Median Lymphocyte Count Research Articles

Time-Limited Therapy with Zanubrutinib Plus Rituximab in Treatment-Naïve Chronic Lymphocytic Leukemia: Early Results of an Ongoing Phase 2 Trial

Introduction: The Bruton tyrosine kinase inhibitor (BTKi) zanubrutinib has recently been approved for treatment of chronic lymphocytic leukemia (CLL). Zanubrutinib induces durable remissions in most patients with CLL, and treatment is typically given as continuous monotherapy, until disease progression or toxicities prohibit further use. We developed time-limited therapy with zanubrutinib in combination with rituximab as an alternative to long-term BTKi monotherapy. Here, we report early results from the first 17 treatment-naïve patients with CLL who enrolled in this ongoing phase 2 trial (NCT04458610) between July 2020 and April 2023 at MD Anderson Cancer Center. Patients and Study Design: Patients with treatment-naïve CLL requiring therapy per iwCLL criteria receive zanubrutinib 160 mg orally twice daily and rituximab (375 mg/m 2 intravenously) on days 1, 8, 15, 22 of cycle 1, and then on day 1 of cycles 2 - 6 (one cycle is 28 days). Patients who achieve a complete remission (CR) by iwCLL 2018 criteria after 6 cycles of combination therapy continue with zanubrutinib alone for another 6 cycles. Patients who achieve a partial remission (PR) or stable disease (SD) after 6 cycles continue for another 6 cycles of the combination. Patients who achieve a CR after 12 cycles will receive 6 additional cycles of zanubrutinib alone, and then stop treatment. Patients who achieve a PR or SD after 12 cycles will continue zanubrutinib alone for 12 cycles and the stop therapy after a total of 24 cycles. After this time-limited therapy, patients transition to observation and can resume therapy if they relapse and fulfill iwCLL criteria for salvage therapy. The primary objective of the trial is to determine the proportion of patients who have treatment-free remission 6 months after discontinuation of zanubrutinib. Secondary objectives are to determine the length of treatment-free remission, identify clinical factors associated with long versus short remissions, and to evaluate the efficacy of re-treatment with zanubrutinib plus rituximab in patients who relapse. Results: The median age of the patients was 68 years (range, 54 - 77 years), 47% had unmutated IgHV and 41% advance stage disease (RAI stage III and IV). The median baseline absolute lymphocyte count (ALC) and β2 microglobulin were 51.9x10 9/L (range, 1.7 - 231.0x10 9/L) and 3.9 mg/L (range, 2.5 - 6.8 mg/L), respectively. After a median follow-up of 13 months (range, 0.5 - 29 months), all patients remain on study, and the estimated one-year progression-free (PFS) and overall survival (OS) is 100%. Seven patients completed therapy (1 patient after 12 cycles, 6 patients after 24 cycles) and have moved on to observation (median observation time post-therapy 4.5 months). So far, we have not observed any progression events after treatment discontinuation. Overall response rate is 100%, with 9% CR and 91% PR after 6 months (n=11), 11% CR and 89% PR after 12 months (n=9), and 33% CR and 67% PR after 24 months of therapy (n=6). The median levels of bone marrow involvement by CLL cells, quantified by flow cytometry, declined from 81.6% at baseline (range, 25.8 - 93.2%, n=16) to 20.3% after 6 cycles (range, 0.07 - 82%, n=11, p<0.0001), to 12.1% after 12 cycles (range, 0.04 - 55.60%, n=9, p<0.0001), and to 7.23% after 24 cycles (range, 0.2 - 41.4%, n=6, p=0.001). Grade ≥3 adverse events (AE) were observed in 9 patients (52.9%), which included hypertension (n=4) and decreased neutrophil counts (n=3). The most frequent grade 1-2 AE were decreased neutrophil (59%) and platelet counts (47%), bruising (41%), chills, increased creatinine, arterial hypertension, nausea (35% each), fatigue, and headache (29% each). No atrial fibrillation events were observed. Conclusion: This early analysis indicates that time-limited therapy with zanubrutinib and rituximab is well tolerated and induces remissions with a major reduction in bone marrow disease burden in patients with treatment-naïve CLL. The first 7 patients who stopped therapy so far have not progressed, but longer follow-up in more patients is needed to determine the durability of responses after therapy discontinuation, and how those compare to more intensive CLL combination regimens.

Splanchnic vein thrombosis associated with SARS-CoV-2 infection: A VALDIG case–control study

Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a risk factor for splanchnic vein thrombosis (SVT) is unknown. This study aims to assess the impact of SARS-CoV-2 infection on the presentation and prognosis of recent SVT and to identify specific characteristics of SARS-CoV-2-associated SVT. This is a retrospective study collecting health-related data of 27 patients presenting with recent SVT in the context of SARS-CoV-2 infection in 12 Vascular Liver Disease Group (VALDIG) centres and in comparison with 494 patients with recent SVT before the SARS-CoV-2 pandemic. Twenty-one patients with SARS-CoV-2 had portal vein thrombosis with or without thrombosis of another splanchnic vein, two had superior mesenteric vein thrombosis, one had splenic vein thrombosis, and three had hepatic vein thrombosis. Diagnosis of SVT was made 10 days (95% CI 0-24 days) after the diagnosis of SARS-CoV-2 infection. Fever (52 vs. 15%; p <0.001) and respiratory symptoms (44 vs. 0%; p <0.001) were more frequent, and median lymphocyte count was lower (1.1×103/mm3vs. 1.6×103/mm3; p= 0.043) in patients with infection than in those without SARS-CoV-2 infection. A prothrombotic condition was identified in 44 and 52% of patients with and without SARS-CoV-2 infection, respectively (p= 0.5). All patients with SARS-CoV-2 received anticoagulation therapy. During a median follow-up of 250 days, three SARS-CoV-2-infected patients (11%) required intestinal resection for infarction 1 to 3 months after diagnosis of SVT compared with 13 (2.6%) controls (p= 0.044). Partial or complete recanalisation of the thrombosed splanchnic vein was performed in 33% of patients with SARS-CoV-2. SARS-CoV-2 infection can be associated with recent SVT. Intestinal infarction leading to intestinal resection might be more frequent in patients with SARS-CoV-2. SARS-CoV-2 infection can be associated with recent SVT. SVT occurring during SARS-CoV-2 infection is characterised by a higher frequency of respiratory symptoms and a lower lymphocyte count. Intestinal infarction leading to intestinal resection appears to occur more frequently in patients with SARS-CoV-2.

Outcome of COVID-19 and tolerance of Remdesivir in patients with renal failure: a single center experience from Pakistan

Introduction: Coronavirus disease-19 (COVID-19) is known to cause severe disease in chronic kidney disease and maintenance dialysis patients. We aim to report the outcome of COVID-19 and the adverse effects of Remdesivir (RDV) in patients with renal failure. Methodology: A retrospective observational study included all admitted patients with COVID-19 who received Remdesivir. Clinical characteristics and outcomes were compared in patients with renal failure (RF) and non-renal failure (NRF). We also evaluated RDV-associated nephrotoxicity and observed renal functions during antiviral treatment. Results: A total of 142 patients received RDV, 38 (26.76%) in RF and 104 (73.23%) in the non-RF group. The median absolute lymphocyte count was low while C-reactive protein, ferritin, and D-dimer were significantly high on admission in the RF group. A significant number of patients in the RF group required ICU admission (58% vs. 35% p = 0.01) and expired (29% vs. 12.5 p = 0.02). Among survivors and non-survivors in the RF group, raised inflammatory markers and low platelet count on presentation were significantly associated with high mortality. Median serum creatinine (mg/dL) was 0.88 on admission, remained at 0.85 in the NRF group, and improved from 4.59 to 3.87 (mg/dL) after receiving five days of RDV in the RF group. Conclusions: COVID-19 in renal failure has a high risk for ICU admissions leading to increased mortality. Multiple comorbidities and raised inflammatory markers are predictors of poor outcomes. We observed no significant drug-related adverse effects, and none of our patients required discontinuation of RDV due to worsening renal function.

Real-World Safety and Effectiveness After 5 Years of Dimethyl Fumarate Treatment in Black and Hispanic Patients with Multiple Sclerosis in ESTEEM.

Multiple sclerosis(MS) clinical trials have included low numbers of patients from racial and ethnic minority populations; therefore, it is uncertain whether differences exist in response to disease-modifying therapies. We evaluated the real-world safety and effectiveness of dimethyl fumarate (DMF) treatment over 5years in four patient cohorts: Black, non-Black, Hispanic, and non-Hispanic people with relapsing-remitting MS. ESTEEM is an ongoing, 5-year, multinational, prospective study evaluating the long-term safety and effectiveness of DMF in people with MS. The analysis included patients newly prescribed DMF in routine practice at 393 sites globally. Overall, 5251 patients were analyzed (220 Black, 5031 non-Black; 105 Hispanic, 5146 non-Hispanic). Median (min-max) months of follow-up was 32 (0-72) for Black, 29 (1-77) for Hispanic, and 41 (0-85) for both the non-Black and non-Hispanic populations. In total, 39 (18%) Black and 29 (28%) Hispanic patients reported adverse events leading to treatment discontinuation versus 1126 (22%) non-Black and 1136 (22%) non-Hispanic patients; gastrointestinal disorders were the most common in all subgroups. Median lymphocyte counts decreased by 37% in Black, 40% in non-Black, 10% in Hispanic, and 39% in non-Hispanic patients in the first year, then remained stable and above the lower limit of normal in most patients. Annualized relapse rates (ARRs) (95% confidence intervals) up to 5years were 0.054 (0.038-0.078) for Black, 0.077 (0.072-0.081) for non-Black, 0.069 (0.043-0.112) for Hispanic, and 0.076 (0.072-0.081) for non-Hispanic populations, representing reductions of 91-92% compared with ARR 12months before study entry (all p < 0.0001). The safety profile of DMF in these subgroups was consistent with the overall ESTEEM population. Relapse rates remained low in Black and Hispanic patients, and consistent with non-Black and non-Hispanic patients. These data demonstrate a comparable real-world treatment benefit of DMF in Black and Hispanic patients. ClinicalTrials.gov identifier NCT02047097.

Granulocyte transfusion during cord blood transplant for relapsed, refractory AML is associated with massive CD8+ T-cell expansion, significant cytokine release syndrome and induction of disease remission.

In high-risk myeloid malignancy, relapse is reduced using cord blood transplant (CBT) but remains the principal cause of treatment failure. We previously described T-cell expansion in CBT recipients receiving granulocyte transfusions. We now report the safety and tolerability of such transfusions, T-cell expansion data, immunophenotype, cytokine profiles and clinical response in children with post-transplant relapsed acute leukaemia who received T-replete, HLA-mismatched CBT and pooled granulocytes within a phase I/II trial (ClinicalTrials.Gov NCT05425043). All patients received the transfusion schedule without significant clinical toxicity. Nine of ten patients treated had detectable measurable residual disease (MRD) pre-transplant. Nine patients achieved haematological remission, and eight became MRD negative. There were five deaths: transplant complications (n = 2), disease (n = 3), including two late relapses. Five patients are alive and in remission with 12.7 months median follow up. Significant T-cell expansion occurred in nine patients with a greater median lymphocyte count than a historical cohort between days 7-13 (median 1.73 × 109 /L vs. 0.1 × 109 /L; p < 0.0001). Expanded T-cells were predominantly CD8+ and effector memory or TEMRA phenotype. They exhibited markers of activation and cytotoxicity with interferon-gamma production. All patients developed grade 1-3 cytokine release syndrome (CRS) with elevated serum IL-6 and interferon-gamma.

The Frequency of Pancreatic Enzyme Elevations and Effect on Disease Severity in COVID-19

Aim: In this study, we aimed to evaluate the frequency of pancreatic enzyme elevations in COVID-19-infected patients and to examine the effect on disease severity.&#x0D; Material and Methods: A total of 1249 patients who hospitalized with COVID-19 infection were included. The frequency of pancreatic enzyme elevations and the effect on disease severity in patients infected with COVID-19 were investigated.&#x0D; Results: The pancreatic enzyme elevations (amylase/lipase or both) were detected in 32 of 1249 patients (incidence 2.96%). 32 cases with a mean age of 64.97±5.63 years were included in this study. 30 (93.75%) of the cases were men’s gender. 31 (96.87%) of them had elevated amylase levels, 26 (81.25%) had elevated lipase levels and 25 (78.12%) of them had elevated both amylase and lipase levels. Only 10 (31.25%) of them tested radiological for acute pancreatitis (AP) and there was no radiological finding compatible with AP in any of the limited numbers of abdominal computerized tomography scans performed. 18 (56.25%) of the patients were transferred to the intensive care unit due to clinical worsening and mortality developed in 13 (40.62%) patients. The mean age of the deceased cases was 66.4±6.6 years and there was no statistically significant difference between deceased and survived COVID-19 patients (&gt;0.05).&#x0D; Conclusion: The median lymphocyte count was lower, and the median AST, ALT, and lipase levels were higher in the deceased group. Perhaps close clinical follow-up of patients with pathological findings in these values and radiological imaging, if necessary, may be beneficial in the method of the disease.&#x0D; Keywords: COVID-19; disease severity; pancreatic enzyme elevations.

Maternal Health Characteristics Associated with Idiopathic T Cell Lymphopenia of Infancy

Newborn TREC screening has identified infants with idiopathic T cell lymphopenia (TCL). By convention, lymphopenia resolves by 12 months of age in transient TCL. We aimed to characterize demographic, laboratory, and maternal health characteristics that differentiate infants with transient vs. persistent idiopathic TCL. A single-center retrospective analysis was performed on patients born from September 2010 through August 2021. Chart review was performed on 53 eligible infants with abnormal TREC screening at corrected gestational age 37 weeks or greater. Descriptive statistics were calculated for initial TREC levels, and T-cell lymphocyte counts at initial referral. Mann-Whitney tests compared initial lymphocyte and average TREC counts. Chi-square analysis assessed associations between transient and persistent TCL patients and select maternal characteristics and risk factors. 25 patients demonstrated persistent TCL while 28 had transient TCL. The persistent cohort was 60.0% male and 24.0% white, while the transient cohort was 60.7% male and 21.4% white. Mean maternal age at birth was 29.7 vs 30.6 years in the persistent and transient groups, respectively. Medians initial TREC levels were lower in the persistent group, but not significantly (52 vs. 73 TRECs/µL of blood, p = .219). The median initial lymphocyte counts were significantly lower in the persistent compared to the transient cohort for CD3+ (1176 vs. 2144 cells/µL, p < .001), CD4+ (866 vs. 1460 cells/µL, p <.001) and CD8+ (293 vs. 539 cells/µL, p = .003). Persistent TCL mothers had more chronic comorbidities (44.0% vs 42.9%, χ2 (1, N = 53) = 0.007, p = .933) and gestational complications (60.0% vs 39.3%, χ2(1, N = 53) = 2.27, p = .132) than transient TCL mothers, but these differences were not significant. Persistent TCL infants were more lymphopenic initially than their transient counterparts. No statistically significant differences in maternal chronic comorbidities or gestational complications exist between the transient or persistent TCL infants. Further work is necessary to characterize if specific maternal-fetal stress factors contribute to persistent TCL.

Diagnosis and treatment of 26 cases of adenovirus infection after allogeneic hematopoietic stem cell transplantation

Objective: To analyze the clinical characteristics and prognosis of adenovirus infection after allogeneic hematopoietic stem cell transplantation. Methods: A total of 26 patients with adenovirus infection admitted to the posttransplant ward of the First Affiliated Hospital of Soochow University from 2018 to 2022 were enrolled. Their data on baseline and clinical characteristics, treatment, and follow-up were analyzed. Results: The median patient age was 30 (22, 44) years. Twenty-two patients received related haploid stem cell transplantation, three received unrelated stem cell transplantation, and one received umbilical cord stem cell transplantation. Antithymocyte globulin was included in the conditioning regimen in 25 patients. The median time of adenovirus infection was +95 (+44, +152) days. The median peripheral blood lymphocyte count was 0.30 (0.11, 0.69) × 10(9)/L. Twelve patients had acute graft-versus-host disease. Twenty-four patients received antirejection therapies at diagnosis. Sixteen cases had combined infection with other pathogens with adenovirus infection. Eight cases were diagnosed as asymptomatic infection, and 18 were diagnosed as adenovirus disease, including pneumonia (38.89% ) , gastrointestinal disease (38.89% ) , encephalitis (33.33% ) , hepatitis (5.56% ) , and urinary tract inflammation (5.56% ) . The age of >30 years was a risk factor for adenovirus disease (P=0.03) . Eighteen patients received tapering of immunosuppression, and all 26 patients received at least one antiviral drug. Other treatments included high-dose gamma globulin and donor lymphocyte infusion. Adenovirus infection improved in 10 cases and progressed in 16 cases. The median follow-up time was 30 (7, 237) days. Twenty-two patients died. The all-cause mortality rate was (88.5±7.1) % , and the attributable mortality rate was 45.5% . There was no significant difference in the 100 d survival rate between asymptomatic infected patients and patients diagnosed with adenovirus disease (37.5% vs 22.2% , HR=1.83, 95% CI 0.66-5.04, P=0.24) . Conclusion: The age of >30 years was a risk factor for adenovirus disease. Mortality was high in patients with adenovirus infection after allogeneic hematopoietic stem cell transplantation.

Legionella pneumophila Infections during a 7-Year Retrospective Analysis (2016-2022): Epidemiological, Clinical Features and Outcomes in Patients with Legionnaires' Disease.

Legionella pneumophila (LP) is one of the main causative agents of community-acquired pneumonia in Europe and its fifth bacterial cause in Italy (4.9%). We conducted a seven year retrospective analysis of LP infection serogroup 1 in Asti, Piedmont, between 2016 and 2022. Patients were included if they tested positive for the Legionella urinary antigen. Clinical, laboratory, and radiologic data were analyzed to describe the risk factors for mortality. Fifty patients with LD were collected, mainly male, with a median age of 69 years. The main comorbidities were cardiovascular diseases (50%), pulmonary diseases (26%), and neurological diseases (12%). The most common clinical presentations were fever, respiratory, gastrointestinal, and neurologic symptoms. Older age (p = 0.004), underlying cardiovascular diseases (p = 0.009), late diagnosis at admission (p = 0.035), and neurological symptoms at diagnosis (p = 0.046) were more common in the non-survivor group. Moreover, a septic-shock presentation or the need for non-invasive ventilation at admission were associated with a higher mortality. No considerable differences in the biochemical data were found between the two groups except for the median neutrophil count, lymphocyte count, neutrophil-to-lymphocyte ratio, and PCT value. We did not find any differences in mortality related to the choice of antibiotic regimen. Differences in outcome were associated with the median duration of treatment (p =< 0.001) but not to the choice of antibiotic regimen (mainly levofloxacin or azithromycin). In conclusion, early individuation of the wide spectrum of clinical characteristics of LP infection such as respiratory, cardiac, and neurological manifestations of the patient's comorbidities, and significant biochemical data should help clinicians flag high risk patients and potentially improve their outcome.

Anti-SARS-CoV-2 spike immunoglobulinG and immunoglobulinM titers decline as interval from the second inactivated vaccine dose to the onset of illness is prolonged in breakthrough infection patients.

Understanding of the early immune response in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infections is limited. Ninety-eight patients with coronavirus disease 2019 (COVID-19) breakthrough infections were divided into two groups, with intervals from receiving the second dose of inactivated vaccine to the onset of illness <60 or ≥60 days. The median lymphocyte count and the median anti-SARS-CoV-2 spike immunoglobulin G (IgG) and immunoglobulin M (IgM) titers were higher in the <60-day interval group compared with the corresponding medians in the ≥60-day interval group (p = 0.005, p = 0.001, and p = 0.001, respectively). The median interleukin-6 (IL-6) level in the <60-day interval group was significantly lower than the median IL-6 level in the ≥60-day interval group (p < 0.001). Our results highlight the different anti-SARS-CoV-2 spike IgG and IgM antibody titers among patients with different intervals from receiving the second dose of inactivated vaccine to the onset of illness.

Pneumocystis jirovecii Infections Among COVID-19 Patients: A Case Series and Literature Review.

Pneumocystis jirovecii pneumonia (PCP) is a serious, emerging complication of coronavirus disease 2019 (COVID-19). We performed a systematic review of published cases. We describe 6 new cases of PCP/COVID-19 coinfection. Among our cases (n = 6) and those in the literature (n = 69) with available data, the median age (interquartile range [IQR]) was 59 (44-77) years (n = 38), 72% (47/65) were male, and the mortality rate was 30.9% (21/68). Long-term corticosteroid use was noted in 45.1% (23/51), advanced HIV infection (defined as a CD4 count <200 cells/μL) in 17.6% (9/51), and antineoplastic chemotherapy in 13.7% (7/51), consistent with known PCP risk factors. Notably, 56.7% (38/47) had verifiable risk factors for PCP (high-dose corticosteroids, immunosuppressive therapy, and HIV infection) before COVID-19 infection. A median absolute lymphocyte count (IQR) of 0.61 (0.28-0.92) ×103 cells/mm3 (n = 23) and CD4 count (IQR) of 66 (33-291.5) cells/mm3 (n = 20) were also discovered among the study population. These findings suggest a need for greater attention to PCP risk factors among COVID-19 patients and consideration of PCP prophylaxis in these high-risk populations.

The modified systemic inflammation score is a predictor of ICU admission of COVID-19 patients

Objective: To evaluate the effect of the modified systemic inflammation score (mSIS) on prognosis in patients diagnosed with COVID-19. Methods: In this retrospective cross-sectional study, 181 patients were selected and divided into two groups: patients with and without admission to the intensive care unit (ICU). An albumin level of ≥4.0 g/dL and lymphocyte-to-monocyte ratio (LMR) of ≥3.4 was scored 0, an albumin level of &lt;4.0 g/dL or LMR of &lt;3.4 was scored 1, and an albumin level of &lt;4.0 g/dL and LMR of &lt;3.4 was scored 2. Results: A total of 242 COVID-19 positive patients were initially included in this study. Of these patients, 61 were excluded and 181 patients remained. Among the 181 participants, 94 (51.9%) were female, and the median age was 61 (51, 75) years. The mSIS scale ranged from 0 to 2. After analysis, the median score was 0 (0, 0) in the non-ICU group and 2 (0, 2) in the ICU group (P&lt;0.001). The median white blood cell, lymphocyte counts, and albumin levels were lower in the ICU group (P&lt;0.001, P&lt;0.001, and P&lt;0.001, respectively). In logistic regression analysis lymphocytopenia (OR=5.158, 95% CI=1.249-21.304, P=0.023), hypoalbuminemia (OR=49.921, 95% CI=1.843-1 352.114, P=0.020), AST elevation (OR=3.939, 95% CI=1.017-15.261, P=0.047), and mSIS=2 (OR=5.853, 95% CI=1.338-25.604, P=0.019) were identified as independent predictors of ICU admission. Conclusion: The mSIS can be used as an independent parameter for establishing the intensive care needs of patients with COVID-19.

COVID-19 in kidney transplant recipients: A experience in Colombia

Background: Patients with kidney transplants seem to be at particularly high risk for severe COVID19 disease due to their impaired immune responses and comorbidities. Purpose: This study aims to describe kidney transplant patients’ clinical characteristics and outcomes with SARSCOV-2 infection in a fourth-level hospital in Cali, Colombia. Methodology: We performed an observational study of kidney transplant recipients with SARS-CoV2 infection admitted at Fundación Valle del Lili from June to December 2020. To be eligible for this study, patients have symptoms compatible, a positive RT-PCR and inpatient management. Asymptomatic patients were excluded. Results: We enrolled a total of 50 patients. 64% were male, and the median age was 53.5 years (range 46-60). The comorbidities were 36 (70%) hypertension, 16 (32%) diabetes mellitus, 5 (10%) obesity. The most common immunosuppressive regimen was tacrolimus, mycophenolate and prednisone. The median time from symptoms onset to the positive RT-PCR was 7 days. The most common initial symptom was fever (64%), and fatigue (58%), cough (44%) and dyspnea (36%). Baseline levels of CRP was 6.43 mg/dL (3.25-11.22). The median lymphocyte count was 785 mm3/uL (550-1230). Baseline D-Dimer was 0.767 ug/ml (0.484-1153.5), ferritin median level was 1011ng/ml (670-2145). Six of the patients died (12%), 4/6 were by sepsis-related multi-organ failure and 2/6 were by ARDS. Conclusions: Major complications such as acute kidney injury, acute respiratory distress syndrome and mortality related to COVID-19 infection observed in our study are lower than those reported in other countries.

Multisystem Inflammatory Syndrome in Children Presenting as Acute Appendicitis

Background The majority of multisystemic inflammatory syndrome in children (MIS-C) patients presented with gastrointestinal symptoms. To draw attention to association of MIS-C and acute appendicitis, we reported a number of patients presented with localized symptoms as appendicitis but later diagnosed as MIS-C. The main goal of this study was to point out that localized presentation of MIS-C, and the secondary outcome was to compare 2 different treatment modalities of MIS-C. Methods The patients admitted to intensive care units of 2 tertiary hospitals, with diagnosis of MIS-C and accompanying clinically or radiologically suspected or confirmed appendicitis, were included. Data were retrospectively analyzed. The patients were examined in 2 groups as intravenous immunoglobulin (IVIG)-only and combined therapy. The combined therapy was defined as at least 2 immunomodulatory treatments of which included IVIG, steroid, Anakinra, and plasmapheresis. Results Between June 2020 and December 2020, 9 patients were enrolled in the study. The mean age was 8.7 ± 3.4 years. All patients had delayed diagnosis because of investigations focusing on abdominal pathologies such as appendicitis. Four patients had typical ultrasonographic findings of appendicitis and 2 were complicated with perforation. All patients had cardiovascular compromise accompanying at least 1 more organ dysfunction. In the IVIG only group, the median lymphocyte count was 480 cells/mm3 and the median levels of ferritin, C-reactive protein (CRP), procalcitonin, and interleukin 6 were 955 pg/mL, 17.4 mg/dL, 33.9 ng/mL, and 136.3 pg/mL, respectively. In the combined therapy group, the median lymphocyte count was 1200 cells/mm3 and the median levels of ferritin, CRP, procalcitonin, and interleukin 6 were 1650 pg/mL, 28 mg/dL, 47.8 ng/mL, and 56.7 pg/mL, respectively. The median pediatric risk of mortality 3 and pediatric logistic organ dysfunction scores of the combined therapy group were higher than IVIG-only group. The IVIG-only patients were more lymphopenic at presentation (P = 0.014), while ferritin, CRP, and procalcitonin levels of combined therapy group were higher than IVIG-only group (P = 0.376, P = 0.181, and P = 0.346, respectively). The mean length of stay in pediatric intensive care unit of combined therapy group was shorter than IVIG-only group. Conclusions Multisystemic inflammatory syndrome in children should be kept in mind in the differential diagnosis of patients with localized gastrointestinal symptoms, such as acute appendicitis. Early diagnosis and proper treatment of MIS-C may have a critical role in the patient's outcome.

Exploratory Results of PET-CT and Residual Lymph Node Fine Needle Aspiration of Patients Treated with First-Line Venetoclax and Ibrutinib for CLL/Sll; First Interim Analysis of the Phase 2 HOVON 158/Next STEP Trial

Background: Fixed-duration treatment of chronic lymphocytic leukemia (CLL) with venetoclax combined with a BTK-inhibitor(i) results in prolonged progression free survival (PFS). Undetectable levels of minimal residual disease (uMRD) reach an early plateau and are highly predictive for PFS in case of venetoclax in combination with anti-CD20, but kinetics are different when combined with a BTK-i. MRD-levels mirror disease activity in blood (PB) and bone marrow but much less of lymph node (LN) disease, the suspected critical site of CLL proliferation and development of resistance. Although regular CT-scans do provide information on tumor-bulk, there is a high uncertainty concerning the bio-clinical significance of the frequently observed minimally enlarged LN. The NEXT-STEP trial evaluates the efficacy of adding 6 cycles ibrutinib and obinutuzumab for treatment naive patients who do not achieve complete remission (CR) and uMRD after 3 cycles of ibrutinib lead-in and 12 cycles of combined ibrutinib and venetoclax. The first preplanned interim analysis evaluates safety and efficacy for the first 30 eligible patients until the end of cycle 8. In addition, exploratory analyses of 18F-fluorodeoxyglucose (FDG) PET-CT as well as presence of CLL cells in residual LN by fine-needle aspirations (FNA) were performed. We here present this interim analysis. Methods: HOVON 158/NEXT STEP trial is an open-label, single arm phase 2 study. Eligible patients with untreated CLL or small lymphocytic lymphoma (SLL) receive three 28 days cycles of ibrutinib followed by 12 cycles of combined ibrutinib and venetoclax. IwCLL response and MRD bone marrow are assessed after cycle 15. Patients achieving CR with uMRD4 (8-colour flow cytometry, <10-4) stop treatment. Intensification with an additional 6 cycles of ibrutinib combined with obinutuzumab is provided for patients with MRD positivity and/or less than CR. After cycle 8 an exploratory analysis is done with locally assessed Deauville score (DS) on PET-CT. In addition, if at end of cycle 8 a LN > 1.5 cm is present on physical examination or CT scan and located cervical, axillar or inguinal (for safe accessibility), a fine needle aspiration (FNA) by ultrasound is requested. Obtained cells are centrally analyzed by flow cytometry. Results: Median age was 69 years (range 34-85), 70% were male. One patient had SLL. CIRS score > 6 was found in 6 patients (20%). Median eGFR was 65 ml/min (range 39-132). Median lymphocyte count was 157.3 x 109/l (range 2.50-475). CLL-IPI score was low and intermediate in one (3%) and 6 (20%) and high and very high in 18 (60%) and one (3%) patients, respectively. Del (17p)/TP53 mutation was found in 3 patients (10%). Genomic complexity (≥ 3 aberrations) was found in 3 patients (10%). Overall response rate based on PB and CT scan after cycle 8 was 100%. Levels of responses are depicted in table 1. One patient discontinued therapy during the first 8 cycles, due to adverse events. No progression events or death have occurred and no new safety signals were reported at interim analysis. Of all the PET-scans at baseline 13 (43%) demonstrated an increased uptake (DS4) and 5 (17%) uptake > mediastinal blood pool (DS3). In all but one patient DS decreased after 8 cycles; 1 (3%) remainded DS4, 2 (7%) had DS3, 9 (31%) had uptake equal or below mediastinal blood pool (DS2) and 16 (55%) had no uptake (DS1). In 1 patient PET was not performed. Of 13 patients with enlarged LN after cycle 8, FNA could be done in 9 patients, of which 5 contained sufficient number of cells for analysis. FNA was performed in all 3 patients with DS3-4 because of remaining enlarged LN. In all cases, persistent nodular CLL cells were detected by flow cytometry. In 4 of the 5 patients, MRD levels were higher in the LN as compared to PB. The patient with DS4 demonstrated the highest CLL cells percentage in FNA (Figure 1). Conclusion: Three cycles of ibrutinib followed by 5 cycles of ibrutinib and venetoclax results in tumor bulk reduction with a decrease in metabolic uptake on PET-CT in all but one patient. We demonstrated persistent CLL cells by flow cytometry in enlarged LN, suggesting residual LN serve as a sanctuary of CLL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Immune checkpoint inhibitor therapy and outcomes from SARS-CoV-2 infection in patients with cancer: a joint analysis of OnCovid and ESMO-CoCARE registries

BackgroundAs management and prevention strategies against COVID-19 evolve, it is still uncertain whether prior exposure to immune checkpoint inhibitors (ICIs) affects COVID-19 severity in patients with cancer.MethodsIn a joint analysis...

72 Distinguishing features of MIS-C to other paediatric febrile diseases in the acute setting

BackgroundMultisystem inflammatory syndrome in children (MIS-C) presents with fever, shock, rash, abdominal pain and raised inflammatory markers, as well as common features of inflammatory childhood illnesses. In the acute setting, especially in countries where infectious diseases are common differential diagnoses, it is challenging to diagnose MIS-C. Therefore, data differentiating MIS-C from other inflammatory and/or febrile diseases at presentation is needed.MethodsProspective data was collected from children admitted to the Red Cross War Memorial Children’s Hospital in Cape Town, South Africa from May 2020 to end November 2021 where MIS-C was part of their differential diagnoses. Clinical features on the day of admission were compared between children with confirmed MIS-C (MIS-C+) and those with alternate diagnoses (MIS-C-).ResultsIn this time period, 60 children were MIS-C+ and 34 were MIS-C-. There was no significant difference in age (p = 0.321), sex (p = 0.525), ethnicity (p = 0.279), or in the frequency of comorbidities (p = 0.151) between the two groups. The presence of conjunctivitis (OR = 8.12), rash (OR = 8.67), tachycardia (OR = 2.8) and oral mucositis (OR = 3.75) was associated with MIS-C+ while abdominal pain and hypotension were not. MIS-C+ had statistically higher median C-reactive protein (CRP), pro-brain natriuretic protein (pro-BNP) and ferritin, and lower median lymphocyte count, platelet count and sodium levels than MIS-C-. Ferritin discriminated MIS-C+ well (AUC = 0.86) with a 94% sensitivity and 60% specificity at a cut off of > 195ng/l. Sodium had an AUC of 0.72, with a 70% sensitivity and 71% specificity at a cut off of < 132.5 mmol/l. CRP did not distinguish MIS-C well (AUC = 0.52) and although they had good AUC, platelet count and pro-BNP had cut off values in the normal range decreasing clinical utility.ConclusionWe provide evidence for the use of accessible clinical and laboratory variables for the diagnosis of MIS-C in diverse settings.ImplicationsThese data will aid clinicians to do a rapid diagnosis (and ultimately treat earlier) of patients with MIS-C in the acute setting, especially those in under-resourced settings. 72 Table 4ROC analysis of laboratory tests which were different between MIS-C- and MIS-C+Test AUC (95%CI) p Potential cut-off value Sensitivity Specificity Youden ratio Ferritin 0.86 (0.70, 1) 0.017 *>19594%60% 54% 7-84 ng/L ** >31672%80% 52% Pro-BNP 0.80 (0.62, 0.98) 0.044 *>23983%40%23%<450 ng/L ** >37878%80% 57% Platelet count 0.75 (0.59, 0.90) 0.006 *<285 81% 71% 52% 180-440 x109/LSodium 0.726 (0.56, 0.88) 0.014 *<134.587%35.7%22%136-145 mmol/L ** <132.570%71%41%CRP0.54 (0.62, 0.98) 0.766 *>77100%40%40%<10 mg/L ** >161.550%60%10%2 potentials cut off values are given.*the value which gives the best specificity with a sensitivity >80% and.**the value that achieves the best sensitivity with a specificity of at least 60%.

Clinical characteristics of children with MIS-C fulfilling classification criteria for macrophage activation syndrome.

BackgroundMacrophage activation syndrome (MAS) is a potentially life-threatening complication of various inflammatory disorders, including multisystem inflammatory syndrome in children (MIS-C). MIS-C refractory to treatment should raise suspicion of MAS, which can be fatal if a definitive diagnosis is delayed. Unfortunately, there is a lack of data on MAS in children with MIS-C.ObjectiveOur study aims to analyze the risk factors for the development of MAS in MIS-C, its clinical course and response to treatment, and identify predictive factors for pediatric intensive care.Material and methodsWe analyzed data from the Polish MIS-C registry of the MultiOrgan Inflammatory Syndromes COVID-19 Related Study. Patients were diagnosed according to the WHO MIS-C definition and treated according to national guidelines (Polish Pediatric Society) based on international consensus. MAS definition was based on 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis.ResultsTwo-hundred and seventy four children met the study inclusion criteria. Fifty-nine patients fulfilled MAS classification criteria, nine of which required admission to the pediatric intensive care unit (PICU). MIS-C patients with MAS were significantly older than patients without MAS (median 11.2 vs. 8.1 years). Multivariable analysis showed that age, symptoms characteristic of atypical Kawasaki disease, and skin erosions were significant factors associated with MAS in MIS-C patients. Analysis of laboratory parameters showed that on admission, MIS-C patients with MAS had significantly lower median lymphocyte and platelet counts, albumin and sodium levels, and higher median levels of C-reactive protein, procalcitonin, ferritin, D-dimers, triglycerides, serum creatinine, urea, and γ-glutamyl transpeptidase, and neutrophil count. Multivariate analysis showed that higher procalcitonin, ferritin, and fibrinogen levels at admission were predictive of MAS. Only elevated troponin level was a factor indicating a requirement of PICU hospitalization for children with MAS. MIS-C patients fulfilling MAS criteria were treated more often with intravenous immunoglobulins and steroids than children without MAS. Children with MAS more often required mechanical ventilation. None of the patients required biological agents.ConclusionsThe clinical course of MAS in MIS-C seems milder, treatment less aggressive, and the prognosis better than expected based on the current knowledge on MAS complicating other rheumatological diseases.

The role of electrolyte imbalances in predicting the severity of COVID-19 in the hospitalized patients: a cross-sectional study

Coronavirus disease 2019 (COVID-19) can be fatal in severe cases. Accordingly, predicting the severity and prognosis of the disease is valuable. This study examined the role of electrolyte imbalances in predicting the severity of COVID-19. In this cross-sectional study, 169 hospitalized patients with COVID-19 were included and categorized into three groups based on the severity of the disease (moderate, severe, and critical). Serum levels of electrolytes (calcium [Ca], phosphorus [P], sodium [Na], potassium [k], and magnesium [Mg]), inflammatory markers (D-dimer, C-reactive protein [CRP], ferritin, and lactate dehydrogenase [LDH]), and 25OHVitamin D were measured. The mean age of patients was 53 years, and 54% were male. They had moderate, severe, and critical illnesses in 22%, 47%, and 31%, respectively. CRP, D-dimer, and ferritin increased with the severity of the disease. The lower median values of Mg, Na, 25OHVitamin D, Ca, LDH, and higher median lymphocyte counts were observed in the moderate vs. the severe group (P < 0.05). These parameters have acceptable sensitivity and specificity at the suggested cut-off level to discriminate the moderate and critical cases. Serum parameters introduced in this study are appropriate for differentiating between critical and moderate cases. The electrolyte imbalance can predict critical patients.

Karbon Monoksit Zehirlenme Şiddeti ile Kan Parametrelerinin İlişkisi

Introduction: Carbon monoxide (CO) poisoning is one of the most common poisonings worldwide. Many studies have investigated the relationship between predictive parameters and CO poisoning severity. We aimed to investigate the relationship between blood parameter values with poor outcome in CO poisoning, and CO values measured in blood. Methods: This is a retrospective study. Patients who had CO levels ≥ %10 in their blood gas were included in the study. Patients were divided into 2 groups as those who required hyperbaric oxygen and those who do not. Demographic data such as age, gender of the patients, as well as CO levels in the blood gases of the patients, hemoglobin, leukocyte, neutrophil, platelet counts of the blood count, and MPV and PDW values were recorded. Also, creatinine, troponin, CRP, ALT values were recorded as well. Results: The study was conducted with 110 patients. The mean age of the patients was 46.80±18.18 years. When the parameters were examined, the median WBC count of patients with patients who required HBO therapy was 8.73[7.54-11.83], and the median WBC count of patients who did not require HBO therapy was 8.01[6.96-9.72] (p=0.038). The median lymphocyte count of patients who required HBO therapy was determined as 2.73[1.85-3.36], and this value was found to be higher than patients who did not require HBO therapy (p=0.026). Conclusion: WBC and lymphocyte counts are higher in CO poisoning patients who required hyperbaric oxygen therapy. But these two values were not found to be independent risk factors in predicting hyperbaric oxygen therapy.