Leukopenia Research Articles

Evaluation of Platelet and Clotting Parameters in Hematologic Malignancies and Hematopoietic Stem Cell Transplantation Patients with Candidemia

1.Backgroud In recent years, the number and proportion of deaths from fungal infections have increased year by year. The fatality rate of fungemia is about 0.4 per 100 000 [Pfaller MA, et al. Clin Microbiol Rev. 2007]. Chemotherapy can effectively treat hematological malignancies. Data from multi-center studies in China show that the overall mortality rate of patients receiving chemotherapy for hematological malignancies is only 1.5%, and the mortality rate of patients with clinically diagnosed invasive fungi is as high as 11.7% [ Sun Y, et al. Tumor Biol, 2015]. The surveillance data of China Hospital Invasive Fungal Disease Surveillance Network from 2015 to 2017 showed that Candida albicans was the most common pathogen among 4 010 Candida strains isolated from patients with candidemia from 77 hospitals in China [Xiao M, et al. J Infect Dis, 2020]. 2.Methods We conducted a retrospective study that collected relevant clinical information from 34 hematologic malignancies and hematopoietic stem cell transplantation (HSCT) patients with candidemia between 2017 to 2022 in Hematology Hospital, Chinese Academy of Medical Sciences. The blood specimens of patients suspected to have candidemia were collected and cultured. After diagnosis, they were regarded as the candidemia group, and 107 healthy people were selected as the control group. Candidemia is classified as invasive or non-invasive according to whether it involves tissues or organs damage. Blood routine and clotting related tests were performed at the Clinical Laboratory Center of Hematology Hospital, Chinese Academy of Medical Sciences. 3.Results 3.1 General Characteristics of the Study Subjects A total of 34 hematologic malignancies and HSCT patients with candidemia were recruited. Of these 34 patients, 28 were male and 6 were female. Meanwhile, 107 healthy people were recruited as control group. The characteristics of two groups are presented in Table 1. 3.2 Hematologic malignancies and HSCT patients with abnormal blood routine are at increased risk of candidemia Hematologic malignancies and HSCT patients with candidemia present as lower white blood cell count, lower red blood cell count, higher lymphocyte ratio, lower lymphocyte count, lower monocyte count, lower neutrophil count and ratio, and lower NEU/PLT compared with control group. 3.3 Candidemia cause platelet activation in hematologic malignancies and HSCT patients The PLT and PCT of hematologic malignancies and HSCT patients with candidemia were significantly lower than control group. Meanwhile, MPV and P-LCR were higher than control group. It revealed that hematologic malignancies and HSCT patients with candidemia may present with platelet activation, while PLT and PCT level were low in this group. 3.4 Invasive candidemia can cause a decrease in platelets and an increase in MPV/PLT Furthermore, we found that PLT level was lower and MPV/PLT level was higher in hematologic malignancies and HSCT patients with invasive candidemia than hematologic malignancies and HSCT patients with non-invasive candidemia. 3.5 Candidemia can cause coagulation dysfunction in hematologic malignancies and HSCT patients Hematologic malignancies and HSCT patients with candidemia had coagulation dysfunction symptoms such as prolonged PT and APTT, reduced antithrombin III activity, and high INR. 3.6 Candidemia can cause hyperfibrinolysis in hematologic malignancies and HSCT patients Meanwhile, hematologic malignancies and HSCT patients with candidemia showed reduced TT, increasing fibrinogen, fibrinogen degradation products, and D-Dimer. 4.Conclusion In conclusion, we demonstrated for the first time that decreasing platelet count and activated platelet function in hematologic malignancies and HSCT patients with candidemia. Invasive candidemia may cause lower platelet count and more activated platelet function in hematologic malignancies and HSCT patients. At the same time, we found that candidemia can cause coagulation dysfunction and hyperfibrinolysis in hematologic malignancies and HSCT patients. We hope that our study can provide a new perspective on the cognition and diagnosis of hematologic malignancies and HSCT patients with candidemia.

Tasquinimod Improves Erythropoiesis and Mitigates Bone Loss in Myelodysplastic Mice

Myelodysplastic neoplasms (MDS) are characterized by ineffective hematopoiesis, peripheral cytopenia, and a risk of transforming into acute myeloid leukemia (AML). Interestingly, MDS is also associated with an increased prevalence of osteoporosis. Studies have suggested that dysregulated innate immune responses and a proinflammatory bone marrow (BM) microenvironment play significant roles in the pathogenesis of MDS. Targeting inflammatory pathways, especially in low-risk MDS patients, presents a potential strategy to modulate the progression of the disease. One such candidate is Tasquinimod (TASQ, ABR-215050, Active Biotech AB), a small-molecule oral inhibitor and second-generation quinoline-3-carboxamide compound. TASQ binds to the inflammatory protein S100A9 and inhibits its interaction with the proinflammatory toll-like receptor 4, thereby displaying both immunomodulatory and antitumor properties. Our in vitro data provided evidence for a rescuing effect of TASQ on inflammatory signal-primed MDS stromal cells, leading to enhanced hematopoietic support. This study aims to validate these findings using a transgenic MDS mouse model expressing the NUP98/HOXD13 (NHD13) fusion protein in hematopoietic cells. NHD13 mice, generated on a C57BL/6J background, were obtained from Jackson Laboratory. TASQ was administered orally by adding it to the drinking water at a dose of 30 mg/kg. Both transgenic and littermate control (WT) mice (12 weeks old, n=5-10 per group) were treated with or without TASQ for 12 weeks. Throughout the experiment, peripheral blood cell counts were measured every 4 weeks using Sysmex analysis. In the final analysis, primary BM cells were isolated from the femora, and the number of lineage-negative, sca-1-positive, and c-kit-positive (LSK) cells, as well as erythroid differentiation, were assessed using flow cytometry. Additionally, bone volume, trabecular number, and thickness were analyzed in femora using µCT. Transgenic NHD13 mice displayed MDS-like characteristics, including peripheral cytopenias, dysplasia in blood and BM cells, and microstructural abnormalities in the bone microenvironment. As expected, hemoglobin levels (Hb) and red blood cell (RBC) counts were lower in NHD13 mice compared to WT mice [Hb: 8.9 vs. 9.5 mmol/L; RBC: 9.5 vs. 10.3x1012/L] and showed a consistent decrease in the untreated group from 12 to 24 weeks. Notably, treatment with TASQ significantly improved red blood cell counts in NHD13 mice [+14%; p<0.01] after 24 weeks, while having no effect on WT mice. White blood cells were significantly decreased in WT mice after 4 weeks of TASQ treatment [-19%; p<0.001] until the end of the experiment [-36%; p<0.001]. In contrast, in transgenic mice, the lower white blood cell counts [-76%; p<0.001] were not further diminished. Interestingly, TASQ led to an elevation in neutrophil counts. The platelet count was not affected by the treatment in both transgenic and WT mice. Using flow cytometry, an increase in the total number of LSK cells was detected in the BM of WT mice after TASQ treatment. However, no increase was observed in NHD13 mice, which already had lower LSK numbers compared to WT controls. Late-stage erythropoiesis was slightly increased in both WT and transgenic mice after TASQ treatment, whereas early erythroid differentiation was unaffected or even decreased by TASQ. Moreover, BM cells were used for colony-forming assays ex vivo. NHD13 mice had a lower erythroid differentiation potential compared to WT mice, which was improved after TASQ treatment. To assess the potential influence of the microenvironment, adherent BM cells were assayed for their CFU-F forming capacity. BM cells of transgenic mice exhibited a slightly lower CFU-F forming capacity compared to WT mice, which was partially reversed by TASQ treatment. Finally, the bone microarchitecture was analyzed. NHD13 mice showed a lower bone volume [-43%; p<0.01] compared to WT mice. Notably, treatment with TASQ abolished the bone loss in NHD13 mice by increasing the trabecular number [+35% p<0.001], whereas the trabecular thickness was not affected. In conclusion, this study provides the first evidence for an in vivo effect of TASQ in a murine model of MDS, suggesting improved erythropoiesis and positive effects on the bone phenotype. These results warrant further investigations of TASQ in human trials, particularly in MDS patients in whom anemia and bone loss often coexist.

COVID-19 in Adults with Sickle Cell Disease

Introduction Sickle cell disease (SCD) is the most common inherited hemoglobinopathy and is estimated to affect more than 100,000 Americans. The unique constellation of SCD manifestations complicates both the diagnosis and management of COVID-19, particularly related to anticoagulation and transfusion practices. A previous literature review of COVID-19 outcome and SCD noted the need for studies evaluating genotype and SCD-modifying therapies (Hoogenboom et al. 2022). We report on the outcomes for all hospitalized inpatients with SARS-CoV-2 and SCD at institutions using the Cerner Real World Database (RWDB). Methods The Cerner RWD is a large, cloud-based deidentified database that includes electronic health records (EHR) data from >100 United States health systems (Ehwerhemuepha et al. 2022). We obtained approval to access these data with an exempt status from IRB to conduct a retrospective study including patients records from February 27, 2020 to August 14, 2022. Those with sickle cell trait were excluded. Descriptive statistics were performed. Results: The final dataset included 1547 adult patients, 609 of whom were hospitalized, 25 of whom received invasive ventilation, and 51 of whom died. Hospitalized patients were more likely to be male, have Medicaid or Medicare, and have Hgb SS or Hgb SC genotype than the 938 ambulatory patients (Table 1). Of the hospitalized patients, the 51 who died and the 25 who received invasive ventilation were, older, and as expected, had longer length of stays. Labs and treatments for hospitalized patients are summarized in Tables 2 & 3. We were not able to find evidence of exchange transfusion; however, 14% of hospitalized patients received red blood cell transfusion. Those who were under invasive ventilation were more likely to have higher C-reactive protein (CRP), creatinine (CRT), erythrocyte sedimentation rate (ESR), and procalcitonin as well as lower white blood cell counts on initial labs. Hemoglobin, hematocrit, and ferritin levels were similar. A majority of patients under invasive ventilation received dexamethasone and heparin while as many as 24% of all hospitalized patients received dexamethasone and 57% received heparin or enoxaparin. Only 199 (33%) hospitalized patients received hydroxyurea while admitted and few patients who received invasive ventilation were transfused (<44%). Discussion This study describes one of the largest populations of patients with SCD and COVID-19 in the United States. Demographics of the overall cohort were consistent with known characteristics. More patients with Hgb SS or Hgb SC were hospitalized than expected. Although steroids are used with caution in patients with SCD, almost a quarter of hospitalized patients were treated with dexamethasone. The small number of hospitalized patients receiving hydroxyurea while admitted is surprising, although it is not known how this compares to ambulatory patients with COVID-19. The small number of patients being transfused is also concerning. One of the notable limitations is that the dataset draws only from institutions using Cerner EHR, a 26% market share. Additionally, there is likely significant variability between institutions' treatment protocols, particularly in the early months of the pandemic. Finally, we were not able to compare these patients to a control population, an area which offers opportunity for future investigation. TABLE 1- Demographics- hospitalized vs. ambulatory patients TABLE 2- Hospitalized patients- all vs. mechanically ventilated vs. deaths TABLE 3- Treatments- Invasively ventilated vs. all hospitalized patients

A Mouse Model of CD19 CAR - T Cell Therapy Reveals Mechanism of Cytopenia

Immunotherapy with Chimeric Antigen Receptor (CAR) T cells against CD19 can cure patients with refractory B cell lymphoma and leukemia. However, complications of CAR-T cell therapy can cause morbidity. Among the complications of CAR-T cell therapy is cytopenia, i.e. decreased peripheral blood counts of platelets, leukocytes and / or erythrocytes. The exact mechanism of this side - effect is not known, retrospective analysis showed it affects 10-20% of patients and is linked with the severity of cytokine release syndrome (Juluri et al, PMID34666344). We have previously developed a mouse model of CAR-T cell therapy using C56BL/6 mouse expressing human CD19 under a B- Cell specific promoter (Pennell et al, PMID29735365). The recipient mice are heterozygous for human hCD19 on CD45.2 background. Congenic C56BL/6 CD45.1 mice served as T cell donors. The aim of this study was to investigate if the mouse model recapitulates cytopenia seen in patients after CAR-T cell therapy. C56BL/6 recipient mice were treated with lymphodepleting chemotherapy (Cyclophosphamide (CY) 300 mg/kg) and infused with 1) no T cells 2) control T cells transfected with hEGFR 3) T cells transfected with CD19 CAR with hCD137 and hCD3zeta signaling domains. The chosen dose of infused T cells at 0.3E+6 per animal was low, approximately 10x below the lethal dose and 3x less than IC50 dose, to reduce early mortality. The animals were weighed and examined regularly, and appearance and activity were scored from 0 (healthy) to 8 (moribund). Total of 30 animals per group were harvested at 5 time points, 6 mice each, on days 5, 12, 26, 40 and 54. Peripheral blood counts were measured using HemaVet CBC counter. Flow cytometry was performed on blood and bone marrow. Spleens, long bones (femur, tibia) and sternum were harvested for histopathologic assessment. Multiparametric immunohistochemistry (IHC) was performed using Codex (Phenocycler, Akoya). The mice receiving CAR-19 T cells showed significant, but transient loss of weight and transient increase in morbidity score during the first 2 weeks. Mortality was not significantly different between groups: 0, 1 and 2 deceased animals in CY, control T and CAR-T cell groups, respectively. We observed transient significant cytopenia in the CAR-T cell treated mice, with significantly lower platelet counts on day 5 (p<0.05) and lower White Blood Cell counts on days 12 (p<0.06) and day 26 (p<0.05). These changes were associated with 100-fold larger expansion of CAR-T cells in blood as compared to the control hEGFR T cells and 20-fold higher relative expansion of CAR-T cells in the bone marrow. Multiparametric IHC showed loss of B cell follicles and increased density of donor T cells in the CAR-T cells recipients compared to hEGFR T cell control. Pathologic evaluation of sternums revealed individual segments (sternebra) with necrosis of the hematopoietic elements at the first time point (day 5). At subsequent time points there were progressive changes reminiscent of evolution of infarct with organization, proliferation of fibroblasts and fibrosis with increased osteogenesis and finally with regression of mesenchymal elements and reestablishment of hematopoiesis (Figure 1). The number of segments with necrosis and sequalae was significantly higher in the CAR-T cell group as compared to the hEGFR T cell control (p=0.0005). The necrosis of hematopoietic elements within individual sternum segments involved at the most 3 segments out of 6. The involved segments appeared to distribute randomly: either adjacent or separated by viable segments. The necrotic segments showed paucity of erythrocytes with foci of recent erythrocyte extravasation consistent with ischemic infarct. The mouse model of CAR-T cell therapy against CD19 recapitulates cytopenia in early post - treatment period. The observed pattern of necrosis of the hematopoietic elements in entire segments suggests compromised blood supply. We hypothesize sternebra are more susceptible to necrosis due to limited blood supply, separate for each segment. We hypothesize that occlusion of arteries or capillaries in the bone marrow may contribute to the mechanism of cytopenia following CAR-T cell therapy. Prior retrospective analysis linked the cytopenia with increased levels of inflammatory mediators of Cytokine Release Syndrome. The present findings highlight a role of local factors in situ, which may be influenced by systemic cytokines.

Clinical features and risk factors for appendiceal diverticulitis: a comparative study with acute appendicitis.

Despite their similar clinical characteristics, appendiceal diverticulitis (AD) and acute appendicitis (AA) are pathologically distinct. This study compared the clinical features of AD and AA and identified relevant risk factors. Patients who underwent appendectomy with a preoperative diagnosis of either AD or AA were categorized based on histopathological findings. The two groups were compared in terms of various clinical factors. Among the 854 patients included in the study, a histopathological evaluation revealed 49 and 805 cases of AD and AA, respectively. A univariate analysis demonstrated that AD was more prevalent than AA among older, taller, and heavier males. A multivariate analysis revealed that male sex, a white blood cell (WBC) count < 13.5 × 103/μL, an eosinophil count ≥ 0.4%, and a mean corpuscular volume (MCV) ≥ 91.6 fL were significant factors differentiating AD from AA. In addition, pathological AD emerged as an independent risk factor for abscess and/or perforation. AD was associated with an older age, robust physique, and significant risk of abscess and/or perforation despite a low WBC count. In addition to imaging modalities, the preoperative factors of male sex, a WBC count < 13.5 × 103/μL, an eosinophil count ≥ 0.4%, and a MCV ≥ 91.6 fL may be useful for distinguishing AD from AA.

UBTF Tandem Duplications in Pediatric MDS and AML: Implications for Clinical Screening and Diagnosis

Recent genomic studies in adult and pediatric acute myeloid leukemia (AML) demonstrated recurrent in-frame tandem duplications (TD) in exon 13 of upstream binding transcription factor ( UBTF) (PMID: 35176137, PMID:37085611). UBTF-TDs are subtype-defining genomic alterations associated with poor outcomes that account for ~4.3% of AMLs in childhood and up to 3% in adult AMLs under the age of 60. UBTF-TD AMLs are characterized by HOXA/HOXB dysregulation, trisomy 8 or normal cytogenetics and frequent FLT3-ITD and/or WT1 mutations. A more comprehensive investigation into the clinicopathological features of UBTF-TD AMLs is needed to better understand disease features for appropriate diagnosis and to develop more effective therapies. Here, we present 94 unique pediatric cases harboring a tandem duplication in exon 13 of UBTF with a median size of 60bp (range 21-1173bp). Of these 94 cases, 6 (6.4%) were diagnosed with childhood MDS with increased blasts (WHO), suggesting that like in adults, UBTF-TDs are not only confined to AML. UBTF-TD AMLs are associated with an overall lower median white blood cell (WBC) when compared to other common HOXA/B dysregulated leukemias ( UBTF-TD median = 10.2x10 9/L, NPM1-mutation median = 21.8x10 9/L, NUP98-rearranged ( NUP98r) median = 97x10 9/L). Available immunophenotyping on 32 U BTF-TD tumors demonstrated positivity for HLA-DR (31/31; 100%), CD117 (28/29; 95%), and CD34 (26/30; 86%) with variable positivity for CD7 (17/30; 56%) and CD64 (13/25; 52%). A limited number of cases tested for CD123 (n=11) and CD11c (n=15) were all positive for the respective marker. Furthermore, morphologic assessment of these cases revealed pleomorphic blasts with occasional Auer rods and increased immature myeloid cells with salmon-colored granules, commonly with background multilineage dysplasia and increased erythroid precursors. At the transcriptional level, UBTF-TD leukemias are largely similar to NPM1-mutated and NUP98::NSD1 AMLs with the exception of UBTF-TD cases having marked increase in expression of histone genes (e.g., HIST1H4F and HIST1H2B1) and a subset of posterior HOXB cluster genes (e.g., HOXB9). Further inspection using UMAP (Uniform Manifold Approximation and Projection) of expression profiles across different pediatric AML cohorts revealed two unclassified cases of AML that clustered with the UBTF-TD subtype ( Figure 1). One case had a WT1p.S364* and the other a somatic GATA2 p.R338fs and FLT3-ITD, but did not contain an exon 13 duplication or other defining alterations. Upon closer inspection of the UBTF gene in these cases, we uncovered that each case had an in-frame tandem duplication in exon 9 of UBTF encoding a region between HMG box 2 and 3 with features similar to those in exon 13 ( Figure 2). We therefore postulated that exon 9 TDs ( UBTF-e9) could represent a functionally equivalent subgroup of UBTF-TDalterations. To test this hypothesis, cord-blood CD34+ (cbCD34+) cells were transduced to test the transforming potential of UBTF-e9 duplications. Like with UBTF-e13 duplications, cbCD34+ cells expressing UBTF-e9 duplications displayed increased proliferation compared to UBTF -WT and lentiviral empty vector control in liquid culture; and increased colony counts and replating capacity, increased CD117 expression, and a more blast-like morphology in CFU assays. Collectively, these data suggest that like TDs in exon 13, exon 9 TDs are also sufficient to promote leukemogenic phenotypes. In conclusion, we find that UBTF-TDs occur in both MDS and AML and are associated with lower WBC count, myelodysplasia, and stem cell-related surface marker expression. We have also expanded the spectrum of UBTFalterations in myeloid neoplasms through the identification of rare UBTF duplications in exon 9 that induce a similar transcriptional signature to exon 13 UBTF-TDs. The recent identification of UBTF-TDs in adult and pediatric high-risk myeloid neoplasms has highlighted the importance of understanding and appropriately diagnosing tumors with this genomic alteration, including a new class of alterations that will not be detected by PCR-based screening strategies that specifically target exon 13 of UBTF.

Secondary-Type Mutations Do Not Impact the Favorable Outcome of NPM1-Mutated Acute Myeloid Leukemia Patients - Results from a Large Cohort of Intensively Treated Patients

Introduction: In 2022, the ELN risk classification for AML was updated for the second time. One of the major novelties of the ELN2022 is that all secondary-type mutations (STMs, i.e., mutations in the genes SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2) were now added to the adverse risk characteristics. However, a pertinent question also raised by the ELN expert panel is whether STMs abrogate the positive prognostic value of co-occurring, favorable NPM1 mutations. Aim: The aim of this study was to analyze the prognostic value of STMs in AML patients (pts) who also harbor an NPM1 mutation. Methods: We investigated a pooled cohort of 936 NPM1-mutated AML pts who were treated in previously reported multicenter trials of the Study Alliance Leukemia or the AML Cooperative Group. Eligibility was determined based on diagnosis of non-APL, age ≥ 18 years, NPM1 mutation detected in targeted sequencing, curative treatment intent, and available biomaterial at diagnosis. Standard techniques for chromosome banding and fluorescence-in-situ-hybridization (FISH) were used for karyotyping. Next-generation panel sequencing was performed to detect genetic alterations that are recurrently found in myeloid neoplasms. Results: In our multicenter cohort of 936 NPM1-mutated AML pts, median follow-up for the entire cohort was 8.0 years. We found 125 patients (13.4%) harboring at least one STM ( SRSF2 [n=48; 5.1%], STAG2 [n=32; 3.2%], EZH2 [n=22, 2.4%], BCOR [n=16; 1.7%], SF3B1 [n=13; 1.4%], ASXL1 [n=12; 1.3%], ZRSR2 [n=5; 0.5%], and U2AF1 [n=4; 0,4%]). A comparison of pretreatment clinical and genetic features revealed that pts with a STM were significantly older ( p=.003, median 59 vs. 55 years), had lower white blood cell counts ( p&amp;lt;.001, 22.2*10 9/L vs. 39.7*10 9/L,) and platelet counts ( p&amp;lt;.001, 46.5*10 9/L vs. 65.0 10 9/L). The strongest pair-wise associations between gene mutations were observed between U2AF1 and RUNX1 ( p&amp;lt;.001) as well as SRSF2 and IDH2 ( p&amp;lt;.001). With respect to outcome, complete remission (CR) rate did not differ significantly between NPM1-mutated patients with or without additional STMs ( p=.41, 74.4% vs. 77.7%, OR 0.83 [95%-CI 0.54-1.29]). Median RFS for NPM1-mutated pts with STMs was 32.9 months (95%-CI: 13.0-46.0) while patients without STMs had a median RFS of 24.3 months (95%-CI: 18.7-33.3) corresponding to a HR of 1.04 ( p=0.80, 95%-CI 0.79-1.37; Figure A). Median OS for NPM1-mutated pts with or without STMs was 27.2 months (95%-CI: 14.2-49.0) and 29.1 months (95%-CI: 23.5-41.4), respectively, corresponding to a HR of 1.11 ( p=.37, 95%-CI 0.88-1.41; Figure B). To focus solely on the impact of STMs, we subsequently excluded patients with co-occurring mutations in TP53 or myelodysplasia-related cytogenetics, which all define an ELN adverse risk. Again, we observed no differences in CR rate ( p=.54, 78% vs. 75.4%), RFS ( p=.59, median 33.2 months vs. 26.6 months), or OS ( p=.33, median 27.4 month vs. 32.6 month) between NPM1-mutated patients with or without STMs. Next, we restricted our analysis to pts who are classified favorable risk according to ELN2022. Again, we found no significant outcome differences based on the STM status (unmutated vs. mutated: CR rate, 80% vs. 70.7% [ p=.072]; RFS, median 49.7 months vs. 46.0 months [ p=.702]; OS, median 45.3 months vs. 59.8 months [ p=.092]). Conclusion: NPM1 mutations rank as the second most frequent mutations in AMLand the most common in patients with a normal karyotype and serve as an established favorable prognostic marker. Our data from a large cohort demonstrate that additional STMs have no adverse effect on the clinical outcome of NPM1-mutated patients. As a result, these patients should still be considered ELN favorable risk.

Zanubrutinib in Mantle Cell Lymphoma Management: A Comprehensive Review.

The pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of zanbrutinib are described. Mantle cell lymphoma (MCL) is a mature B-cell lymphoma that is typically associated with unfavorable outcomes, and virtually all patients with MCL have refractory or relapsed disease despite aggressive treatment. The treatment paradigm for MCL has transformed dramatically over the past decade owing to rapid advancements in immunotherapy and molecular-targeted therapies. Zanubrutinib, a second-generation Bruton's tyrosine kinase inhibitor (BTKI) designated for mature B-cell non-Hodgkin's lymphoma (NHL), has drastically improved the survival outcomes in relapsed/refractory (R/R) MCL patients. This selective BTKI is a small molecule that functions by forming a covalent bond in the active site of BTK. The inhibition of BTK activity is essential for the signaling of B-cell antigen receptor (BCR) and cytokine receptor pathways. In a preclinical study, zanubrutinib inhibited malignant B-cell proliferation and reduced tumor growth. Zanubrutinib was granted FDA-accelerated approval based on the results of Phase I and II trials. The investigator-assessed overall response rate was 83.7%, of which 78% of patients achieved complete response. The median duration of response was 19.5 months, and the median progression-free survival was 22.1 months. The most common (≥20%) all-grade adverse events were low neutrophil count (46.5%), upper respiratory tract infection (38.4%), rash (36.0%), low white blood cell count (33.7%), and low platelet count (32.6%). Zanubrutinib is a selective, next-generation, orally active, irreversible BTK inhibitor. The selectivity of zanubrutinib and its superior efficacy, with a well-tolerated safety profile, have proven to be attractive options for other malignancies.

Associations Between Leisure-Time Physical Activity Level and Peripheral Immune Cell Populations in the US General Population, Analysis of the National Health and Nutrition Examination Survey Data, 1999–2018

BackgroundChronic levels of inflammation are associated with higher risk of many chronic diseases. Physical activity (PA) lowers the risk of cancer, cardiovascular disease (CVD), diabetes and others. One mechanism for PA-induced protection may be through the immune system. We investigated the association between leisure-time PA and peripheral immune cell populations in a large nationally representative sample of the US general population.MethodsA total of 17,093 participants [mean (SE) age of 41.6 (0.3) years] of the National Health and Nutrition Examination Survey 1999–2018 were included. Self-reported leisure-time PA was converted to metabolic equivalent of task hours per week (MET-hrs/wk). White blood cell (WBC) count, WBC ratios, and platelet count were derived. Multivariable linear regression analyses were used to estimate associations between leisure-time PA level and peripheral immune cell populations. Multivariable logistic regression analyses were used to estimate associations between leisure-time PA and metrics of WBC count and neutrophil-to-lymphocyte ratio (NLR) which may predict mortality.ResultsA higher leisure-time PA level was associated with a lower WBC count (> 14.0 vs. < 1.2 MET-hrs/wk adjusted mean (95% confidence interval [CI]): 7.12 (6.86, 7.38) vs. 7.38 (7.12, 7.64) 1000 cells/μL, Ptrend < 0.001) and a lower NLR (> 14.0 vs. < 1.2 MET-hrs/wk adjusted mean (95% CI) 2.04 (1.90, 2.18) vs. 2.13 (1.99, 2.28), Ptrend = 0.007). Leisure-time PA level was not associated with lymphocyte-to-monocyte ratio (LMR; Ptrend = 0.25) or platelet-to-lymphocyte ratio (PLR; Ptrend = 0.69). Compared to the lowest leisure-time PA level (< 1.2 MET-hrs/wk), the highest leisure-time PA level (≥ 14.0 MET-hrs/wk) was associated with a lower probability of a high WBC count (> 8.1 × 109 cells/L; odds ratio [OR] = 0.76, 95% CI = 0.66–0.88) and high NLR (> 2.68; OR = 0.84, 95% CI = 0.72–0.99), which may predict CVD and all-cause mortality. The highest leisure-time PA level also linked to a lower probability of a high WBC count (≥ 8.3 × 109 cells/L; OR = 0.76, 95% CI = 0.66–0.88), which may predict cancer mortality.ConclusionsWe observed an inverse association between leisure-time PA level, WBC count, and NLR, particularly for neutrophil levels. These results suggest that participants at higher levels of leisure-time PA may have lower levels of inflammation, which may be important for future chronic disease outcomes.

Characteristics and outcomes for pulmonary aspergillosis in critically ill patients without influenza: A 3-year retrospective study

BackgroundPrevious studies have revealed higher mortality rates in patients of severe influenza coinfected with invasive pulmonary aspergillosis (IPA) than in those without the coinfection; nonetheless, the clinical outcome of IPA in critically ill patients without influenza remains unclear. Patients and methodsThis retrospective study was conducted in three institutes. From 2016–2018, all adult patients diagnosed with IPA in the intensive care units (ICUs) were identified. The logistic regression was used to identify the potential risk factors associated with in-hospital mortality in patients with non-influenza IPA. The stratified analysis of IPA patients with and without antifungal therapy was also performed. The final model was established using a forward approach, selecting variables with p-values less than 0.05. ResultsNinety patients were included during the study period, and 63 (70%) were men. The most common comorbidity was diabetes mellitus (n = 24, 27%), followed by solid cancers (n = 22, 24%). Antifungal therapy was administered to 50 (56%) patients, mostly voriconazole (n = 44). The in-hospital mortality rate was 49% (n = 44). Univariate analysis revealed that the risk factors for mortality included daily steroid dose, APACHE II score, SOFA score, C-reactive protein (CRP) level, carbapenem use, antifungal therapy, and caspofungin use. Multiple regression analysis identified four independent risk factors for mortality: age (Odds ratio [OR], 1.052, p = 0.013), daily steroid dose (OR, 1.057, p = 0.002), APACHE II score (OR, 1.094, p = 0.012), and CRP level (OR, 1.007, p = 0.008). Furthermore, the multivariable analysis identified that more physicians would initiate antifungal therapy for patients with prolonged steroid use (p = 0.001), lower white blood cell count (p = 0.021), and higher SOFA score (p = 0.048). Thus, under the selection bias, the independent risk factors for mortality in the antifungal treatment subgroup were daily steroid dose (OR, 1.046, p = 0.001) and CRP (OR, 1.006, p = 0.018), whereas the independent risk factor for mortality in the untreated group became APACHE II score (OR, 1.232, p = 0.007). ConclusionsPatients with IPA had a substantially high mortality. Overall, age, steroid use, APACHE II score, and CRP level were identified as the independent risk factors for mortality in patients in the ICU.

Complete heart block is a significant predictor of mortality in immune checkpoint inhibitor myocarditis

BackgroundImmune checkpoint inhibitor (ICI) myocarditis is associated with significant mortality risk. Electrocardiogram (ECG) changes in ICI myocarditis have strong prognostic value. However the impact of complete heart block (CHB) is not well defined. This study sought to evaluate the impact of CHB on mortality in ICI myocarditis, and to identify clinical predictors of mortality and CHB incidence.MethodsWe conducted a retrospective cohort study of patients with ICI myocarditis at three Mayo Clinic sites from 1st January 2010 to 31st September 2022 to evaluate mortality rates at 180 days. Clinical, laboratory, ECG, echocardiographic, and cardiac magnetic resonance imaging (CMR) characteristics were assessed. Cox and logistic regression were performed for associations with mortality and CHB respectively.ResultsOf 34 identified cases of ICI myocarditis, 7 (20.6%) had CHB. CHB was associated with higher mortality (HR 7.41, p = 0.03, attributable fraction 86.5%). Among those with CHB, troponin T (TnT) < 1000 ng/dL, low white blood cell count and high ventricular rate at admission were protective. There was trend towards increased survival among patients who underwent permanent pacemaker insertion (p = 0.051), although most experienced device lead complications. Factors associated with development of CHB included prolonged PR and QRS intervals and low Sokolow Lyon Index. Where these were normal and TnT was < 1000 ng/dL, no deaths occurred. Impaired myocardial longitudinal strain was sensitive for ICI myocarditis but was not prognostically significant.ConclusionThere is a strong temporal association between CHB and early mortality in people with ICI myocarditis. Focusing on arrhythmogenic complications can be helpful in predicting outcomes for this group of critically ill individuals.

Interactions between Polygenetic Variants and Lifestyle Factors in Hypothyroidism: A Hospital-Based Cohort Study.

Hypothyroidism is a prevalent endocrine disorder and is associated with a variety of metabolic disturbances. This study aimed to investigate the polygenic variants associated with hypothyroidism risk and the interaction of polygenic risk scores (PRS) with dietary patterns in influencing disease risk in 56,664 participants aged >40 in a hospital-based cohort. The participants were classified as having hypothyroidism (n = 870) diagnosed by a physician and no hypothyroidism (n = 55,794). Genetic variants associated with hypothyroidism were identified using a genome-wide association study (GWAS). Genetic variants interacting with each other were selected using a generalized multifactor dimensionality reduction analysis, and the PRS generated was evaluated for interaction with lifestyle parameters. Coffee, alcohol, meat intake, and a Korean balanced diet were inversely associated with hypothyroidism risk, as were selenium, copper, and manganese intakes. White blood cell (WBC) counts and serum alkaline phosphatase and triglyceride concentrations were positively associated with hypothyroidism risk, as were osteoporosis and thyroid cancer. The GMDR analysis generated a three-single nucleotide polymorphism (SNP) model comprising dual oxidase-1 (DUOX1)_rs1648314; thyroid-stimulating hormone receptor (TSHR)_rs75664963; and major histocompatibility complex, class-II, DQ Alpha-1 (HLA-DQA1)_rs17426593. The PRS derived from the three- and seven-SNP models were associated with a 2.11- and 2.32-fold increase in hypothyroidism risk, respectively. Furthermore, the PRS from the three-SNP model showed interactions with WBC counts, wherein the positive association with hypothyroidism risk was more pronounced in participants with low WBC counts than those with high WBC counts (≥4 × 109 /L). Dietary patterns, such as the plant-based diet (PBD) and the Western-style diet (WSD), along with smoking status, exhibited interactions with the PRS, influencing hypothyroidism risk. In participants with a high PRS, those in the high-PBD, low-WSD, and smoker groups had a higher proportion of hypothyroidism than those in the low-PBD, high-WSD, and non-smoker groups. In conclusion, genetic variants related to immunity and thyroid hormone secretion were linked to hypothyroidism risk, and their PRS interacted with PBD and WSD intake and smoking status. These results contribute to a better understanding of hypothyroidism and its prevention strategies for precision medicine intervention.

Clinical Features of Cryptococcal Meningoencephalitis in HIV-Positive and -Negative Patients in a Resource-Limited Setting.

Cryptococcal meningoencephalitis is a systemic fungal infection in immunocompromised and immunocompetent individuals. This study investigated the clinical characteristics and factors associated with mortality in HIV-associated and non-HIV-associated cryptococcal meningoencephalitis in a resource-limited setting. This was a retrospective cohort study of patients with cryptococcal meningoencephalitis between January 2009 and December 2019 at a tertiary teaching hospital in Thailand. Overall, 1019 patients with cryptococcal meningoencephalitis were enrolled, and 923 (90.6%) were HIV-positive. The patients with HIV-associated cryptococcal meningoencephalitis were younger than the HIV-negative patients (37 versus 56 years, p < 0.01). The HIV-negative patients were more likely to have underlying conditions (52.1% versus 7.5%; p < 0.01), had a longer median duration of headaches prior to admission (14 days versus 6 days, p < 0.01), and were more likely to have an altered mental status at presentation (36.5% versus 18.6%, p < 0.01) and pulmonary involvement (15.6% versus 0.8%, p < 0.01). The HIV-positive patients had lower cerebrospinal fluid (CSF) white blood cell counts (4 versus 94 cells/mm3; p < 0.01), lower CSF protein (69 versus 157 mg/dL; p < 0.01), higher CSF glucose (38.8 versus 21 mg/dL; p < 0.01), and more frequent cryptococcemia (44.1% versus 20.5%; p < 0.01). The mortality rate was high but not significantly different between the two groups (30.2% versus 33.2%; p = 0.53). The HIV-positive patients with comorbidities, fever, an altered mental status at presentation, a CSF white blood cell count below 20 cell/mm3, fungemia, and positive CSF India ink were independently associated with 30-day mortality. In comparison, an altered mental status at presentation and fungemia were associated with 30-day mortality in HIV-negative patients. In conclusion, HIV-negative patients with cryptococcal meningoencephalitis had more extensive central nervous system inflammation, although the two groups' mortality rates were similar. Unfavorable prognostic factors included comorbidities, fever, an altered mental status at presentation, a low CSF white blood cell count, fungemia, and positive CSF India ink.

Epidemiology, Clinical Characteristics, and Outcomes of Culture-negative Sepsis

Aim: Culture-negative sepsis (CNS) is a common but understudied entity. The objective of this study was to compare the incidence, characteristics, and outcomes of CNS with culture-positive sepsis (CPS). Methods: This was a prospective observational study of patients admitted to the medical intensive care unit (ICU) of a tertiary hospital from January to December 2015 with clinical suspicion of severe sepsis as defined by Consensus Conference Criteria 2001. Results: Patients with severe sepsis ( n = 122) were studied of whom 66 (54%) were CPS and 56 (46%) were CNS. Patients with CNS had fewer comorbidities (0.7 ± 0.70 vs. 2 ± 0.8, P &lt; 0.01). At presentation, CNS patients had less tachycardia (heart rate 92.5 ± 10.5 vs. 105.9 ± 13.2, P &lt; 0.01), lower white blood cell counts (11859 ± 4791 vs. 14224 ± 3898, P = 0.003), lower need for vasopressors (38% vs. 68%, P &lt; 0.01), and mechanical ventilation (23% vs. 53%, P &lt; 0.01) compared to patients with CPS. The number of antibiotics on admission was similar between the groups (1.5 ± 0.6 vs. 1.6 ± 0.6, P = 0.36) but the duration of antibiotics was less in CNS (7.6 ± 1.7 days vs. 10.4 ± 2.6 days, P &lt; 0.01). CNS had lower duration of ICU stay (6 ± 2.1 days vs. 7.8 ± 3.7 days, P &lt; 0.01) and lower ICU mortality (7.1% vs. 22.7%, P = 0.02). Conclusion: CNS is very common in ICU. CNS patients compared to CPS tend to be less sick at presentation utilizing less resources but were initiated on a similar number of antibiotics on admission although for a shorter duration. Patients with CNS had a lower mortality in comparison to those with CPS.

Intravenous lidocaine improves postoperative cognition in patients undergoing laparoscopic colorectal surgery: a randomized, double-blind, controlled study

BackgroundThe risk of postoperative cognitive dysfunction(POCD) in laparoscopic surgery should not be overlooked. Intravenous lidocaine can reduce perioperative inflammatory response in patients undergoing laparoscopic surgery, while the effect of intraoperative intravenous lidocaine on postoperative cognitive function in patients undergoing laparoscopic colorectal cancer surgery has not been well studied. We investigated whether intraoperative lidocaine improves postoperative cognitive function after laparoscopic radical resection for colorectal cancer.MethodsWe conducted a prospective, randomized double blinded controlled trial to investigate the effect of intravenous lidocaine on rapid postoperative recovery in patients undergoing laparoscopic radical resection of colorectal cancer. The patients were randomly assigned to receive either intravenous lidocaine or saline. The primary outcome was cognitive dysfunction defined by a decrease from pre- to postoperative ≥ 2 of the Mini-Mental State Examination (MMSE) score, at the 3rd and the 7th postoperative days. Secondary outcomes were the MMSE raw score and parameters of the patients’ postoperative recovery such as agitation and length of stay in the post-anaesthesia care unit (PACU), length of hospital stay, markers of inflammation (white blood cell count and CRP), and incidence of complications.ResultsSeventy-three patients in the lidocaine group and 77 patients in the control group completed the trial. The rate of cognitive dysfunction was lower in the lidocaine group than that in the control group, both at the 3rd (18.57% vs. 63.64% for each group respectively; RR = 0.26, 95%CI = 0.19–0.32; p < 0.0001) and at the 7th postoperative day (12.33% vs. 53.25% for each group respectively; RR = 0.28, 95%CI = 0.22–0.35; P < 0.001). The postoperative MMSE scores were also higher in the lidocaine group than in the control group both at the 3rd (median 25 vs. 24 respectively) and at the 7th postoperative day (26 vs. 24 respectively). Also, patients in the lidocaine group displayed a lower white blood cell count than the control group at the 1st postoperative day (8.5 ± 2.7 vs. 10.4 ± 3.3; p < 0. 001). No differences were evidenced for the other secondary outcomes.ConclusionsIntraoperative intravenous lidocaine can significantly improve postoperative cognitive function in patients undergoing laparoscopic radical resection of colorectal cancer.Trial registrationChinese Clinical Trial Registry (16/1/2022, registration number: ChiCTR2200055683)

Characterizing distinct profiles of immune and inflammatory response with age to Omicron infection.

Understanding inflammatory and immune responses to Omicron infection based on age is crucial when addressing this global health threat. However, the lacking of comprehensive elucidation hinders the development of distinct treatments tailored to different age populations. 1299 cases of Omicron infection in Shanghai were enrolled between April 10, 2022 and June 3, 2022, dividing into three groups by ages: Adult group (18-59 years), Old group (60-79 years), and Elder group (≥ 80 years). Laboratory data including inflammatory cytokines, cellular, and humoral immunity were collected and analyzed. The mean age of Adult, Old, and Elder groups were 44.14, 69.98, and 89.35 years, respectively, with 40.9% being men. The Elder group patients exhibited higher white blood cell (WBC) counts and elevated levels of inflammatory cytokines, but their lymphocyte counts were relatively lower. In comparison to the Old group patients, the Elder group patients demonstrated significantly lower CD3+ T-cell counts, CD3+ T-cell proportion, CD4+ T-cell counts, CD8+ T-cell counts, and CD19+ B-cell counts, while the NK-cell counts were higher. Omicron negative patients displayed a higher proportion of CD19+ B-cells and higher levels of Complement-3 and IL-17 compared to the positive patients in the Old group. Omicron negative patients had lower WBC counts, CD3+CD8+ T-cells proportion, and the levels of serum amyloid A and IgA in the Elder group, but the CD4+/CD8+ ratio was higher. Our study identified the distinct profiles of inflammatory and immune responses to Omicron infection varying with age and highlighted the diverse correlations between the levels of various biomarkers and Omicron infected/convalescent patients.

A Protocol for Low-Input RNA-Sequencing of Patients with Febrile Neutropenia Captures Relevant Immunological Information.

Improved methods are needed for diagnosing infectious diseases in children with cancer. Most children have fever for other reasons than bacterial infection and are exposed to unnecessary antibiotics and hospital admission. Recent research has shown that host whole blood RNA transcriptomic signatures can distinguish bacterial infection from other causes of fever. Implementation of this method in clinics could change the diagnostic approach for children with cancer and suspected infection. However, extracting sufficient mRNA to perform transcriptome profiling by standard methods is challenging due to the patient's low white blood cell (WBC) counts. In this prospective cohort study, we succeeded in sequencing 95% of samples from children with leukaemia and suspected infection by using a low-input protocol. This could be a solution to the issue of obtaining sufficient RNA for sequencing from patients with low white blood cell counts. Further studies are required to determine whether the captured immune gene signatures are clinically valid and thus useful to clinicians as a diagnostic tool for patients with cancer and suspected infection.

Establishment of a risk model for severe adenovirus pneumonia and prospective study of the timing of intravenous immunoglobulin therapy in children

To develop a risk prediction model for severe adenovirus pneumonia (AVP) in children, and to explore the appropriate timing for intravenous immunoglobulin (IVIG) therapy for severe AVP. Medical data of 1 046 children with AVP were retrospectively analyzed, and a risk prediction model for severe AVP was established using multivariate logistic regression. The model was validated with 102 children with AVP. Then, 75 children aged ≤14 years who were considered at risk of developing severe AVP by the model were prospectively enrolled and divided into three groups (A, B and C) in order of visit, with 25 children in each group. Group A received symptomatic supportive therapy only. With the exception of symptomatic supportive therapy, group B received IVIG treatment at a dose of 1g/(kg·d) for 2 consecutive days, before progressing to severe AVP. With the exception of symptomatic supportive therapy, group C received IVIG treatment at a dose of 1 g/(kg·d) for 2 consecutive days after progressing to severe AVP. Efficacy and related laboratory indicators were compared among the three groups after treatment. Age<18.5 months, underlying diseases, fever duration >6.5 days, hemoglobin level <84.5 g/L, alanine transaminase level >113.5 U/L, and co-infection with bacteria were the six variables that entered into the risk prediction model for severe AVP. The model had an area under the receiver operating characteristic curve of 0.862, sensitivity of 0.878, and specificity of 0.848. The Hosmer-Lemeshow test showed good consistency between the predicted values and the actual observations (P>0.05). After treatment, group B had the shortest fever duration and hospital stay, the lowest hospitalization costs, the highest effective rate of treatment, the lowest incidence of complications, the lowest white blood cell count and interleukin (IL)-1, IL-2, IL-6, IL-8, IL-10 levels, and the highest level of tumor necrosis factor alpha (P<0.05). The risk model for severe AVP established in this study has good value in predicting the development of severe AVP. IVIG therapy before progression to severe AVP is more effective in treating AVP in children.

An unlucky WHIMsical child – A case report

Immunodeficiency in children often has the worst prognosis and there are varied primary and secondary causes for immunodeficiency. Warts Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome is a congenital immune deficiency that increases the likelihood of human papillomavirus infection (Warts), a low white blood cell count, hypogammaglobulinemia, and bone marrow myelokathexis. We present the case of a 3-year-old child brought by an orphanage caretaker with a history of recurrent swelling in both eyelids, multiple skin lesions all over the body, and recurrent respiratory tract infections. The child has been treated with native medications elsewhere with no improvement noted. Work up done for immune deficient states and bone marrow evaluation revealed myelokathexis with neutropenia/lymphopenia which made the possibility of WHIM syndrome. Treatment with colony stimulating factor has been initiated but could not be continued due to financial constraints. This report emphasis on the need for work-up to make early diagnosis and intervention of the disease as such than treating only their manifestations.

Hematological Alterations and their Prognostic Significance in Critically ill Children Admitted to the PICU

ABSTRACT Objective: Hematological parameters such as complete blood count, including red cell distribution width and prothrombin time, activated partial thromboplastin time, and international normalized ratio (INR) are the earliest markers of critical illness. This study was undertaken to evaluate their significance in prognosticating critically ill children admitted to the pediatric intensive care unit (PICU). Methodology: This was a cross-sectional and observational study on 125 critically ill children aged 1 month to 12 years and admitted to the PICU of a tertiary care hospital, conducted from February 2019 to July 2020. Hematological alterations along with clinical profile, Pediatric Risk of Mortality III (PRISM III), and Pediatric Sequential Organ Failure Assessment (pSOFA) scores were analyzed, and prognosis was defined by invasive ventilation requirement, duration of PICU stay, and death. Result: Among the 125 critically ill children, 35.2% were infants. The most common cause of PICU admission was infections (29.6%) followed by the central nervous system (20.8%) and respiratory system (20.8%). Around one-third of the patients required invasive ventilation and about half of the patients required inotropic support in our cohort. Sixty-four percent of critically ill children were found to be anemic at the time of PICU admission. Approximately 50% had leukocytosis and only 6% presented with leukopenia. Thrombocytopenia was present in 24.8%, and 20.8% had thrombocytosis on admission. Fourteen point four percent had deranged INR values. Conclusion: Critically ill children with low hemoglobin (Hb) levels, low white blood cell (WBC) count, high red cell distribution width (RDW) values, and deranged INR required invasive ventilation during PICU stay. Both leukocytosis and leukopenia along with low Hb were associated with prolonged PICU stay and death. No such association was found with either thrombocytopenia or thrombocytosis.