Low Circulating Monocytes Is in Parallel With Lymphopenia Which Predicts Poor Outcome in Anti-melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis-Associated Interstitial Lung Disease

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (DM)-associated interstitial lung disease (ILD) may progress rapidly and lead to high mortality within 6 or 12 months. Except for reported prognostic factors, simple but powerful prognostic biomarkers are still in need in practice. In this study, we focused on circulating monocyte and lymphocyte counts and their variation tendency in the early stage of ILD. A total of 351 patients from two inception anti-MDA5 antibody-positive cohorts were included in this study, with various treatment choices. Lymphocyte count remained lower in the first month after admission in the non-survivor patients. Although baseline monocyte count showed no significant differences, average monocyte count in the following 4 weeks was also lower in the non-survivor group. Based on the C-index and analysis by the “survminer” R package in the discovery cohort, we chose 0.24 × 109/L as the cutoff value for Mono W0-2, 0.61 × 109/L as the cutoff value for lymph W0-2, and 0.78 × 109/L as the cutoff value for peripheral blood mononuclear cell (PBMC) W0-2, to predict the 6-month all-cause mortality. The Kaplan–Meier survival curves and adjusted hazard ratio with age, gender, and the number of immunosuppressants used all validated that patients with lower average monocyte count, lower average lymphocyte count, or lower average PBMC count in the first 2 weeks after admission had higher 6-month death risk, no matter in the validation cohort or in the pooled data. Furthermore, flow cytometry figured out that non-classical monocytes in patients with anti-MDA5 antibody-positive DM were significantly lower than healthy controls and patients with DM without anti-MDA5 antibodies. In conclusion, this study elucidated the predictive value of monocyte and lymphocyte counts in the early stage and may help rheumatologists to understand the possible pathogenesis of this challenging disease.

Peripheral lymphocyte count as a surrogate marker of immune checkpoint inhibitor therapy outcomes in patients with non-small-cell lung cancer

Degree of expression of programmed death-ligand 1 (PD-L1) is related with Immune check point inhibitors (ICIs) response but it needs sufficient tumor tissue. There is unmet need for easily accessible and prognostic peripheral blood (PB) biomarkers. We investigated the application of serum peripheral lymphocyte count (PLC) as a predictive PB biomarker for ICI response in patients with NSCLC. We conducted a retrospective study and reviewed the patients with NSCLC who were treated with ICIs from April 1, 2016, to March 31, 2019. The PLC before and after 1 month of immunotherapy was collected. We evaluated the association between PLC and progression-free survival (PFS), overall survival (OS) and adverse events. A total of 231 patients were treated with ICIs for NSCLC. The median follow-up period was 4.7 months and the disease progressed in 138 patients (59.7%). Compared with the lowest quartile (Q1: the lowest 25%), the highest quartile (Q4: the highest 25%) of post-treatment PLC showed a significantly higher PFS (HR 0.28, 95% CI 0.16–0.52) and OS (HR 0.35, 95% CI 0.19–0.65) in the adjusted model. An association between adverse events and PLC was not observed. We revealed that an increased pre- and post-treatment PLC was associated with favorable PFS and OS with NSCLC patients treated with ICIs. PLC could be a helpful for ICI responses in NSCLC.

Compassionate use of recombinant human IL-7-hyFc as a salvage treatment for restoring lymphopenia in patients with recurrent glioblastoma

Purpose Lymphopenia is frequently observed and is associated with poor prognosis in glioblastoma (GBM) patients. Restoring lymphopenia in cancer patients has been suggested as a novel immunotherapeutic strategy. As interleukin-7 (IL-7) is necessary for proliferation of lymphocytes and to amplify the total lymphocyte count (TLC), IL-7 therapy has been tried for various cancers, although the results are inconclusive. Here, we describe the clinical results of recurrent GBM treated with long-acting engineered version of recombinant human IL-7 (rhIL-7-hyFc). Methods This prospective case series based on compassionate use was approved by the Ministry of Food and Drug Safety in South Korea. Patients with recurrent GBM were enrolled to Seoul St. Mary's Hospital. Primary outcomes were the safety profile and elevated total lymphocyte count (TLC). Secondary outcomes were overall survival (OS) and progressionbfree survival (PFS). The duration of median follow up was 372.6 days (range 98-864 days). Results Among 18 patients enrolled, 10 received rhIL-7-hyFc with temozolomide, 5 received rhIL-7-hyFc with bevacizumab, 1 received rhIL-7-hyFc with PCV chemotherapy, and 2 received rhIL-7-hyFc alone. The mean TLC of enrolled patients after the first treatment with rhIL-7-hyFc was significantly increased from 1,131 cells/mm^3 (range 330-2,989) at baseline to 4,356 cells/mm^3 (range 661-22,661). Similar increase was observed in 16 of 18 patients (88.8%), only after the first treatment of rhIL-7-hyFc. TLCs of these patients were maintained higher while rhIL-7-hyFc was repeatedly administered. Most common adverse events were injection sites reactions (64.7%) including urticaria and itching sensation, however, there were no serious adverse events more than grade III. Median OS and PFS were 378 days (range 107-864 days) and 231 days (55-726 days), respectively. Conclusion Our study first reports that IL-7 immunotherapy can restore lymphopenia and maintain TLC with various salvageable chemotherapies in recurrent GBM patients without serious adverse toxicities. This outcome warrants further larger and randomized clinical trials to validate the clinical benefits of rhIL-7-hyFc for GBM patients.

The Predictive Values of Lymphocytopenia in West Darfur Patients with Malaria

Background: In Sudan malaria is most commonly caused by infection with plasmodium falciparum, although by p.vivax. Malaria causes the most dangerous and highest rates of complication and mortality. Most malaria cases in 2018 were reported by the world health organization (WHO) in the African region(213 million cases of malaria or 93% of all malaria cases in the world and 70% is 5 years or younger). Objectives: The aim of this study was to measure and compare the mean of absolute lymphocyte count in malaria patients and control groups, and to determine positive and negative predictive values of lymphocytopenia in malaria patients. Methods: It was conducted on 100 subjects with malaria as cases and 100 subjects without malaria as controls, at EL Genina Hospital after obtaining the ethical approval and the subjects' consent. It was done by testing the CBC, differential counts, and absolute lymphocyte count then determining the means and p-values. The positive and negative predictive values were also determined. Results: It was found that the mean of TWBC count in the case group was(7,13109/l), and (7,84109/l)in the control group, the p-value was (0.150). The mean of lymphocytes differential in the case group was (20.73%)and (33.96%)in the control group, the p-value was (0.000). While the mean of the absolute lymphocytes counts in the case group was (1.39109/l), it was (2.56109/l)in the control group, with a p-value (0.000). This p-value indicated that there was significant lymphocytopenia in malaria patients. The positive predictive value was 83% and the negative predictive value was 69%. Conclusion: This study concluded that there was no significant lymphocytopenia in malaria patients and that lymphocytopenia cannot be used as the key hematological indicator of malaria infection.

Malnutrition Contributes to Low Lymphocyte Count in Early-Stage Coronavirus Disease-2019

Background and Aim: Lymphocytes play an important role in fighting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Low total lymphocyte count (TLC), which contributes to poor clinical outcomes, is common in persons with coronavirus disease 2019 (COVID-19). The current explanation for the cause of low TLC is that it is directly related to the invasiveness of SARS-CoV-2, which attacks lymphocytes. We hypothesized that malnutrition contributes to the development of low TLC in early-stage COVID-19.Methods: We prospectively enrolled 101 patients with confirmed COVID-19. On their first day of hospitalization, we collected baseline and laboratory data, including clinical symptoms; the Sequential Organ Failure Assessment, Nutrition Risk Screening 2002 and Subjective Global Assessment were used to assess the malnutrition status of the patients. Multivariable logistic regression was used to identify independent risk factors for low TLC and severe COVID-19.Results: Malnutrition was associated with lower TLC in COVID-19. Fifty-nine (58.4%) of the patients showed low TLC, 41 (40.6%) were at risk for malnutrition, and 18 of them were malnourished. Low TLC was an independent risk factor for severe COVID-19. Compared to patients with normal TLC, those with low TLC more often presented with anorexia, malnutrition, higher SOFA scores (P < 0.05) and comorbidities (diabetes and malignancies). Malnutrition (OR: 3.05, 95% CI: 1.5–6.19, P = 0.006) and SOFA scores (OR: 1.51, 95% CI: 1.04-2.43, P = 0.042) were identified as independent risk factors for low TLC.Conclusions: Malnutrition was common among our patients with early-stage COVID-19, and it contributed to the occurrence of low TLC.

Taxane/gemcitabine-containing chemotherapy plus locoregional IMRT for patients with de novo metastatic nasopharyngeal carcinoma: the treatment outcomes and prognostic factors analysis

Purpose To evaluate treatment outcomes of de novo metastatic nasopharyngeal carcinoma (mNPC) patients receiving taxane/gemcitabine-containing chemotherapy followed by locoregional intensity-modulated radiotherapy (IMRT) and analyze potential prognostic factors. Methods A total of 118 patients between March 2008 and November 2018 were retrospectively analyzed. All the patients were treated with taxane/gemcitabine-containing systemic chemotherapy followed by definitive locoregional IMRT. Potential prognostic factors including baseline absolute lymphocyte count (ALC) and the subdivision of metastasis were analyzed. Results The median follow-up time for the whole group was 31.5 months (range 5–138 months). Of the 118 patients, 9 (7.6%) patients experienced local regional failure and 60 (50.8%) patients had progression of distant metastasis. At the time of the last follow-up, 61 (51.7%) patients were dead. The 5-year actuarial progression free survival (PFS), overall survival (OS),distant metastasis relapse free survival (DMFS) and local regional recurrence free survival (LRFS) were 34.2%, 44%, 41.1% and 82.6%, respectively. Baseline lymphocyte count ≥ 1600/μl prior to the treatment conferred better locoregional control (5y-LRFS 96% vs. 64.7%, p < 0.001) and distant metastasis control (5y-MFS 50.4% vs. 32.4%, p = 0.023). The multivariate analysis showed that high lymphocyte count was the most relevant predictor of superior PFS (HR = 0.236, p < 0.001) and OS (HR = 0.518, p = 0.04). M subdivision was found as another independent prognostic factor for OS but not for PFS. Conclusion Taxane/gemcitabine-containing chemotherapy combined with IMRT represents an effective treatment modality for mNPC. Baseline ALC is an independent significant prognostic factor for PFS and OS.

Immune System Dysfunction Criteria in Critically Ill Children: The PODIUM Consensus Conference

CONTEXT Immune system dysfunction is poorly represented in pediatric organ dysfunction definitions. OBJECTIVE To evaluate evidence for criteria that define immune system dysfunction in critically ill children and associations with adverse outcomes and develop consensus criteria for the diagnosis of immune system dysfunction in critically ill children. DATA SOURCES We conducted electronic searches of PubMed and Embase from January 1992 to January 2020, using medical subject heading terms and text words to define immune system dysfunction and outcomes of interest. STUDY SELECTION Studies of critically ill children with an abnormality in leukocyte numbers or function that is currently measurable in the clinical laboratory in which researchers assessed patient-centered outcomes were included. Studies of adults or premature infants, animal studies, reviews and commentaries, case series (≤10 subjects), and studies not published in English with inability to determine eligibility criteria were excluded. DATA EXTRACTION Data were abstracted from eligible studies into a standard data extraction form along with risk of bias assessment by a task force member. RESULTS We identified the following criteria for immune system dysfunction: (1) peripheral absolute neutrophil count &lt;500 cells/μL, (2) peripheral absolute lymphocyte count &lt;1000 cells/μL, (3) reduction in CD4+ lymphocyte count or percentage of total lymphocytes below age-specific thresholds, (4) monocyte HLA-DR expression &lt;30%, or (5) reduction in ex vivo whole blood lipopolysaccharide-induced TNFα production capacity below manufacturer-provided thresholds. LIMITATIONS Many measures of immune system function are currently limited to the research environment. CONCLUSIONS We present consensus criteria for the diagnosis of immune system dysfunction in critically ill children.

A Multimodal Approach for the Risk Prediction of Intensive Care and Mortality in Patients with COVID-19

Background: Although several studies have been launched towards the prediction of risk factors for mortality and admission in the intensive care unit (ICU) in COVID-19, none of them focuses on the development of explainable AI models to define an ICU scoring index using dynamically associated biological markers. Methods: We propose a multimodal approach which combines explainable AI models with dynamic modeling methods to shed light into the clinical features of COVID-19. Dynamic Bayesian networks were used to seek associations among cytokines across four time intervals after hospitalization. Explainable gradient boosting trees were trained to predict the risk for ICU admission and mortality towards the development of an ICU scoring index. Results: Our results highlight LDH, IL-6, IL-8, Cr, number of monocytes, lymphocyte count, TNF as risk predictors for ICU admission and survival along with LDH, age, CRP, Cr, WBC, lymphocyte count for mortality in the ICU, with prediction accuracy 0.79 and 0.81, respectively. These risk factors were combined with dynamically associated biological markers to develop an ICU scoring index with accuracy 0.9. Conclusions: to our knowledge, this is the first multimodal and explainable AI model which quantifies the risk of intensive care with accuracy up to 0.9 across multiple timepoints.