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in category hematology

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1: Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP)
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Posted 12 Feb 2020

Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP)
10,625 downloads medRxiv hematology

Suxin Wan, Qingjie Yi, Shibing Fan, Jinglong Lv, Xianxiang Zhang, Lian Guo, Chunhui Lang, Qing Xiao, Kaihu Xiao, Zhengjun Yi, Mao Qiang, Jianglin Xiang, Bangshuo Zhang, Yongping Chen

BackgroundTo explore the cellular immunity and cytokines status of NCP patients and to predict the correlation between the cellular immunity levels, cytokines and the severity of patients. Methods123 NCP patients were divided into mild and severe groups. Peripheral blood was collected, lymphocyte subsets and cytokines were detected. Correlation analysis was performed on the lymphocyte subsets and cytokines, and the differences between the indexes of the two groups were analyzed. Results102 mild and 21 severe patients were included. Lymphocyte subsets were reduced in two groups. The proportion of CD8 + T reduction in the mild and severe group was 28.43% and 61.9%, respectively; The proportion of B cell reduction was 25.49% and 28.57%; The proportion of NK cell reduction was 34.31% and 47.62%; The detection value of IL-6 was 0 in 55.88% of the mild group, mild group has a significantly lower proportion of patients with IL-6 higher than normal than severe group; There was no significant linear correlation between the lymphocyte subsets and cytokines, while significant differences were noticed between the two groups in CD4 + T, CD8 + T, IL-6 and IL-10. ConclusionsLow levels of CD4+T and CD8+T are common in severe NCP. IL-6 and IL-10 levels were higher in severe patients. T cell subsets and cytokines can be used as one of the basis for predicting the transition from mild to severe. Large number of samples are still needed to confirm the "warning value" of CD4 + T, CD8 + T IL-6 and IL-10.

2: Evidence for structural protein damage and membrane lipid remodeling in red blood cells from COVID-19 patients
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Posted 30 Jun 2020

Evidence for structural protein damage and membrane lipid remodeling in red blood cells from COVID-19 patients
5,006 downloads medRxiv hematology

Tiffany Thomas, Davide Stefanoni, Monika Dzieciatkowska, Aaron Issaian, Travis Nemkov, Ryan C Hill, Richard O Francis, Krystalyn E Hudson, Paul W Buehler, James C Zimring, Eldad A Hod, Kirk C Hansen, Steven L Spitalnik, Angelo D'Alessandro

The SARS-CoV-2 beta coronavirus is the etiological driver of COVID-19 disease, which is primarily characterized by shortness of breath, persistent dry cough, and fever. Because they transport oxygen, red blood cells (RBCs) may play a role in the severity of hypoxemia in COVID-19 patients. The present study combines state-of-the-art metabolomics, proteomics, and lipidomics approaches to investigate the impact of COVID-19 on RBCs from 23 healthy subjects and 29 molecularly-diagnosed COVID-19 patients. RBCs from COVID-19 patients had increased levels of glycolytic intermediates, accompanied by oxidation and fragmentation of ankyrin, spectrin beta, and the N-terminal cytosolic domain of band 3 (AE1). Significantly altered lipid metabolism was also observed, especially short and medium chain saturated fatty acids, acyl-carnitines, and sphingolipids. Nonetheless, there were no alterations of clinical hematological parameters, such as RBC count, hematocrit, and mean corpuscular hemoglobin concentration, with only minor increases in mean corpuscular volume. Taken together, these results suggest a significant impact of SARS-CoV-2 infection on RBC structural membrane homeostasis at the protein and lipid levels. Increases in RBC glycolytic metabolites are consistent with a theoretically improved capacity of hemoglobin to off-load oxygen as a function of allosteric modulation by high-energy phosphate compounds, perhaps to counteract COVID-19-induced hypoxia. Conversely, because the N-terminus of AE1 stabilizes deoxyhemoglobin and finely tunes oxygen off-loading, RBCs from COVID-19 patients may be incapable of responding to environmental variations in hemoglobin oxygen saturation when traveling from the lungs to peripheral capillaries and, as such, may have a compromised capacity to transport and deliver oxygen.

3: Recommendations for standardized management of CML patients in the core epidemic area of COVID-19(Multi-center survey results in Hubei Province, China)
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Posted 16 Mar 2020

Recommendations for standardized management of CML patients in the core epidemic area of COVID-19(Multi-center survey results in Hubei Province, China)
4,412 downloads medRxiv hematology

Dan-Yu Wang, Jing-Ming Guo, Zhuang-Zhi Yang, Guo-Lin Yuan, Li Meng, Wei-Ming Li

BackgroundSince late December 2019, the outbreak of the novel coronavirus disease, COVID-19, that began in Wuhan, has become endemic in China and more than 100 countries and regions in the world. There is no report about the prevalence of COVID-19 in CML patients untill now. We aimed to describe the clinical course, outcomes of CML patients with COVID-19 and prevalence of COVID-19 in CML patients. MethodsIn this multi-center survey, cross-sectional survey, observational study, the clinical data of CML patients with COVID-19 in each center were collected. Simultaneously, an online survey was conducted for information about the CML patients under the management at each center by asking the CML patients to complete a questionnaire,from February 15, 2020 to February 21, 2020. The questionnaire includes demographic data, place of residence, smoking status, CML diagnosis and treatment, comorbidities, combined medications, epidemiological history, symptoms(fever, cough, shortness of breath, etc) during the epidemic. Additional clinical data was collected on respondents suspected or confirmed to have COVID-19. We described and analyzed the prevalence of COVID-19 in CML patients, and focus on the clinical characteristics and outcomes of COVID-19 patients. Data were compared between the CML patients with optimal response and those with non-optimal response. The primary outcome was prevalence of COVID-19 in CML patients, as of Feb 21, 2020. Secondary outcomes included the history of epidemiology of CML patients, the clinical characteristics and outcomes of CML patients with COVID-19. FindingsOf 392 respondents, 223(56.9%) were males, and 240(61.2%) were 50 years or younger. Only 10 patients took drugs irregularly due to the influence of the epidemic because of traffic control, pharmacies unable to operate normally, etc. In the history of epidemiology, there were 4 patients with definite contact with COVID-19, of which 3 were remote contact and 1 was close contact. 12 respondents had fever, cough or shortness of breath during the epidemic, 1 case (common type) was confirmed with COVID-19 and cured after treatment. 1 patient was clinically diagnosed and succumbed. 1 of 299 (0.3%) patients with an optimal response was diagnosed with COVID-19. Of the 50 patients who failed to respond to CML treatment or had a poor response, 1 patient (2%) had a clinical diagnosis of COVID-19. InterpretationWhile the 392 CML respondents required regular referrals to hospitals, they did not have much contact with COVID-19 patients during the outbreak. Patients who failed to achieved an optimal response to CML therapy appear more likely to have a symptomatic infection with SARS-CoV-2. Older patients with comorbidities are at increased risk of death. FundingThis work was supported by grants from the National Natural Science Foundation of China(NSFC)(81873440&81700142).

4: Delayed-Phase Thrombocytopenia in Patients of Coronavirus Disease 2019 (COVID-19)
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Posted 15 Apr 2020

Delayed-Phase Thrombocytopenia in Patients of Coronavirus Disease 2019 (COVID-19)
4,380 downloads medRxiv hematology

Hao Zhou, Wanxin Chen, Ziping Li, Bohan Yang, Qiong Zhou, Ping Wang, Jianhua Zhu, Xuexing Chen, Peng Yang

The pandemic COVID19 pneumonia has engulfed the entire world. Hematopoietic system can also be affected by COVID19. Thrombocytopenia at admission was prevalent, while late phase or delayed phase thrombocytopenia is obscure. This retrospective case series analyzed patients with COVID19 at the Union Hospital, Wuhan, China, from January 25th to March 9th, 2020. Analysis began on March 11th, 2020. COVID19 associated delayed phase thrombocytopenia was occurred in 11.8% percent of enrolled patients. The delayed phase thrombocytopenia in COVID19 is prone to develop in elderly patients or patients with low lymphocyte count on admission. The delayed-phase thrombocytopenia is significantly associated with increased length of hospital stay and higher ICU admission rate. Delayed phase nadir platelet counts demonstrated a high and significantly negative linear correlation with B cell percentages and serum IL 6 levels. We also presented bone marrow aspiration pathology of three patients with delayed phase thrombocytopenia, showing impaired maturation of megakaryocytes. We speculated that the delayed phase platelet destruction might be mediated by antibodies, and suggest immunoregulatory treatment in severe patients to improve outcomes. Besides, clinicians need to pay attention to the delayed phase thrombocytopenia especially at 3 to 4 weeks after symptom onset.

5: Meta-Analysis of Risk of Vaccine-Induced Immune Thrombotic Thrombocytopenia Following ChAdOx1-S Recombinant Vaccine
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Posted 08 May 2021

Meta-Analysis of Risk of Vaccine-Induced Immune Thrombotic Thrombocytopenia Following ChAdOx1-S Recombinant Vaccine
4,350 downloads medRxiv hematology

Benjamin T.B. Chan, Pavlos Bobos, Ayodele Odutayo, Menaka Pai

Context: Vaccine-induced immune thrombotic thrombocytopenia (VITT) has been reported after administering ChAdOx1-S recombinant COVID-19 vaccine (marketed as Vaxzevira by Astra Zeneca, Covishield). Estimates of incidence vary between countries, due to different age distributions chosen, case definitions and choice of denominator (persons vaccinated vs immunizations given). This study clarifies these estimates by pooling data from ten countries and examining differences by age group. Methods: We examined case reports, press releases and immunization data and calculated pooled estimates of VITT incidence using random effects models. Sensitivity analyses considered different combinations of countries and varying assumptions on time between vaccination and reporting of cases. Results: Pooling all countries, VITT incidence was 0.73 per 100,000 persons receiving first dose of Covishield/Vaxzevira [95% CI .43,1.23]. Incidence for age 65 and over was 0.11 per 100,000 persons [95% CI .05-.26], and significantly higher among those under age 55: 1.67 per 100,000 persons [95% CI 1.30-2.14] in the UK, 5.06 per 100,000 persons in Norway [95% CI 2.16, 11.86]. The latter had the best data on counts of persons vaccinated. Incidence for age 55 to 64 years was 0.34 [95% CI 0.13, 0.85] in the UK, lower than for under age 55. Conclusion: VITT is a rare vaccine-associated adverse event. Incidence estimates vary between jurisdictions. However, even the highest reported incidence from Norway is low - and in settings with high community transmission, lower than risk of serious outcomes associated with Covid-19. Policymakers and individuals can use these data to calculate risk-benefit ratios and better target vaccine distribution.

6: Fatal breakthrough infection after anti-BCMA CAR-T therapy highlights suboptimal immune response to SARS-CoV-2 vaccination in myeloma patients
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Posted 15 May 2021

Fatal breakthrough infection after anti-BCMA CAR-T therapy highlights suboptimal immune response to SARS-CoV-2 vaccination in myeloma patients
4,049 downloads medRxiv hematology

Adolfo Aleman, Oliver Van Oekelen, Bhaskar Upadhyaya, Sarita Agte, Katerina Kappes, Katherine Beach, Komal Srivastava, Charles R Gleason, PVI study group, Bo Wang, Tarek H Mouhieddine, Kevin Tuballes, Daniel Geanon, Zenab Khan, Ana S. Gonzalez-Reiche, Harm van Bakel, Konstantinos Mouskas, Nicole W. Simons, Alexander W Charney, Seunghee Kim-Schulze, Adeeb H Rahman, Emilia M. Sordillo, Florian M Krammer, Carlos Cordon-Cardo, Nina Bhardwaj, Sacha Gnjatic, Miriam Merad, Brian D. Brown, Larysa Sanchez, Ajai Chari, Sundar Jagannath, Viviana Simon, Ania Wajnberg, Samir Parekh

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are highly effective in healthy individuals. Patients with multiple myeloma (MM) are immunocompromised due to defects in humoral and cellular immunity as well as immunosuppressive therapies. The efficacy after two doses of SARS-CoV-2 mRNA vaccination in MM patients is currently unknown. Here, we report the case of a MM patient who developed a fatal SARS-CoV-2 infection after full vaccination while in remission after B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T treatment. We show that the patient failed to generate antibodies or SARS-CoV-2-specific B and T cell responses, highlighting the continued risk of severe coronavirus disease 2019 (COVID-19) in vaccine non-responders. In the largest cohort of vaccinated MM patients to date, we demonstrate that 15.9% lack SARS-CoV-2 spike antibody response more than 10 days after the second mRNA vaccine dose. The patients actively receiving MM treatment, especially on regimens containing anti-CD38 and anti-BCMA, have lower antibody responses compared to healthy controls. Thus, it is of critical importance to monitor this patient population for serological responses. Non-responders may benefit from ongoing public health measures and from urgent study of prophylactic treatments to prevent SARS-CoV-2 infection.

7: Heparin for Moderately Ill Patients with Covid-19
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Posted 08 Jul 2021

Heparin for Moderately Ill Patients with Covid-19
3,910 downloads medRxiv hematology

Michelle Sholzberg, Grace H. Tang, Hassan Rahhal, Musaad AlHamzah, Lisa Baumann Kreuziger, Fionnuala Ní Áinle, Faris Alomran, Khalid Alayed, Mohammed AlSheef, Fahad AlSumait, Carlos Eduardo Pompilio, Catherine Sperlich, Sabrena Tangri, Terence Tang, Peter J. Jaksa, Deepa Suryanarayan, Mozah Obaid Almarshoodi, Lana A. Castellucci, Paula D. James, David Lillicrap, Marc Carrier, Andrew Beckett, Christos Colovos, Jai Jayakar, Marie-Pier Arsenault, Cynthia Wu, Karine Doyon, E. Roseann Andreou, Vera Dounaevskaia, Eric K. Tseng, Gloria Lim, Michael Fralick, Saskia Middeldorp, Agnes Y.Y. Lee, Fei Zuo, Bruno R da Costa, Kevin E. Thorpe, Elnara Márcia Negri, Mary Cushman, Peter Jüni, RAPID Trial investigators

BackgroundHeparin, in addition to its anticoagulant properties, has anti-inflammatory and potential anti-viral effects, and may improve endothelial function in patients with Covid-19. Early initiation of therapeutic heparin could decrease the thrombo-inflammatory process, and reduce the risk of critical illness or death. MethodsWe randomly assigned moderately ill hospitalized ward patients admitted for Covid-19 with elevated D-dimer level to therapeutic or prophylactic heparin. The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation or ICU admission. Safety outcomes included major bleeding. Analysis was by intention-to-treat. ResultsAt 28 days, the primary composite outcome occurred in 37 of 228 patients (16.2%) assigned to therapeutic heparin, and 52 of 237 patients (21.9%) assigned to prophylactic heparin (odds ratio, 0.69; 95% confidence interval [CI], 0.43 to 1.10; p=0.12). Four patients (1.8%) assigned to therapeutic heparin died compared with 18 patients (7.6%) assigned to prophylactic heparin (odds ratio, 0.22; 95%-CI, 0.07 to 0.65). The composite of all-cause mortality or any mechanical ventilation occurred in 23 (10.1%) in the therapeutic heparin group and 38 (16.0%) in the prophylactic heparin group (odds ratio, 0.59; 95%-CI, 0.34 to 1.02). Major bleeding occurred in 2 patients (0.9%) with therapeutic heparin and 4 patients (1.7%) with prophylactic heparin (odds ratio, 0.52; 95%-CI, 0.09 to 2.85). ConclusionsIn moderately ill ward patients with Covid-19 and elevated D-dimer level, therapeutic heparin did not significantly reduce the primary outcome but decreased the odds of death at 28 days. Trial registration numbers: NCT04362085; NCT04444700

8: COVID-19 infections and outcomes in patients with multiple myeloma in New York City: a cohort study from five academic centers
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Posted 11 Jun 2020

COVID-19 infections and outcomes in patients with multiple myeloma in New York City: a cohort study from five academic centers
2,906 downloads medRxiv hematology

Malin Hultcrantz, Joshua Richter, Cara Rosenbaum, Dhwani Patel, Eric Smith, Neha Korde, Sydney Lu, Sham Mailankody, Urvi Shah, Alexander Lesokhin, Hani Hassoun, Carlyn Tan, Francesco Maura, Andriy Derkach, Benjamin Diamond, Adriana Rossi, Roger N Pearse, Deppu Madduri, Ajai Chari, David Kaminetzky, Marc Braunstein, Christian Gordillo, Faith Davies, Sundar Jagannath, Ruben Niesvizky, Suzanne Lentzsch, Gareth Morgan, Ola Landgren

Importance: New York City is a global epicenter for the SARS-CoV-2 outbreak with a significant number of individuals infected by the virus. Patients with multiple myeloma have a compromised immune system, due to both the disease and anti-myeloma therapies, and may therefore be particularly susceptible to coronavirus disease 2019 (COVID-19); however, there is limited information to guide clinical management. Objective: To assess risk factors and outcomes of COVID-19 in patients with multiple myeloma. Design: Case-series. Setting: Five large academic centers in New York City. Participants: Patients with multiple myeloma and related plasma cell disorders who were diagnosed with COVID-19 between March 10th, 2020 and April 30th, 2020. Exposures: Clinical features and risk factors were analyzed in relation to severity of COVID-19. Main Outcomes and Measures: Descriptive statistics as well as logistic regression were used to estimate disease severity reflected in hospital admissions, intensive care unit (ICU) admission, need for mechanical ventilation, or death. Results: Of 100 multiple myeloma patients (male 58%; median age 68, range 41-91) diagnosed with COVID-19, 74 (74%) were admitted; of these 13 (18%) patients were placed on mechanical ventilation, and 18 patients (24%) expired. None of the studied risk factors were significantly associated (P>0.05) with adverse outcomes (ICU-admission, mechanical ventilation, or death): hypertension (N=56) odds ratio (OR) 2.3 (95% confidence interval [CI] 0.9-5.9); diabetes (N=18) OR 1.1 (95% CI 0.3-3.2); age >65 years (N=63) OR 2.0 (95% CI 0.8-5.3); high dose melphalan with autologous stem cell transplant <12 months (N=7) OR 1.2 (95% CI 0.2-7.4), IgG<650 mg/dL (N=42) OR=1.2 (95% CI 0.4-3.1). In the entire series of 127 patients with plasma cell disorders, hypertension was significantly associated with the combined end-point (OR 3.4, 95% CI 1.5-8.1). Conclusions and Relevance: Although multiple myeloma patients have a compromised immune system due to both the disease and therapy; in this largest disease specific cohort to date of patients with multiple myeloma and COVID-19, compared to the general population, we found risk factors for adverse outcome to be shared and mortality rates to be within the higher range of officially reported mortality rates.

9: Prevalence of anti-platelet factor4/polyanionic antibodies after COVID-19 vaccination with ChAdOx1 nCoV-19 and CoronaVac in Thais
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Posted 19 Jul 2021

Prevalence of anti-platelet factor4/polyanionic antibodies after COVID-19 vaccination with ChAdOx1 nCoV-19 and CoronaVac in Thais
2,794 downloads medRxiv hematology

Phichchapha Noikongdee, Pornnapa Police, Tichayapa Phojanasenee, Pichika Chantrathammachart, Pimjai Niparuck, Teeraya Puavilai, Angsana Phuphuakrat, Pantep Angchaisuksiri, Kochawan Boonyawat

Introduction: Vaccine-induced thrombotic thrombocytopenia (VITT) has been reported after vaccination with the adenoviral vector COVID-19 vaccine ChAdOx1 nCoV-19 in European countries. To date, no case of VITT has been reported in Thais after COVID-19 vaccination. We determined the frequency of anti-PF4/polyanionic antibodies in the Thai population receiving the COVID-19 vaccines. Methods: We conducted a cross-sectional study to evaluate the prevalence of anti-PF4/polyanionic antibodies in health care workers who received COVID-19 vaccination with ChAdOx1 nCoV-19 or CoronaVac within 7-35 days. A control population who had not been vaccinated was also included. Anti-PF4/polyanionic antibodies were detected using enzyme-link immunosorbent assay (ELISA). Functional assay with platelet aggregation was performed for all positive anti-PF4/polyanionic antibody ELISA tests. Results: A total of 646 participants were included in the study. 221 received ChAdOx1 nCoV-19, 232 received CoronaVac, and 193 participants were in the control group. The prevalence of anti-PF4 antibodies was 2.3% (95% confidence interval [CI] 0.7 to 5.2), 1.7% (95% CI, 0.5 to 4.4) in the ChAdOx1 nCoV-19 and CoronaVac groups, respectively. There was no positive test in the control group. None of the PF4/polyanionic positive sera induced platelet aggregation. Conclusion: We found a low prevalence of anti-PF4 antibodies in Thais after vaccination with ChAdOx1 nCoV-19 and CoronaVac. Low titer positive PF4/polyanionic ELISA results should be interpreted with caution when screening asymptomatic individuals after vaccination against COVID-19.

10: Integrated analysis of bulk multi omic and single-cell sequencing data confirms the molecular origin of hemodynamic changes in Covid-19 infection explaining coagulopathy and higher geriatric mortality
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Posted 29 Apr 2020

Integrated analysis of bulk multi omic and single-cell sequencing data confirms the molecular origin of hemodynamic changes in Covid-19 infection explaining coagulopathy and higher geriatric mortality
2,556 downloads medRxiv hematology

Shreya Johri, Deepali Jain, Ishaan Gupta

Besides severe respiratory distress, recent reports in Covid-19 patients have found a strong association between platelet counts and patient survival. Along with hemodynamic changes such as prolonged clotting time, high fibrin degradation products and D-dimers, increased levels of monocytes with disturbed morphology have also been identified. In this study, through an integrated analysis of bulk RNA-sequencing data from Covid-19 patients with data from single-cell sequencing studies on lung tissues, we found that most of the cell-types that contributed to the altered gene expression were of hematopoietic origin. We also found that differentially expressed genes in Covid-19 patients formed a significant pool of the expressing genes in phagocytic cells such as Monocytes and Platelets. Interestingly, while we observed a general enrichment for Monocytes in Covid-19 patients, we found that the signal for FCGRA3+ Monocytes was depleted. Further, we found evidence that age-associated gene expression changes in Monocytes and Platelets, associated with inflammation, mirror gene expression changes in Covid-19 patients suggesting that pro-inflammatory signalling during aging may worsen the infection in older patients. We identified more than 20 genes that change in the same direction between Covid-19 infection and aging cells that may act as potential therapeutic targets. Of particular interest were IL2RG, GNLY and GMZA expressed in Platelets, which facilitates cytokine signalling in Monocytes through an interaction with Platelets. To understand whether infection can directly manipulate the biology of Monocytes and Platelets, we hypothesize that these non-ACE2 expressing cells may be infected by the virus through the phagocytic route. We observed that phagocytic cells such as Monocytes, T-cells, and Platelets have a significantly higher expression of genes that are a part of the Covid-19 viral interactome. Hence these cell-types may have an active rather than a reactive role in viral pathogenesis to manifest clinical symptoms such as coagulopathy. Therefore, our results present molecular evidence for pursuing both anti-inflammatory and anticoagulation therapy for better patient management especially in older patients.

11: In-depth Analysis of Laboratory Parameters Reveals the Interplay Between Sex, Age and Systemic Inflammation in Individuals with COVID-19
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Posted 11 Aug 2020

In-depth Analysis of Laboratory Parameters Reveals the Interplay Between Sex, Age and Systemic Inflammation in Individuals with COVID-19
2,386 downloads medRxiv hematology

Felipe ten-Caten, Patricia Gonzalez-Dias, Icaro Castro, Rodrigo Ogava, Jeevan Giddaluru, Juan CS Silva, Felipe Martins, Andre NA Goncalves, Andre G Costa-Martins, Jose D Araujo, Ana C Viegas, Fernando Q Cunha, Sandra Farsky, Fernando A. Bozza, Anna S Levin, Pia S Pannaraj, Thushan I de Silva, Paola Minoprio, Bruno B. Andrade, Fabiano P da Silva, Helder Nakaya

Introduction: The progression and severity of the coronavirus disease 2019 (COVID-19), an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), varies significantly in the population. While the hallmarks of SARS-CoV-2 and severe COVID-19 within routine laboratory parameters are emerging, little is known about the impact of sex and age on these profiles. Methods: We performed multidimensional analysis of millions of records of laboratory parameters and diagnostic tests for 178,887 individuals, of which 33,266 tested positive for SARS-CoV-2. These included complete blood cell count, electrolytes, metabolites, arterial blood gases, enzymes, hormones, cancer biomarkers, and others. Results: COVID-19 induced more alterations in the laboratory parameters in males compared to females between 13 and 60 years old, in contrast to older individuals, where several parameters were altered by COVID-19 in both men and women. Biomarkers of inflammation, such as C-reactive protein (CRP) and ferritin, were increased especially in older men with COVID-19, whereas other markers such as abnormal liver function tests were common across several age groups, except for young women. Low peripheral blood basophils and eosinophils were also more common in the elderly with COVID-19. Both male and female COVID-19 patients admitted to the intensive care unit (ICU) displayed alterations in the coagulation system, and higher levels of neutrophils, CRP, lactate dehydrogenase (LDH), among others. Discussion: Our study uncovers the laboratory profile of a large cohort of COVID-19 patients that underly discrepancies influenced by aging and biological sex. These profiles directly link COVID-19 disease presentation to an intricate interplay between sex, age and the immune response.

12: Unified classification and risk-stratification in Acute Myeloid Leukemia
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Posted 12 Mar 2022

Unified classification and risk-stratification in Acute Myeloid Leukemia
2,289 downloads medRxiv hematology

Yanis Tazi, Juan Arango Ossa, Yangyu Zhou, Elsa Bernard, Ian Thomas, Amanda Gilkes, Sylvie Freeman, Yoann Pradat, Sean Johnson, Robert Hills, Richard Dillon, Max Levine, Dan Leongamornlert, Adam Butler, Arnold Ganser, Lars Bullinger, Konstanze Dohner, Oliver Ottmann, Richard Adams, Hartmut Dohner, Peter Campbell, Alan Burnett, Michael Dennis, Nigel Russell, Sean Devlin, Brian Huntly, Elli Papaemmanuil

Clinical recommendations for AML classification and risk-stratification remain heavily reliant on cytogenetic findings at diagnosis, which are present in <50% of patients. Using comprehensive molecular profiling data from 3,653 patients we characterize and validate 16 molecular classes describing 100% of AML patients. Each class represents diverse biological AML subgroups, and is associated with distinct clinical presentation, likelihood of response to induction chemotherapy, risk of relapse and death over time. Secondary AML-2, emerges as the second largest class (24%), associates with high-risk disease, poor prognosis irrespective of flow MRD negativity, and derives significant benefit from transplantation. Guided by class membership we derive a 3-tier risk-stratification score that re-stratifies 26% of patients as compared to standard of care. This results in a unified framework for disease classification and risk-stratification in AML that relies on information from cytogenetics and 32 genes. Last, we develop an open-access patient-tailored clinical decision support tool.

13: Blood group A Secretors are associated with a higher risk of COVID-19 cardiovascular disease complications
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Posted 19 Dec 2020

Blood group A Secretors are associated with a higher risk of COVID-19 cardiovascular disease complications
2,202 downloads medRxiv hematology

TJ Mankelow, BK Singleton, PL Moura, CJ Stevens-Hernandez, NM Cogan, G Gyorffy, S Kupzig, L Nichols, C Asby, J Pooley, G Ruffino, F Hosseini, F Moghaddas, M Attwood, A Noel, Alan Cooper, D Arnold, F Hamilton, C Hyams, A Finn, AM Toye, DJ Anstee

The SARS-CoV-2 virus causes COVID-19, an infection capable of causing severe disease and death but which may also be asymptomatic or oligosymptomatic in many individuals. While several risk factors, including age, have been described, the mechanisms of this variation are poorly understood. Several studies have described associations between blood group and COVID-19 severity, while others do not. Expression of ABO glycans on secreted proteins and non-erythroid cells is controlled by a fucosyltransferase (FUT2). Inactivating mutations result in a non-secretor phenotype which is known to protect against some viral infections. We investigated whether ABO or secretor status was associated with COVID-19 severity. Data combined from healthcare records and laboratory tests (n=275) of SARS-CoV-2 PCR positive patients hospitalised with COVID-19, confirmed higher than expected numbers of blood group A individuals compared to O (RR=1.24, CI 95% [1.05,1.47], P=0.0111). There was also a significant association between group A and COVID-19-related cardiovascular complications (RR=2.56, CI 95% [1.43,4.55], P=0.0011) which is independent of gender. Molecular analysis of phenotype revealed that group A patients who are non-secretors are significantly less likely to be hospitalised than secretors. In a larger cohort of 1000 convalescent plasma donors, among whom the majority displayed COVID-19 symptoms and only a small minority required hospitalisation, group A non-secretors were slightly over-represented. Our findings indicate that group A non-secretors are not resistant to infection by SARS-CoV-2, but they are likely to experience a less severe form of its associated disease. Key PointsO_LIBlood group type A is associated with an increased risk of cardiovascular complications in COVID-19 patients. C_LIO_LIFUT2 "non-secretor" status reduces the risk of severe COVID-19 outcomes in patients with blood group A. C_LI

14: Clonal hematopoiesis is associated with protection from Alzheimer's disease
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Posted 13 Dec 2021

Clonal hematopoiesis is associated with protection from Alzheimer's disease
2,039 downloads medRxiv hematology

HIND BOUZID, Julia A Belk, Max Jan, Yanyan Qi, Chloe Sarnowski, Sara Wirth, Lisa Ma, Matthew Chrostek, Herra Ahmad, Daniel Nachun, Winnie Yao, Alexa Beiser, Alexander G Bick, Joshua C. Bis, Myriam Fornage, William T. Longstreth, Oscar Lopez, Pradeep Natarajan, Bruce M. Psaty, Claudia L. Satizabal, Joshua S Weinstock, Eric Larson, Paul K. Crane, C. Dirk Keene, Sudha Seshadri, Ansuman T. Satpathy, thomas Montine, Siddhartha Jaiswal

Clonal hematopoiesis of indeterminate potential (CHIP) is a pre-malignant expansion of mutated blood stem cells that also associates with non-hematological disorders. Here, we tested whether CHIP was associated with Alzheimer's disease (AD). Surprisingly, we found that CHIP carriers had reduced risk of AD dementia or AD neuropathologic features in multiple cohorts. The same mutations found in blood were also detected in the microglia-enriched fraction of brain in 7 out of 8 CHIP carriers. Single-cell chromatin accessibility profiling of brain-derived nuclei in two CHIP carriers revealed that the mutated cells were indistinguishable from microglia and comprised between 42-77% of the total microglial pool. These results suggest a role for mutant, marrow-derived cells in attenuating risk of AD, possibly by supplementing a failing microglial system during aging.

15: Background rates of five thrombosis with thrombocytopenia syndromes of special interest for COVID-19 vaccine safety surveillance: incidence between 2017 and 2019 and patient profiles from 20.6 million people in six European countries
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Posted 13 May 2021

Background rates of five thrombosis with thrombocytopenia syndromes of special interest for COVID-19 vaccine safety surveillance: incidence between 2017 and 2019 and patient profiles from 20.6 million people in six European countries
1,923 downloads medRxiv hematology

Edward Burn, Xintong Li, Kristin Kostka, Henry Morgan Stewart, Christian Reich, Sarah Seager, Talita Duarte-Salles, Sergio Fernandez-Bertolin, María Aragón, Carlen Reyes, Eugenia Martinez-Hernandez, Edelmira Marti, Antonella Delmestri, Katia MC Verhamme, Peter Rijnbeek, Daniel Prieto-Alhambra

Background Thrombosis with thrombocytopenia syndrome (TTS) has been reported among individuals vaccinated with adenovirus-vectored COVID-19 vaccines. In this study we describe the background incidence of TTS in 6 European countries. Methods Electronic medical records from France, Netherlands, Italy, Germany, Spain, and the United Kingdom informed the study. Incidence rates of cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis (SVT), deep vein thrombosis (DVT), pulmonary embolism (PE), and stroke, all with concurrent thrombocytopenia, were estimated among the general population between 2017 to 2019. A range of additional adverse events of special interest for COVID-19 vaccinations were also studied in a similar manner. Findings A total of 20,599,134 individuals were included. Background rates ranged from 1.0 (0.7 to 1.4) to 1.5 (1.0 to 2.0) per 100,000 person-years for DVT with thrombocytopenia, from 0.5 (0.3 to 0.6) to 1.4 (1.1 to 1.8) for PE with thrombocytopenia, from 0.1 (0.0 to 0.1) to 0.7 (0.5 to 0.9) for SVT with thrombocytopenia, and from 0.2 (0.0 to 0.4) to 4.4 (3.9 to 5.0) for stroke with thrombocytopenia. CVST with thrombocytopenia was only identified in one database, with incidence rate of 0.1 (0.0 to 0.2) per 100,000 person-years. The incidence of TTS increased with age, with those affected typically having more comorbidities and greater medication use than the general population. TTS was also more often seen in men than women. A sizeable proportion of those affected were seen to have been taking antithrombotic and anticoagulant therapies prior to their TTS event. Interpretation Although rates vary across databases, TTS has consistently been seen to be a very rare event among the general population. While still very rare, rates of TTS are typically higher among older individuals, and those affected were also seen to generally be male and have more comorbidities and greater medication use than the general population. Funding This study was funded by the European Medicines Agency (EMA/2017/09/PE Lot 3).

16: Red blood cell distribution width (RDW) in Hospitalized COVID-19 Patients
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Posted 03 Jul 2020

Red blood cell distribution width (RDW) in Hospitalized COVID-19 Patients
1,900 downloads medRxiv hematology

Preethi Ramachandran, Mahesh Gajendran, Abhilash Perisetti, Karim Osama Elkholy, Abhishek Chakraborti, Giuseppe Lippi, Hemant Goyal

Introduction: Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is causing dramatic morbidity and mortality worldwide. The Red Blood Cell Distribution Width (RDW) has been strongly associated with increased morbidity and mortality in multiple diseases. Objective: To assess if elevated RDW is associated with unfavorable outcomes in hospitalized COVID-19. Methods: We retrospectively studied clinical outcomes of hospitalized COVID-19 patients for their RDW values. In-hospital mortality was defined as primary outcome, while septic shock, need for mechanical ventilation, and length of stay (LOS) were secondary outcomes. Results- A total of 294 COVID-19 patients were finally studied. Overall prevalence of increased RDW was 49.7% (146/294). RDW was associated with increased risk of in-hospital mortality (aOR, 4.5; 95%CI, 1.4-14.3) and septic shock (aOR, 4.6; 95%CI, 1.4-15.1) after adjusting for anemia, ferritin, and lactate. The association remained unchanged even after adjusting for other clinical confounders such as age, sex, body mass index, coronary artery disease, hypertension, diabetes mellitus, and chronic obstructive pulmonary disease. No association was found instead with mechanical ventilation and median LOS. Conclusion: Elevated RDW in hospitalized COVID-19 patients is associated with a significantly increased risk of mortality and septic shock.

17: Impaired Humoral Immunity to SARS-CoV-2 Vaccination in Non-Hodgkin Lymphoma and CLL Patients
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Posted 03 Jun 2021

Impaired Humoral Immunity to SARS-CoV-2 Vaccination in Non-Hodgkin Lymphoma and CLL Patients
1,875 downloads medRxiv hematology

Catherine Diefenbach, Jessica Caro, Akiko Koide, Michael Grossbard, Judith Goldberg, Bruce Raphael, Kenneth Hymes, Tibor Moskovits, Maxim Kreditor, David Kaminetzky, Shella Saint-Fleur Lominy, Jun Choi, Sara A Thannickal, Kenneth A. Stapleford, Shohei Koide

Patients with hematologic malignancies are a high priority for SARS-CoV-2 vaccination, yet the benefit they will derive is uncertain. We investigated the humoral response to vaccination in 53 non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), or CLL patients. Peripheral blood was obtained 2 weeks after first vaccination and 6 weeks after second vaccination for antibody profiling using the multiplex bead-binding assay. Serum IgG, IgA, and IgM antibody levels to the spike specific receptor binding domain (RBD) were evaluated as a measure of response. Subsequently, antibody-positive serum were assayed for neutralization capacity against authentic SARS-CoV-2. Histology was 68% lymphoma and 32% CLL; groups were: patients receiving anti- CD20-based therapy (45%), monitored with disease (28%), receiving BTK inhibitors (19%), or chemotherapy (all HL) (8%). SARS-CoV-2 specific RBD IgG antibody response was decreased across all NHL and CLL groups: 25%, 73%, and 40%, respectively. Antibody IgG titers were significantly reduced (p < 0.001) for CD20 treated and targeted therapy patients, and (p = 0.003) for monitored patients. In 94% of patients evaluated after first and second vaccination, antibody titers did not significantly boost after second vaccination. Only 13% of CD20 treated and 13% of monitored patients generated neutralizing antibodies to SARS-CoV-2 with ICD50s 135 to 1767, and 445 and > 10240. This data has profound implications given the current guidance relaxing masking restrictions and for timing of vaccinations. Unless immunity is confirmed with laboratory testing, these patients should continue to mask, socially distance, and to avoid close contact with non-vaccinated individuals.

18: Single-cell spatial analysis of tumor immune architecture in diffuse large B cell lymphoma
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Posted 03 Feb 2021

Single-cell spatial analysis of tumor immune architecture in diffuse large B cell lymphoma
1,865 downloads medRxiv hematology

Anthony R. Colombo, Monirath Hav, Erik Gerdtsson, Mohan B Singh, Alexander Xu, Alicia Gamboa, Denaly Chen, Jane Houldsworth, Rita Shaknovich, Tomohiro Aoki, Lauren Chong, Katsuyoshi Takata, Elizabeht Chavez, Christian Steidl, James Hicks, Peter Kuhn, Akil Merchant

Multiplexed immune cell profiling of the tumor microenvironment (TME) in cancer has improved our understanding of cancer immunology, but complex spatial analyses of tumor-immune interactions in lymphoma are lacking. Here we used imaging mass cytometry (IMC) on 33 cases of diffuse large B cell lymphoma (DLBCL) to characterize tumor and immune cell architecture and correlate it to clinicopathological features such as cell of origin, gene mutations, and responsiveness to chemotherapy. To understand the poor response of DLBCL to immune check point inhibitors (ICI), we compared our results to IMC data from Hodgkin lymphoma (HL), a cancer highly responsive to ICI, and observed differences in the expression of PD-L1, PD-1, and TIM-3. We created a spatial classification of tumor cells and identified sub-regions of immune activation, immune suppression, and immune exclusion within the topology of DLBCL. Finally, the spatial analysis allowed us to identify markers such as CXCR3, which are associated with penetration of immune cells into immune desert regions, with important implications for engineered cellular therapies.

19: Antibody Responses after SARS-CoV-2 Vaccination in Lymphoma
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Posted 12 Jun 2021

Antibody Responses after SARS-CoV-2 Vaccination in Lymphoma
1,677 downloads medRxiv hematology

Sean Hua Lim, Nicola Campbell, Marina Johnson, Debora Joseph-Pietras, Graham P Collins, Ann O'Callaghan, Christopher P Fox, Matthew Ahearne, Peter WM Johnson, David Goldblatt, Andrew J Davies

Individuals with lymphoid malignancies have an increased mortality risk from COVID-19. Paradoxically, this population is least likely to be protected by SARS-CoV-2 vaccination as a result of disease- or treatment-related immunosuppression. Current data on vaccine responses in persons with lymphoid malignancies is limited. PROSECO is a UK multi-centre prospective observational study evaluating COVID-19 vaccine immune responses in individuals with lymphoma. This early interim analysis details the antibody responses to first- and second- SARS-CoV-2 vaccination with either BNT162b2 (Pfizer-BioNTech) and ChAdOx1 (AstraZeneca), in 129 participants. Responses are compared to those obtained in healthy volunteers. The key findings of this interim analysis are first, 61% of participants who are vaccinated during or within 6 months of receiving systemic anti-lymphoma treatment, do not have detectable antibodies despite two doses of vaccine. Second, individuals with curable disease such has Hodgkin (100%) and aggressive B-cell non-Hodgkin lymphoma (81%) develop robust antibody levels to either first or second doses, when vaccinated > 6 months after treatment completion. Third, participants incurable, indolent lymphomas have reduced antibody levels to first and second vaccine doses, irrespective of treatment history. Finally, whilst there was no difference in antibody responses between BNT162b2 and ChAdOx1 in lymphoma participants, BNT162b2 induces 11-fold higher antibody responses than ChAdOx1 after the second dose in healthy donors. These findings serve to reassure the community that individuals with treated Hodgkin and aggressive B-NHL can develop antibody responses to SARS-CoV-2 vaccine. Simultaneously it also highlights the critical need to identify an alternative strategy against COVID-19 for those undergoing systemic anti-lymphoma treatment, and for individuals with indolent lymphomas.

20: Clinical presentation and differential splicing of SRSF2, U2AF1 and SF3B1 mutations in patients with Acute Myeloid Leukaemia
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Posted 10 Jan 2020

Clinical presentation and differential splicing of SRSF2, U2AF1 and SF3B1 mutations in patients with Acute Myeloid Leukaemia
1,440 downloads medRxiv hematology

Stefanos A. Bamopoulos, Aarif M. N. Batcha, Vindi Jurinovic, Maja Rothenberg-Thurley, Hanna Janke, Bianka Ksienzyk, Julia Philippou-Massier, Alexander Graf, Stefan Krebs, Helmut Blum, Stephanie Schneider, Nikola Konstandin, Maria Cristina Sauerland, Dennis Goerlich, Wolfgang E. Berdel, Bernhard J. Woermann, Stefan K Bohlander, Stefan Canzar, Ulrich Mansmann, Wolfgang Hiddemann, Jan Braess, Karsten Spiekermann, Klaus H. Metzeler, Tobias Herold

Previous studies have demonstrated that splicing factor mutations are recurrent events in hematopoietic malignancies. Their clinical characteristics and aberrant splicing patterns have been explored in myelodysplasia, however, their functional consequences in acute myeloid leukaemia are largely unknown. The aim of this study was the comprehensive clinical and functional analysis of mutations in the three most commonly afflicted splicing factor genes: SRSF2, U2AF1 and SF3B1. To this end, we examined the prognostic role of splicing factor mutations in two large independent cohorts, encompassing a total of 2678 acute myeloid leukaemia patients treated with intensive chemotherapy. The clinical analysis was complemented by RNA-sequencing of 246 patients to identify targets of splicing dysregulation. Results were validated in an additional RNA-sequencing dataset of 177 patients. Patients with splicing factor mutations show inferior relapse-free and overall survival, however, these mutations do not represent independent prognostic markers. Differential isoform expression analysis revealed a characteristic expression profile for each splicing factor mutation with a strong dysregulation of several isoforms. Furthermore, by establishing a custom differential splice junction usage pipeline we accurately detected aberrant splicing in splicing factor mutated samples. Mutated samples were characterized by predominantly decreased splice junction utilization of a large number of genes. A large proportion of differentially used spliced junctions were novel. Targets of splicing dysregulation included several genes with a known role in acute myeloid leukaemia. In SRSF2(P95H) mutants we further explored the possibility of a cascading effect through the dysregulation of the splicing pathway. Taken together, our findings suggest that splicing factor mutations does not represent independent prognostic markers. However, they do have genome-wide consequences on gene splicing leading to dysregulated isoform expression of several genes.

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