HUBUNGAN TITER WIDAL DENGAN JUMLAH LIMFOSIT PADA KASUS DEMAM TIFOID DI WILAYAH KERJA PUSKESMAS SAWOO

Typhoid fever is a systemic infection that is still a global problem, especially in Indonesia. This disease is caused by Salmonella bacteria. The Widal test is used to detect antibodies to Salmonella bacteria based on agglutination reactions between bacterial antigens and antibodies called agglutinins. Routine blood tests be used to see the body's defense mechanism against infection. Lymphocytes are produced by bone marrow, the presence of bacterial endotoxin causes inhibition of the formation of lymphocytes, so that in some cases of typhoid fever, low lymphocyte counts are often found. The purpose of this study was to determine the relationship between Widal titer and lymphocyte count in patients with suspected typhoid fever. The Widal test was examined using a microscope to see the agglutination formed, while the number of lymphocytes was calculated using a hematology analyzer. The results of the Widal test with a titer of 1/160 were 63.3% with normal lymphocyte counts and 10% with low lymphocytes. While the titer 1/320 obtained 10% of respondents with normal lymphocyte count and 16.7% with low lymphocyte count. The research design used was analytic observation with the type of cross sectional study. Statistical analysis using Kendall's Tau-b correlation test with SPSS. From the correlation test, the significance value is 0.009, and the correlation coefficient is -0.404**, which means that there is a relationship between the Widal titer and the number of lymphocytes with sufficient closeness.

Methylprednisolone was Associated with Reduced in-Hospital Mortality in COVID-19 Patients with Low Lymphocyte Counts: a Multicenter Retrospective Propensity Analysis

Background: To assess the effect of methylprednisolone on the prognosis of patients with novel coronavirus pneumonia.Methods: Patients with confirmed novel coronavirus pneumonia discharged from Wuhan Third Hospital Guanggu Campus, Shouyi Campus, and Lei Shen Shan Hospital from January 31, 2020, to March 4, 2020, were included. The patients were divided into treatment and control groups according to whether methylprednisolone was used during hospitalization. Propensity score (PS) matching analysis was used to assess in-hospital mortality as the primary outcome and trends in the changes in lymphocytes and the C-reactive protein, creatinine and transaminase levels 7 days after admission (secondary outcomes).Results: A total of 2,062 patients with confirmed novel coronavirus pneumonia were included in this study. Univariate Cox regression analysis suggested that methylprednisolone treatment was associated with increased in-hospital mortality (hazard ratio (HR) 3.70, 95% confidence interval (CI) 2.62-5.23, P<0.01). A total of 624 patients were included after PS matching. The patients were further subdivided into a low lymphocyte count group and a normal lymphocyte count group according to a lymphocyte count cutoff value of 0.9*109/L. Kaplan-Meier survival curve analysis showed that methylprednisolone treatment reduced the risk of in-hospital death in patients with lymphocyte counts less than 0.9×109/L (P=0.022). In contrast, in the normal lymphocyte group, methylprednisolone treatment was not associated with in-hospital mortality (p=0.88).Conclusion: Treatment with methylprednisolone may be associated with reduced in-hospital mortality in coronavirus disease (COVID) patients with low lymphocyte counts.

Successful Treatment of a 19-Month-Old Boy with Hepatitis Associated Aplastic Anemia by Infusion of Umbilical Cord-Derived Mesenchymal Stromal Cells: A Case Report

Here we presented a case of a 19-month-old boy who developed severe aplastic anemia postacute hepatitis. He was treated successfully with the umbilical cord-derived mesenchymal stromal cells (UC-MSCs) infusion and cyclosporine A (CsA). The boy achieved both hematopoietic recovery and normal lymphocyte proportion. So far, his condition still remains stable. To our knowledge, there is a rare previous report on the utility of MSCs infusion for the treatment of hepatitis-associated aplastic anemia (HAAA). Considering the efficacy, safety, and strong operability, particularly for pediatric patient, the infusion of UC-MSCs combined with CsA could be an effective alternative for the treatment of HAAA.

Lymphocyte subtypes in relapsing–remitting multiple sclerosis patients treated with dimethyl fumarate

Background Recent data suggest that lymphopenia is more prevalent than reported in relapsing–remitting multiple sclerosis (RRMS) patients taking dimethyl fumarate (DMF). Objective The objective of this study was to investigate the effect of DMF on lymphocyte subtypes in RRMS patients with and without lymphopenia. Method A retrospective study compared lymphocyte subtypes in DMF-treated RRMS patients with low (G1, n = 35) and normal lymphocyte counts (G2, n = 24). Results Fifty-nine patients were identified, with mean age 49, 71.2% females, and average DMF duration 20 months. Age, sex, baseline white blood count, disease and treatment durations were similar between groups. Prior interferon therapy and baseline lower normal lymphocyte counts were more frequent in G1. Mean lymphocyte counts were 0.8 ± 0.2 × 109/L in G1 and 1.6 ± 0.3 × 109/L in G2. CD3+, CD4+, and CD8+ T cell mean counts were lower ( p < 0.0001), while CD4/CD8 ratio higher ( p = 0.03) in G1 than G2. Mean CD19 + B cell counts were normal; however, values were lower in G1 ( p = 0.04). After adjusting for confounders, significantly positive correlations were noted between lymphocyte counts and CD3 + , CD4+, CD8+ T, and B cell counts. Negative correlation was observed between lymphocyte counts and CD4/CD8 ratio driven by low CD8+ T cell counts. Conclusion DMF treatment predominantly impacts T cells, in particular CD8+ subtype. This finding may have implications in this population’s immunocompetence.

Plasma matrix metalloprotease 9 correlates with blood lymphocytosis, leukemic cell invasiveness, and prognosis in B-cell chronic lymphocytic leukemia

The complex biology underlying chronic lymphocytic leukemia cell migration and tissue invasiveness is not yet completely understood and might provide novel predictive markers and therapeutic targets. A total of 36 patients out of treatment from at least 3 months were enrolled and followed up for a median period of 44.2 months (range: 4.4–99.2). Matrix metalloprotease 9 and tissue inhibitor of metalloproteases 1 plasma levels and production/release from lymphoid cells were measured by zymography and enzyme-linked immunosorbent assay (ELISA) analysis. Malignant and normal lymphocyte mobility and matrix-degradation capability were studied using a Boyden chamber system, with and without autologous plasma. Free matrix metalloprotease 9 plasma levels were related with blood lymphocytosis, especially in more advanced stages (p = 0.003), and higher concentrations were associated with an increased disease progression risk (hazard ratio = 9.0, 95% confidence interval = 1.5–13.8). Leukemic cells expressed and secreted very little matrix metalloprotease 9. On the contrary, normal lymphocytes derived from the same leukemic patients showed matrix metalloprotease 9 intracellular levels that were lower in subjects with higher blood lymphocytosis (p = 0.024) and more advanced stages (p = 0.03); the released quantities were inversely associated with matrix metalloprotease 9 plasma concentrations (p = 0.035). Leukemic cells had a reduced spontaneous mobility and matrix-degradation capability that were stimulated by autologous plasma (p = 0.001) and normal lymphocytes (p = 0.005), respectively. Matrix metalloprotease 9 affected cell invasiveness depending on concentration and disease stage. In conclusion, chronic lymphocytic leukemia cells have a reduced mobility, matrix-degradation capability, and matrix metalloprotease 9 production compared to their own autologous normal lymphocytes. They are exposed to matrix metalloprotease 9 of prevalently systemic origin whose higher levels are associated with both leukemic and normal lymphocyte accumulation in the peripheral blood and have a negative prognostic value.

Comparison of the Clinical Characteristics of Pneumocystis Pneumonia between Patients with Rheumatoid Arthritis Being Treated with Biologics and Those Being Treated without Biologics

Objective. The aim of this study was to compare the clinical characteristics of pneumocystis pneumonia (PCP) between patients with rheumatoid arthritis (RA) being treated with biologics and those being treated without biologics. Methods. From 8,630 patients with RA in our institution, we enrolled 24 patients who had developed PCP during the course of their treatment. They were divided into two groups according to the treatment they were receiving for RA: the biologics group (n=12) and the nonbiologics group (n=12). Clinical characteristics of PCP were compared between the two groups. Results. At PCP diagnosis, the biologics group showed significantly lower serum levels of β-D-glucan and C-reactive protein than the nonbiologics group, while the biologics group had significantly higher lymphocyte counts than the nonbiologics group. In the nonbiologics group, lower lymphocyte counts were associated with higher β-D-glucan levels; however, this was not observed in the biologics group. Conclusion. The finding that RA patients being treated with biologics developed PCP with relatively normal lymphocyte counts and lower β-D-glucan levels suggests that the pathophysiology of PCP in those patients is different from that in patients being treated with other antirheumatic drugs.

Pleiotropic Effects of IL-2 on Cancer: Its Role in Cervical Cancer

IL-2 receptor (IL-2R) signalling is critical for normal lymphocyte proliferation, but its role in cervical cancer is not fully understood. The receptor is composed of three chains: IL-2α, IL-2β, and IL-2γ. Intracellular signalling is initiated by ligand-induced heterodimerization of the IL-2βand IL-2γchains, resulting in the activation of multiple intracellular kinases. Recently, IL-2R was shown to be expressed on nonhaematopoietic cells, especially on several types of tumour cells. However, the function of this receptor on malignant cells has not been clearly defined. The expression of IL-2R and the production of IL-2 in cervical cancer cells have been documented as well as expression of molecules of the JAK-STAT pathway. In the current review we have highlighted the differences in the responses of molecules downstream from the IL-2R in normal lymphocytes and tumour cells that could explain the presence of tumour cells in an environment in which cytotoxic lymphocytes also exist and compete and also the effect of different concentrations of IL-2 that could activate effector cells of the immune system cells, which favour the elimination of tumour cells, or concentrations that may promote a regulatory microenvironment in which tumour cells can easily grow.

CAR-Engineered T Cells Specific for the Elotuzumab Target SLAMF7 Eliminate Primary Myeloma Cells and Confer Selective Fratricide of SLAMF7+ Normal Lymphocyte Subsets

Background: SLAMF7 (CS1, CD319) is uniformly and highly expressed in multiple myeloma (MM) where it promotes adhesion and survival of malignant plasma cells (mPCs) in the bone marrow niche. It is absent on normal solid organ tissues but known to be expressed on lymphocyte subsets (T, B and NK cells). Clinical evaluation of the anti-SLAMF7 monoclonal antibody (mAb) Elotuzumab (huLuc63) has resulted in marked reversible lymphodepletion and conferred potent anti-MM efficacy in combination therapy. Here, we evaluated the potential to generate SLAMF7-directed chimeric antigen receptor (CAR) modified T cells from previously treated MM patients and analyzed their potency against autologous mPCs as well as fratricidal activity against normal lymphocyte subsets. Methods: Flow cytometric analyses for SLAMF7 expression on mPCs and normal lymphocyte subsets of MM patients (n=67) and healthy donors (n=20) was performed using specific mAbs and matched isotype controls. A SLAMF7-specific CAR was constructed using the VH/VL targeting domains of mAb huLuc63, fused to an Ig-Fc spacer and a signaling module of CD3ζ and CD28. Lentiviral gene transfer was performed into CD3/CD28-bead stimulated bulk CD4+ and CD8+ T cells of MM patients (n=7). CAR transgene positive T cells were enriched using an EGFRt transduction marker and expanded for functional analyses. Results: We confirmed high SLAMF7 expression levels on mPCs in all analyzed samples and detected SLAMF7 expression on a fraction of normal lymphocytes obtained from peripheral blood of MM patients, including naïve and memory CD4+ (95% CI: 33-59%) and CD8+ T cells (75-95%), B cells (25-35%) and NK cells (94-98%). Remarkably, the proportion of SLAMF7+ cells was significantly higher in MM patients compared to healthy donors in all corresponding lymphocyte subsets (p<0.05). Despite high level SLAMF7 expression on the input T cell population, functional CD4+ and CD8+ T cells expressing the SLAMF7-CAR could be readily generated in all 7 MM patients, and expanded to therapeutically relevant doses in a single expansion cycle following enrichment (>107 cells). We analyzed the kinetics of SLAMF7 expression on CD4+ and CD8+ CAR T cells during the manufacturing process and detected rapid disappearance of SLAMF7+ T cells in T cell lines modified with the SLAMF7-CAR. By contrast unmodified T cells and T cell lines expressing a CD19-CAR retained a significant proportion of SLAMF7+ T cells, suggesting that expression of the SLAMF7-CAR induced killing of SLAMF7+ T cells. In vitro functional testing of SLAMF7-CAR CD4+ and CD8+ T-cell lines confirmed potent specific lysis of SLAMF7+ MM cell lines including MM1.S and OPM-2 and stable SLAMF7-transfectants of K562, as well as antigen specific IFNγ secretion and productive proliferation. In a flow cytometry based cytotoxicity assay, co-incubation of mPCs with autologous (or allogeneic) SLAMF7-CAR T cells resulted in elimination of >90% of mPCs after a 4-hour incubation period, whereas CD19-CAR or unmodified T cells had no discernible effects. Moreover, in an in vivo xenograft MM model (NSG/MM1.S) a single administration of SLAMF7-CAR T cells resulted in complete MM clearance and long-term survival, whereas mice treated with CD19-CAR or unmodified T cells rapidly expired from progressive disease. Finally, we analyzed the fratricidal potential of SLAMF7-CAR T cells to predict hematologic toxicities that might occur in a clinical setting. Co-incubation of purified CD4+ and CD8+ primary T cells, B cells and NK cells with SLAMF7-CAR T cells resulted in rapid and specific elimination of only SLAMF7+ subsets, whereas SLAMF7- cells remained viable and functional as confirmed for CD4+ and CD8+ T cells by inducible IFNγ secretion. Conclusion: Our data demonstrate that SLAMF7-specific CAR T cells can be reproducibly generated from MM patients and exert remarkable anti-myeloma efficacy in pre-clinical models in vitro and in vivo. Lymphocytic fratricide does not preclude the manufacture of SLAMF7-CAR T cells but might be associated with acute (cytokine storm) or chronic (viral infections) side effects in a clinical setting. However, such toxicities may be prevented e.g. by preparative lymphodepletion and antiviral prophylaxis and enable the implementation of SLAMF7-CAR T cell therapy as a safe and effective modality in the treatment of MM. Disclosures Knop: Celgene Corporation: Consultancy. Einsele:Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Metabolic dysfunction in lymphocytes promotes postoperative morbidity

Acquired/established lymphopenia is associated with an increased risk of infectious complications and characterized by reduced oxidative phosphorylation and impaired glycolysis. This hypometabolic phenotype triggered by glucocorticoid-induced mitochondrial dysfunction activating the NLRP1 inflammasome prevents normal lymphocyte functionality and increases apoptosis.