64, and 172, respectively, in patients with severe COVID-19. CONCLUSION:Lower T lymphocyte subsets were significantly associated with higher admission to ICU, mechanical ventilation, and mortality among patients with COVID-19. A cutoff value of ICU admission, mechanical ventilation, and mortality below CD4+ cells (267, 198, and 405), CD8+ cells (263, 203, 182), and CD4+/CD8+ cells (1.4, 1.8, 1.4) may help identify patients at high risk of disease progression. The continuous evaluation of laboratory indices may help with dismal prognosis and prompt intervention to improve outcomes.
10.1177/17534666211049739
Relationship between lymphocyte subsets values and C-reactive protein in COVID-19 patients.
Cytometry. Part A : the journal of the International Society for Analytical Cytology
We enrolled 33 patients with COVID-19 (23 men and 10 women; age 59 ± 15; males, n = 23; females, n = 10) admitted to the Department of Infectious Diseases of Grande Ospedale Metropolitano "Bianchi-Melacrino-Morelli" of Reggio Calabria, Italy, between March and May 2020. Whole blood samples were collected before the start of therapeutic treatment using all virus spread containment measures. Sample preparation protocols were designed in order to minimize operators direct specimen's manipulation. On univariate analysis, circulating levels of CRP were strongly and inversely related to CD3+ (rho = -0.77, p < 0.001), CD3+4+ (rho = -0.74, p < 0.001), and CD3+8+ (rho = -0.66, p = 0.001) implying that the shared variances between absolute values T cells and CRP ranged from 44 to 59%. Of note, the strength of these associations was higher in patients with relatively lower (below the median value) white blood cells (WBC) as compared to those with WBC above the median value. CRP also correlated with NK bright (rho = -0.56, p = 0.005) but failed to be related with CD19+ (rho = -0.38, p = 0.07), CD4+/CD8+ ratio (rho = 0.03, p = 0.89), CD16+ CD56+ (rho = -0.18, p = 0.43), and NKdim (rho = -0.15, p = 0.49). Lymphocyte subsets alteration monitoring in COVID-19 positive patients may be a valid aid to control treatment efficacy of therapy and to choose better clinical approach. In particular, the negative correlation between CD3+, CD3+CD4+, CD3+CD8+ T cells values and CRP could be a useful tool to predict patient's response to therapy, particularly in patients with relatively lower WBC.
10.1002/cyto.a.24327
The characteristics and predictive role of lymphocyte subsets in COVID-19 patients.
Zhang Wenjing,Li Lei,Liu Jihai,Chen Li,Zhou Fangfang,Jin Ting,Jiang Lin,Li Xiang,Yang Ming,Wang Hongxiang
International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases
OBJECTIVE:To investigate the characteristics and predictive roles of lymphocyte subsets in COVID-19 patients. METHOD:We evaluated lymphocyte subsets and other clinical features of COVID-19 patients, and analyzed their potential impacts on COVID-19 outcomes. RESULTS:1. Lymphocyte subset counts in the peripheral blood of patients with COVID-19 were significantly reduced, especially in patients with severe disease. 2. In patients with non-severe disease, the time from symptom onset to hospital admission was positively correlated with total T cell counts. 3. Among COVID-19 patients who did not reach the composite endpoint, lymphocyte subset counts were higher than in patients who had reached the composite endpoint. 4. The Kaplan-Meier survival curves showed significant differences in COVID-19 patients, classified by the levels of total, CD8, and CD4 T cells at admission. CONCLUSION:Our study showed that total, CD8, and CD4 T cell counts in patients with COVID-19 were significantly reduced, especially in patients with severe disease. Lower T lymphocyte subsets were significantly associated with a higher occurrence of composite endpoint events. These subsets may help identify patients with a high risk of composite endpoint events.
10.1016/j.ijid.2020.06.079
Dynamic changes in peripheral blood lymphocyte subsets in adult patients with COVID-19.
International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases
INTRODUCTION:Coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread widely. The aim of this study was to investigate the dynamic changes in peripheral blood lymphocyte subsets in adult patients with COVID-19. METHODS:The electronic medical records were reviewed. Data including demographic characteristics, clinical manifestations, comorbidities, laboratory data, and radiological examinations of 435 hospitalized COVID-19 patients with a confirmed SARS-CoV-2 viral infection were extracted and analyzed retrospectively. Lymphocyte subset counts at each week after the onset of the illness were compared with those of the other weeks of illness and with those of control individuals. RESULTS:The various lymphocyte subsets (CD3+, CD4+, CD8+, CD19+, and CD16/56+) were below the normal ranges at 1 week after the onset of illness, reaching a nadir during the second week. They increased gradually during the third week and returned to normal levels in the fifth week, but were still lower than those of the healthy controls. The CD3+, CD4+, and CD8+ counts were significantly lower in patients with severe disease compared to those with non-severe disease, and in patients who died compared to those who recovered. DISCUSSION:This research indicates that the levels of peripheral blood lymphocyte subsets (CD3+, CD4+, and CD8+) are associated with disease progression and severity, and with the prognosis in patients with COVID-19. Dynamic monitoring of human immune function is one of the indicators for evaluating the severity of disease and the prognosis of COVID-19 patients, and is useful for formulating appropriate treatment strategies.
10.1016/j.ijid.2020.07.003
Alterations of T helper lymphocyte subpopulations in sepsis, severe sepsis, and septic shock: a prospective observational study.
Li Jia,Li Ming,Su Longxiang,Wang Huijuan,Xiao Kun,Deng Jie,Jia Yanhong,Han Gencheng,Xie Lixin
Inflammation
Circulating lymphocyte number was significantly decreased in patients with sepsis. However, it remains unknown which severity phase (sepsis, severe sepsis, and septic shock) does it develop and what happen on each subpopulation. Eight patients with differing severities of sepsis (31 sepses, 33 severe sepses, and 16 septic shocks) were enrolled. Quantitative real-time polymerase chain reaction (RT-PCR) of Th1, Th2, and Th17; regulatory T (Treg) cell-specific transcription factor T-bet; GATA-3; RORgammat (RORγt); forkhead box P3 (FOXP3); and IL-17 mRNA were performed, and the enzyme-linked immunosorbent assay (ELISA) was used to detect serum interferon (IFN)-γ, IL-4, and IL-10. In this study, the Th1, Th2, Treg transcription factors, and related cytokines IFN-γ, IL-4, and IL-10 levels of sepsis and severe sepsis patients in peripheral blood were significantly higher than those of the normal controls. Except for IL-17, the T-bet, GATA-3, and IFN-γ levels of septic shock patients were lower than those of sepsis patients. We also observed that the proportions of Th17/Treg in the sepsis and septic shock groups were inversed. From the above, the inflammatory response especially the adaptive immune response is still activated in sepsis and severe sepsis, but significant immunosuppression was developed in septic shock. In addition, the proportion of Th17/Treg inversed may be associated with the illness aggravation of patients with sepsis.
10.1007/s10753-014-0063-3
[Evaluation value of the levels of peripheral blood CD20 CD24 CD38 regulatory B cells on the prognosis of elderly patients with sepsis].
Wang Chunmei,Tang Lunxian,Xu Huihui,Zhang Xiaoming,Bai Jianwen
Zhonghua wei zhong bing ji jiu yi xue
OBJECTIVE:To explore the predicting value of peripheral blood CD20 CD24 CD38 regulatory B cells (Bregs) on the prognosis of elderly patients with sepsis. METHODS:A prospective study was conducted. Septic patients aged > 65 years old, compliance with diagnostic criteria for Sepsis-3, admitted to emergency and emergency intensive care unit (ICU) of Shanghai East Hospital of Tongji University from April 2016 to February 2017 were enrolled. Procalcitonin (PCT), C-reaction protein (CRP) and lactate (Lac) were routinely measured. According to the worst clinical index value within 24 hours, acute physiology and chronic health evaluation II (APACHE II) score and sequential organ failure assessment (SOFA) score were recorded. The concentrations of peripheral blood CD20 CD24 CD38 Bregs were measured by flow cytometry at 1, 3 and 7 days after diagnosed in elderly patients. All patients with sepsis were followed up for 28 days and then divided into death group and survival group according to 28-day outcome. The difference of clinic data and Bregs were compared between the two groups. The significant different factors of elderly sepsis patients were analyzed by binary logistic regression analysis. The correlation between Bregs level and other indicators was analyzed by Spearman correlation. The receiver operating characteristic curve (ROC) was used to evaluate the prognosis value of Bregs in elderly patients with sepsis. RESULTS:Fifty-eight patients were enrolled in the study, with 38 male and 20 female; age of (79.91±7.97) years; 32 in sepsis group, 26 in septic shock group; 35 deaths, 28-day mortality rate was 60.3%. APACHE II score and SOFA score in death group exhibited much higher than that in survival group (APACHE II: 18.14±4.52 vs. 14.91±3.56, SOFA: 8.80±4.56 vs. 6.35±3.00, both P < 0.05), the Bregs was significantly decreased at 1, 3 and 7 days in death group [cells/μL: 0.70 (0.20, 1.40) vs. 1.50 (0.70, 2.20), 0.54 (0.20, 1.00) vs. 1.42 (1.10, 2.12), 0.25 (0.10, 0.50) vs. 0.80 (0.50, 1.00), all P < 0.05]. Correlation analysis showed that the concentrations of peripheral blood Bregs at 1 day in elderly patients with sepsis was negatively correlated with APACHE II score (r = -0.351, P = 0.007), and it was not correlated with PCT, CRP, Lac or SOFA score. It was shown by binary logistic regression that Bregs [odds ratio (OR) = 1.865, P = 0.028] and APACHE II score (OR = 0.853, P = 0.026) were independent risk factors for elderly sepsis outcome. It was shown by ROC curve analysis that the prognostic value of the levels of Bregs at 1, 3, 7 days and APACHE II score were higher in the elderly patients with sepsis, and the area under ROC curve (AUC) and 95% confidence interval (95%CI) were 0.842 (0.647-0.954), 0.770 (0.564-0.911), 0.888 (0.703-0.977), 0.855 (0.661-0.961), respectively, all P < 0.01. The 7-day Bregs was most powerful to predict outcome, when the cut-off value was 0.50 cells/μL, the sensitivity was 72.73% and specificity was 86.67%. CONCLUSIONS:The level of peripheral blood CD20 CD24 CD38 Bregs could predict the clinical outcome of elderly patients with sepsis.
10.3760/cma.j.issn.2095-4352.2017.08.001
Lymphocyte phenotyping to distinguish septic from nonseptic critical illness.
Schwulst Steven J,Muenzer Jared T,Chang Katherine C,Brahmbhatt Tejal S,Coopersmith Craig M,Hotchkiss Richard S
Journal of the American College of Surgeons
BACKGROUND:Clinical signs and symptoms of sepsis are nonspecific and often indistinguishable from those of nonseptic critical illness. This ambiguity frequently delays the diagnosis of sepsis until culture results can confirm the presence or absence of an infectious organism. Lymphocyte phenotyping can be conducted rapidly and may provide information on the presence of infection before culture results are available. In this study, we hypothesized that lymphocyte phenotype can distinguish between septic and nonseptic critical illness. STUDY DESIGN:C57Bl/6 mice were subjected to either P aeruginosa pneumonia or lipopolysaccharide-induced acute lung injury (ALI). Animals were sacrificed 24 hours postinjury and splenic lymphocytes were harvested. Additionally, 13 patients in a surgical ICU were enrolled in the study. Whole blood was obtained and lymphocytes were isolated by density gradient centrifugation. Lymphocyte phenotype was identified through flow cytometry after labeling lymphocytes for CD3, CD4, CD8, CD20, CD40, CD69, and CD86 with fluorochrome-conjugated antibodies. RESULTS:CD69 expression on B cells and CD8+ splenocytes from septic mice was significantly increased compared with acute lung injury mice (p < 0.001 and p < 0.05, respectively). Similarly, CD4+ and CD8+ lymphocytes from septic patients had a two- to threefold increase in the expression of CD69 compared with nonseptic critically ill patients (p < 0.05). CONCLUSIONS:These data indicated that CD69 expression on lymphocytes may be useful in distinguishing between septic and nonseptic critical illness. Continued investigation into the expression of CD69 during sepsis is warranted.
10.1016/j.jamcollsurg.2007.07.038
Effect of Interleukin-36β on Activating Autophagy of CD4+CD25+ Regulatory T cells and Its Immune Regulation in Sepsis.
Ge Yun,Huang Man,Dong Ning,Yao Yong-Ming
The Journal of infectious diseases
BACKGROUND:CD4+CD25+ regulatory T cells (Tregs) play an essential role in sepsis-induced immunosuppression. How, the effects of interleukin 36 (IL-36) cytokines on CD4+CD25+ Tregs and their underlying mechanism(s) in sepsis remain unknown. METHODS:Our study was designed to investigate the impacts of IL-36 cytokines on murine CD4+CD25+ Tregs in presence of lipopolysaccharide (LPS) and in a mouse model of sepsis induced by cecal ligation and puncture (CLP). IL-36-activated autophagy was evaluated by autophagy markers, autophagosome formation, and autophagic flux. RESULTS:IL-36α, IL-36β, and IL-36γ were expressed in murine CD4+CD25+ Tregs. Stimulation of CD4+CD25+ Tregs with LPS markedly up-regulated the expression of these cytokines, particularly IL-36β. IL-36β strongly suppressed CD4+CD25+ Tregs under LPS stimulation and in septic mice challenged with CLP, resulting in the amplification of T-helper 1 response and the proliferation of effector T cells. Mechanistic studies revealed that IL-36β triggered autophagy of CD4+CD25+ Tregs. These effects were significantly attenuated in the presence of the autophagy inhibitor 3-methyladenine or Beclin1 knockdown. In addition, early IL-36β administration reduced the mortality rate in mice subjected to CLP. Depletion of CD4+CD25+ Tregs before the onset of sepsis obviously abrogated IL-36β-mediated protection against sepsis. CONCLUSIONS:These findings suggest that IL-36β diminishes the immunosuppressive activity of CD4+CD25+ Tregs by activating the autophagic process, thereby contributing to improvement of the host immune response and prognosis in sepsis.
10.1093/infdis/jiaa258
Role of circulating lymphocytes in patients with sepsis.
BioMed research international
Sepsis is a systemic inflammatory response syndrome due to infection. The incidence rate is estimated to be up to 19 million cases worldwide per year and the number of cases is rising. Infection triggers a complex and prolonged host response, in which both the innate and adaptive immune response are involved. The disturbance of immune system cells plays a key role in the induction of abnormal levels of immunoregulatory molecules. Furthermore, the involvement of effector immune system cells also impairs the host response to the infective agents and tissue damage. Recently, postmortem studies of patients who died of sepsis have provided important insights into why septic patients die and showed an extensive depletion of CD4 and CD8 lymphocytes and they found that circulating blood cells showed similar findings. Thus, the knowledge of the characterization of circulating lymphocyte abnormalities is relevant for the understanding of the sepsis pathophysiology. In addition, monitoring the immune response in sepsis, including circulating lymphocyte subsets count, appears to be potential biomarker for predicting the clinical outcome of the patient. This paper analyzes the lymphocyte involvement and dysfunction found in patients with sepsis and new opportunities to prevent sepsis and guide therapeutic intervention have been revealed.
10.1155/2014/671087
Regulatory T Cells: Angels or Demons in the Pathophysiology of Sepsis?
Frontiers in immunology
Sepsis is a syndrome characterized by life-threatening organ dysfunction caused by the dysregulated host response to an infection. Sepsis, especially septic shock and multiple organ dysfunction is a medical emergency associated with high morbidity, high mortality, and prolonged after-effects. Over the past 20 years, regulatory T cells (Tregs) have been a key topic of focus in all stages of sepsis research. Tregs play a controversial role in sepsis based on their heterogeneous characteristics, complex organ/tissue-specific patterns in the host, the multi-dimensional heterogeneous syndrome of sepsis, the different types of pathogenic microbiology, and even different types of laboratory research models and clinical research methods. In the context of sepsis, Tregs may be considered both angels and demons. We propose that the symptoms and signs of sepsis can be attenuated by regulating Tregs. This review summarizes the controversial roles and Treg checkpoints in sepsis.
10.3389/fimmu.2022.829210
Early natural killer cell counts in blood predict mortality in severe sepsis.
Andaluz-Ojeda David,Iglesias Verónica,Bobillo Felipe,Almansa Raquel,Rico Lucía,Gandía Francisco,Loma Ana Ma,Nieto Concepción,Diego Rosa,Ramos Epifanio,Nocito Mercedes,Resino Salvador,Eiros Jose M,Tamayo Eduardo,de Lejarazu Raul Ortiz,Bermejo-Martin Jesús F
Critical care (London, England)
INTRODUCTION:Host immunity should play a principal role in determining both the outcome and recovery of patients with sepsis that originated from a microbial infection. Quantification of the levels of key elements of the immune response could have a prognostic value in this disease. METHODS:In an attempt to evaluate the quantitative changes in the status of immunocompetence in severe sepsis over time and its potential influence on clinical outcome, we monitored the evolution of immunoglobulins (Igs) (IgG, IgA and IgM), complement factors (C3 and C4) and lymphocyte subsets (CD4+ T cells, CD8+ T cells, B cells (CD19+) and natural killer (NK) cells (CD3-CD16+CD56+)) in the blood of 50 patients with severe sepsis or septic shock at day 1, day 3 and day 10 following admission to the ICU. RESULTS:Twenty-one patients died, ten of whom died within the 72 hours following admission to the ICU. The most frequent cause of death (n = 12) was multiorgan dysfunction syndrome. At day 1, survivors showed significantly higher levels of IgG and C4 than those who ultimately died. On the contrary, NK cell levels were significantly higher in the patients who died. Survivors exhibited a progressive increase from day 1 to day 10 on most of the immunological parameters evaluated (IgG, IgA, IgM, C3, CD4+, CD8+ T cells and NK cells). Multivariate Cox regression analysis, including age, sex, APACHE II score, severe sepsis or septic shock status and each one of the immunological parameters showed that NK cell counts at day 1 were independently associated with increased risk of death at 28 days (hazard ratio = 3.34, 95% CI = 1.29 to 8.64; P = 0.013). Analysis of survival curves provided evidence that levels of NK cells at day 1 (> 83 cells/mm³) were associated with early mortality. CONCLUSIONS:Our results demonstrate the prognostic role of NK cells in severe sepsis and provide evidence for a direct association of early counts of these cells in blood with mortality.
10.1186/cc10501
Impact of sepsis on CD4 T cell immunity.
Cabrera-Perez Javier,Condotta Stephanie A,Badovinac Vladimir P,Griffith Thomas S
Journal of leukocyte biology
Sepsis remains the primary cause of death from infection in hospital patients, despite improvements in antibiotics and intensive-care practices. Patients who survive severe sepsis can display suppressed immune function, often manifested as an increased susceptibility to (and mortality from) nosocomial infections. Not only is there a significant reduction in the number of various immune cell populations during sepsis, but there is also decreased function in the remaining lymphocytes. Within the immune system, CD4 T cells are important players in the proper development of numerous cellular and humoral immune responses. Despite sufficient clinical evidence of CD4 T cell loss in septic patients of all ages, the impact of sepsis on CD4 T cell responses is not well understood. Recent findings suggest that CD4 T cell impairment is a multipronged problem that results from initial sepsis-induced cell loss. However, the subsequent lymphopenia-induced numerical recovery of the CD4 T cell compartment leads to intrinsic alterations in phenotype and effector function, reduced repertoire diversity, changes in the composition of naive antigen-specific CD4 T cell pools, and changes in the representation of different CD4 T cell subpopulations (e.g., increases in Treg frequency). This review focuses on sepsis-induced alterations within the CD4 T cell compartment that influence the ability of the immune system to control secondary heterologous infections. The understanding of how sepsis affects CD4 T cells through their numerical loss and recovery, as well as function, is important in the development of future treatments designed to restore CD4 T cells to their presepsis state.
10.1189/jlb.5MR0114-067R
Characterization of Circulating IL-10-Producing Cells in Septic Shock Patients: A Proof of Concept Study.
Fabri Astrid,Kandara Khalil,Coudereau Rémy,Gossez Morgane,Abraham Paul,Monard Céline,Cour Martin,Rimmelé Thomas,Argaud Laurent,Monneret Guillaume,Venet Fabienne
Frontiers in immunology
Sepsis is a worldwide health priority characterized by the occurrence of severe immunosuppression associated with increased risk of death and secondary infections. Interleukin 10 (IL-10) is a potent immunosuppressive cytokine which plasma concentration is increased in septic patients in association with deleterious outcomes. Despite studies evaluating IL-10 production in specific subpopulations of purified cells, the concomitant description of IL-10 production in monocytes and lymphocytes in septic patients' whole blood has never been performed. In this pilot study, we characterized IL-10 producing leukocytes in septic shock patients through whole blood intracellular staining by flow cytometry. Twelve adult septic shock patients and 9 healthy volunteers were included. Intracellular tumor necrosis factor-α (TNFα) and IL-10 productions after lipopolysaccharide stimulation by monocytes and IL-10 production after PMA/Ionomycine stimulation by lymphocytes were evaluated. Standard immunomonitoring (HLA-DR expression on monocytes, CD4+ T lymphocyte count) of patients was also performed. TNFα expression by stimulated monocytes was reduced in patients compared with controls while IL-10 production was increased. This was correlated with a reduced monocyte HLA-DR expression. B cells, CD4+, and CD4- T lymphocytes were the three circulating IL-10 producing lymphocyte subsets in both patients and controls. No difference in IL-10 production between patients and controls was observed for B and CD4- T cells. However, IL-10 production by CD4+ T lymphocytes significantly increased in patients in parallel with reduced CD4+ T cells number. Parameters reflecting altered monocyte (increased IL-10 production, decreased HLA-DR expression and decreased TNFα synthesis) and CD4+ T lymphocyte (increased IL-10 production, decreased circulating number) responses were correlated. Using a novel technique for intracellular cytokine measurement in whole blood, our results identify monocytes and CD4+ T cells as the main IL-10 producers in septic patients' whole blood and illustrate the development of a global immunosuppressive profile in septic shock. Overall, these preliminary results add to our understanding of the global increase in IL-10 production induced by septic shock. Further research is mandatory to determine the pathophysiological mechanisms leading to such increased IL-10 production in monocytes and CD4+ T cells.
10.3389/fimmu.2020.615009
[Alterations of peripheral blood T cell subsets in patients with sepsis and the clinical implications].
Li Zhi-tao,Gong Yu-qiang,Wang Sheng-biao,Jin Sheng-wei,Sun Lai-fang,Wang Zheng,Hu Xue-zhen,Chen Ying,Xu Jun-nan,Qi Yan-hong,Lian Qing-quan
Nan fang yi ke da xue xue bao = Journal of Southern Medical University
OBJECTIVE:To observe the dynamic changes of CD3+, CD4+, and CD8+ T lymphocytes in the peripheral blood of patients with sepsis and discuss the clinical significance. METHODS:Sixty-four patients admitted in the Emergency Center and Emergency Intensive Care Unit of the Second Hospital of Wenzhou Medical University between August, 2007 and July, 2009 were enrolled in this study. CD3+, CD4+, and CD8+ T lymphocytes in the peripheral blood were detected by flow cytometry on days 1, 7 and 14 after admission, and the results were compared between the patients with improvement of the condition and those without improvement, with 20 healthy subjects as the control group. RESULTS:On day 1 after admission, CD3+ and CD4+ T lymphocytes and CD4+/CD8+ T cell ratio were obviously lower in the 2 groups of patients with sepsis than in the control group (P<0.05), but no significant difference was found in CD8+ T lymphocytes. The sepsis patients with clinical improvement showed significant higher CD3+ and CD4+ T lymphocyte percentages and CD4+/CD8+ T cell ratio than those without improvement on day 1. In the patients with clinical improvement, CD3+ and CD4+T lymphocytes and CD4+/CD8+ T cell ratio increased gradually with time and till day 14, they were comparable with the control levels; in the patients without improvement, CD3+ and CD4+ T lymphocytes and CD4+/CD8+ T cell ratio showed no obvious alterations in the course of observation. CONCLUSION:Immune imbalance occurs in patients with sepsis represented by lowered CD3+ and CD4+T lymphocyte percentages and CD4+/CD8+ T cell ratio in relation to the severity of the condition. CD3+ and CD4+ T lymphocytes and CD4+/CD8+ T cell ratio can be used as the indicators for assessing the severity of sepsis.
Prognostic Relevance of Altered Lymphocyte Subpopulations in Critical Illness and Sepsis.
Hohlstein Philipp,Gussen Hendrik,Bartneck Matthias,Warzecha Klaudia Theresa,Roderburg Christoph,Buendgens Lukas,Trautwein Christian,Koch Alexander,Tacke Frank
Journal of clinical medicine
Lymphopenia and functional defects in lymphocytes may impact the prognosis in patients with critical illness or sepsis. Therefore, we prospectively analyzed peripheral blood leukocytes from 63 healthy volunteers, 50 non-critically ill standard care (SC) patients with infections, and 105 intensive care unit (ICU) patients (52 with sepsis, 53 without sepsis) using flow cytometry. Compared to healthy volunteers, SC and ICU patients showed significant leukocytosis, especially in sepsis, while lymphocyte numbers were significantly decreased. All major lymphocyte populations (B, T, and natural killer (NK) cells) decreased in ICU patients. However, we observed a relative reduction of T cells, alongside decreased CD8+ T cells, in critically ill patients, independent of sepsis. High absolute T cell counts (>0.36/nL) at ICU admission were associated with a significantly reduced mortality, independent of patient's age. Moreover, patients that survived ICU treatment showed dynamic changes within 48 h towards restoration of lymphopenia and T cell depletion, while non-surviving patients failed to restore lymphocyte counts. In conclusion, the flow-cytometric analysis of peripheral blood revealed striking changes in circulating lymphocyte subsets in critically ill patients, independent of sepsis. Lymphopenia and T cell depletion at ICU admission were associated with increased mortality, supporting their relevance as predictive biomarkers and potential therapeutic targets in intensive care medicine.
10.3390/jcm8030353
Severity of Sepsis Determines the Degree of Impairment Observed in Circulatory and Tissue-Resident Memory CD8 T Cell Populations.
Journal of immunology (Baltimore, Md. : 1950)
Sepsis reduces the number and function of memory CD8 T cells within the host, contributing to the long-lasting state of immunoparalysis. Interestingly, the relative susceptibility of memory CD8 T cell subsets to quantitative/qualitative changes differ after cecal ligation and puncture (CLP)-induced sepsis. Compared with circulatory memory CD8 T cells (T), moderate sepsis (0-10% mortality) does not result in numerical decline of CD8 tissue-resident memory T cells (T), which retain their "sensing and alarm" IFN-γ-mediated effector function. To interrogate this biologically important dichotomy, vaccinia virus-immune C57BL/6 (B6) mice containing CD8 T and skin T underwent moderate or severe (∼50% mortality) sepsis. Severe sepsis led to increased morbidity and mortality characterized by increased inflammation compared with moderate CLP or sham controls. Severe CLP mice also displayed increased vascular permeability in the ears. Interestingly, skin CD103 CD8 T, detected by i.v. exclusion or two-photon microscopy, underwent apoptosis and subsequent numerical loss following severe sepsis, which was not observed in mice that experienced moderate CLP or sham surgeries. Consequently, severe septic mice showed diminished CD8 T cell-mediated protection to localized skin reinfection. Finally, the relationship between severity of sepsis and demise in circulatory versus tissue-embedded memory CD8 T cell populations was confirmed by examining tumor-infiltrating and nonspecific CD8 T cells in B16 melanoma tumors. Thus, sepsis can differentially affect the presence and function of Ag-specific CD8 T cells that reside inside tissues/tumors depending on the severity of the insult, a notion with direct relevance to sepsis survivors and their ability to mount protective memory CD8 T cell-dependent responses to localized Ag re-encounter.
10.4049/jimmunol.2001142
Circulating lymphocyte subsets as promising biomarkers to identify septic patients at higher risk of unfavorable outcome.
Polilli Ennio,Esposito Jessica Elisabetta,Frattari Antonella,Trave Francesca,Sozio Federica,Ferrandu Giovanna,Di Iorio Giancarlo,Parruti Giustino
BMC infectious diseases
BACKGROUND:Early recognition of patients hospitalized for sepsis at higher risk of poor clinical outcome is a mandatory task and many studies suggested that indicators of the immune status may be useful for this purpose. We performed a retrospective, monocentric cohort study to evaluate whether lymphocyte subsets may be useful in predicting in-hospital mortality of septic patients. METHODS:Data of all consecutive patients with a diagnosis of sepsis at discharge and an available peripherical blood lymphocyte subset (CD4, CD8, CD16/CD56 and CD19) analysis at hospital entry were retrospectively collected between January 2015 and August 2018. Clinical characteristics of patients, past medical history and other laboratory parameters were also considered. RESULTS:Two-hundred-seventy-eight septic patients, 171 (61.5%) males, mean age 63.2 ± 19.6 years, were enrolled. Total counts of lymphocytes, CD4 T cells, CD8 T cells and B cells were found significantly lower in deceased than in surviving patients. At univariate analyses, CD4 T cells/µL (OR 0.99 for each incremental unit, 95%CI 0.99-1.10, p < 0.0001), age (OR 1.06, 95%CI 1.04-1.09, p < 0.0001), procalcitonin (OR 1.01, 95%CI 1.01-1.02, p < 0.0001) and female gender (OR 2.81, 95%CI 1.49-5.28, p = 0.001) were associated with in-hospital mortality. When a dichotomic threshold of < 400/µL for CD4 T cells as a dependent variable was considered in multivariate models, age (OR 1.04; 95%CI 1.01-1.09, p = 0.018); female gender (OR 3.18; 95%CI 1.40-7.20, p = 0.006), qSOFA (OR 4.00, 95%CI 1.84-8.67, p < 0.001) and CD4 T cells < 400/µL (OR 5.3; 95%CI 1.65-17.00, p = 0.005) were the independent predictors. CONCLUSIONS:In adjunct to biomarkers routinely determined for the prediction of prognosis in sepsis, CD4 T lymphocytes, measured at hospital entry, may be useful in identifying patients at higher risk of in-hospital death.
10.1186/s12879-021-06481-1
Analysis of peripheral blood lymphocyte subsets in critical patients at ICU admission: A preliminary investigation of their role in the prediction of sepsis during ICU stay.
Frattari Antonella,Polilli Ennio,Primiterra Vanessa,Savini Vincenzo,Ursini Tamara,Di Iorio Giancarlo,Parruti Giustino
International journal of immunopathology and pharmacology
A better knowledge of factors predicting the development of sepsis in patients hospitalized in intensive care unit (ICU) might help deploy more targeted preventive and therapeutic strategies. In addition to the known clinical and demographic predictors of septic syndromes, in this study, we investigated whether measuring T and B lymphocyte subsets upon admission in the ICU may help individualize the prediction of ensuing sepsis during ICU stay. Between May 2015 and December 2016, we performed a prospective cohort study evaluating peripheral blood lymphocyte T-CD4+ (T-helper cells), T-CD8+ (cytotoxic T-cells), T-CD56 + (natural killer cells), and T-CD19+ (B-lymphocytes), using flow cytometry on blood samples collected 2 days after admission in the ICU. We enrolled 176 patients, 65.3% males, with mean age of 61.1 ± 15.4 years. At univariate analyses, higher percentages of CD19 B-cells were significantly associated with ensuing sepsis (20.5% (15.7-27.7)% vs 16.9% (11.3-22)%, P = 0.0001), whereas median interquartile range (IQR) proportions of CD4 T-cells (41.2% (33.4-50.6)% vs 40% (35-47)%, P = 0.5), CD8 T-cells (21.1% (15.8-28.2)% vs 19.6% (14.6-25.1)%, P = 0.2) and CD56 T-cells (1.7% (0.9-3.1)% vs 1.45% (0.7-2.3)%, P = 0.4) did not reveal any significant association. An unexpected, highly significant inverse correlation of CD8 T-cells and CD19 B-cells proportions, however, was observed, suggesting that patients with lower CD19 and higher CD8 proportions might be somehow protected from ensuing sepsis. We therefore studied the ability of the CD8/CD19 ratio to predict ensuing sepsis in our sample. In final models of multivariate logistic regression, the following independent associations were found: previous antibiotic exposure (odds ratio (OR): 3.8 (95% confidence interval (CI): 1.35-10.87), P = 0.01), isolation of at least one multi-drug resistant organism at any time during ICU stay (OR: 8.4 (95% CI: 3.47-20.6), P < 0.0001), decreasing age (OR: 0.9 (95% CI: 0.93-0.99), P = 0.02) and a CD8/CD19 ratio >2.2 (OR: 10.3 (95% CI: 1.91-55.36), P = 0.007). Our data provide preliminary evidence that immune characterization of critically ill patients on ICU admission may help personalize the prediction of ensuing sepsis during their ICU stay. Further polycentric evaluation of the true potential of this new tool is warranted.
10.1177/2058738418792310
[T lymphocyte subsets combined with inflammatory indicators for auxiliary diagnosis and prognosis evaluation of sepsis].
Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]
To explore the application value of T lymphocyte subsets combined with procalcitonin (PCT), C-reactive protein (CRP), neutrophil to lymphocyte ratio (NLR) and white blood cell count (WBC) in the auxiliary diagnosis and prognosis evaluation of sepsis. In a retrospective study, seventy-two patients with sepsis diagnosed and treated in Tianjin First Central Hospital from June 2018 to April 2021 were selected as the research objects, and included in the sepsis group were 46 males and 26 females, aged 68 (57.3, 80.3) years. In addition, 111 patients with local infection admitted to hospital during the same period were included in the local infection group, including 62 males and 49 females, aged 68 (51, 77) years. Sepsis patients were divided into survival group (43 cases) and death group (29 cases) according to the 28-day outcome. CD3, CD4, CD8, CD4/CD8 ratio were detected by flow cytometry within 24 h after admission, PCT was detected by ELISA, CRP was detected by immunoturbidimetry, blood routine examination, blood lactic acid (Lac) and oxygen partial pressure (PO) were detected by instrumental method. Multivariate Logistic regression analysis was used to evaluate the correlation between each indicator and sepsis, and receiver operating characteristic curve (ROC) was drawn to evaluate the diagnostic value of each indicator for sepsis. Multivariate Logistic regression analysis and Kaplan Meier survival analysis were used to evaluate the prognostic value of each index for patients with sepsis. Peripheral blood CD3, CD4, CD8, CD4/CD8 ratio and PLT in sepsis group were significantly lower than those in local infection group(=-8.184,<0.001;=-7.210,<0.001;=-5.936,<0.001;=-2.700,=0.007;=-6.381,<0.001); PCT, CRP, NLR and Lac levels were significantly higher than those in local infection group(=-8.262,<0.001;=-3.094,=0.002;=-9.004,<0.001;=-4.770,<0.001). Multivariate Logistic regression model showed that PCT, NLR, CD3, CD8, CD4/CD8 were independent risk factors for sepsis. According to ROC curve analysis, AUC of sepsis patients diagnosed by each indicator were 0.862, 0.894, 0.858, 0.760 and 0.618, respectively. The cut-off values were 3.075 ng/ml, 10.715, 44.935×10/L, 27.463×10/L and 0.750, respectively. The NLR sensitivity was 80.6%, and the CD3 specificity was 94.6%. The AUC of combined detection of PCT and NLR was 0.947, sensitivity was 87.5% and specificity was 91.9%. The combined detection AUC of PCT, NLR, CD3, CD4/CD8 was 0.958, the sensitivity and specificity were 90.3% and 91.0% respectively(<0.001). PCT and Lac in death group were significantly higher than those in survival group(=-2.302,=0.021;=-3.095,=0.002);Peripheral blood CD4/CD8 levels were significantly lower than those in survival group(=-3.691,<0.001),Multivariate Logistic regression model showed that CD4/CD8 ratio was an independent risk factor for 28 d mortality in patients with sepsis (<0.001). The ROC curve showed that the AUC was 0.758, and the Youden index reached the maximum when the cut-off value was 1.27, the sensitivity and specificity were 79.3% and 60.5%, respectively. Compared with patients with CD4/CD8 ≥1.27, 28-day mortality was significantly increased in patients with CD4/CD8<1.27 (=0.032). The combined detection of PCT, NLR, CD3 and CD4/CD8 can improve the auxiliary diagnostic efficiency of sepsis, and the ratio of CD4/CD8 in peripheral blood may have certain predictive value for the prognosis of sepsis.
10.3760/cma.j.cn112150-20210810-00775
CD4 T Cell Responses and the Sepsis-Induced Immunoparalysis State.
Frontiers in immunology
Sepsis remains a major cause of death in the United States and worldwide, and costs associated with treating septic patients place a large burden on the healthcare industry. Patients who survive the acute phase of sepsis display long-term impairments in immune function due to reductions in numbers and function of many immune cell populations. This state of chronic immunoparalysis renders sepsis survivors increasingly susceptible to infection with newly or previously encountered infections. CD4 T cells play important roles in the development of cellular and humoral immune responses following infection. Understanding how sepsis impacts the CD4 T cell compartment is critical for informing efforts to develop treatments intended to restore immune system homeostasis following sepsis. This review will focus on the current understanding of how sepsis impacts the CD4 T cell responses, including numerical representation, repertoire diversity, phenotype and effector functionality, subset representation (e.g., Th1 and Treg frequency), and therapeutic efforts to restore CD4 T cell numbers and function following sepsis. Additionally, we will discuss recent efforts to model the acute sepsis phase and resulting immune dysfunction using mice that have previously encountered infection, which more accurately reflects the immune system of humans with a history of repeated infection throughout life. A thorough understanding of how sepsis impacts CD4 T cells based on previous studies and new models that accurately reflect the human immune system may improve translational value of research aimed at restoring CD4 T cell-mediated immunity, and overall immune fitness following sepsis.
10.3389/fimmu.2020.01364