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Background: Severe Plasmodium falciparum malarial anemia is still the principal cause of death in children in underdeveloped countries. An imbalance between proinflammatory and anti-inflammatory cytokines is associated with malaria progression. This study evaluated circulating levels of selected inflammatory cytokines among malaria-infected children in Ghana., Methods: This case-control study was conducted at Tamale Teaching Hospital, Ghana. One hundred and twenty children with malaria and 60 controls, aged 12-144 months were selected from April to July, 2023 for the study. Malaria was diagnosed through microscopy, full blood count was measured using hematology analyzer, and cytokines were measured using enzyme-linked immunosorbent assay., Results: Malaria-infected children had higher tumor necrosis factor alpha (TNF-α) (p < .001), interferon-gamma (IFN-ɣ) (p < .001), interleukin (IL)-1β (p < .001), IL-6 (p < .001), granulocyte macrophage-colony stimulating factor (GM-CSF) (p < .001), and IL-10 (p < .001) levels than controls. Participants with high parasitemia had raised TNF-α (p < .001), IFN-ɣ (p < .001), IL-1β (p < .001), IL-6 (p < .001), GM-CSF (p < .001), and IL-10 (p < .001), but reduced IL-3 (p < .001) and TGF-β (p < .001) than those with low parasitemia. Severe malarial anemic children had elevated TNF-α (p < .001), IFN-ɣ (p < .001), IL-1β (p < .001), IL-6 (p < .001), GM-CSF (p < .001), and IL-10 (p < .001), but lower IL-3 (p < .001) and TGF-β (p < .001) than those with uncomplicated malaria., Conclusion: Parasite density was the principal predictor of the cytokine levels, as parasitemia positively associated with IL-10, GM-CSF, IL-6, IL-1β, IFN-ɣ, and TNF-α, but negatively associated with IL-3 and TGF-β. Malaria is associated with enhanced secretion of pro- and anti-inflammatory cytokines in Ghanaian children. Inflammatory cytokines may be involved in the development of severe malarial anemia in children. However, IL-3 and TGF-β may offer protection against severe malarial anemia., (© 2024 The Author(s). Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

End-stage renal disease (ESRD) patients are considered immunocompromised, putting them at high risk for infections, including cytomegalovirus (CMV). CMV can affect hematological parameters, causing further complications in ESRD patients. This study intended to determine the seropositivity of CMV infection in hemodialysis patients and its effect on different blood parameters in ESRD patients to help decrease the overall dialysis associated morbidity and mortality. Blood samples were collected from 45 ESRD patients and 45 controls. A complete blood count was performed using an automated cell counter. CMV-specific IgM and IgG levels were measured using immunochemistry testing. The seropositivity for CMV-IgG was 42.2% in ESRD patients which was significantly higher than in control group (22.2%) (p=0.042). The seropositivity for CMV-IgM was 6.7% in ESRD patients with no difference with the control group (4.4%). The prevalence of anemia was significantly higher in CMV seropositive (77.3%) compared to CMV seronegative (47.8%) ESRD patients. Other studied blood parameters were not different between CMV seronegative and seropositive ESRD patients. In conclusion, CMV infection is a significant concern for dialysis patients and can affect hematological parameters, leading to further complications. Early detection and treatment of CMV infection and monitoring of CMV IgM and IgG levels are critical to prevent further complications and improve clinical outcomes., (Copyright© by the Egyptian Association of Immunologists.)

Severe malarial anemia (SMA) increases the morbidity and mortality of Plasmodium , the causative agent of malaria. SMA is mainly developed by children and pregnant women in response to the infection. It is characterized by ineffective erythropoiesis caused by impaired erythropoietin (EPO) signaling. To gain new insights into the pathogenesis of SMA, we investigated the relationship between the immune system and erythropoiesis, conducting comparative analyses in a mouse model of malaria. Red blood cell (RBC) production was evaluated in infected and reinfected animals to mimic endemic occurrences. Higher levels of circulating EPO were observed in response to (re)infection. Despite no major differences in bone marrow erythropoiesis, compensatory mechanisms of splenic RBC production were significantly reduced in reinfected mice. Concomitantly, a pronounced immune response activation was observed in erythropoietic organs of reinfected animals in relation to single-infected mice. Aged mice were also used to mimic the occurrence of malaria in the elderly. The increase in symptom severity was correlated with the enhanced activation of the immune system, which significantly impaired erythropoiesis. Immunocompromised mice further support the existence of an immune-shaping regulation of RBC production. Overall, our data reveal the strict correlation between erythropoiesis and immune cells, which ultimately dictates the severity of SMA.

Background: Inflammation has been reported to be related to anemia. As a novel inflammatory marker, Systemic immune-inflammation index (SII) has not been studied with Anemia. The aim of this study was to investigate the possible relationship between SII and anemia., Methods: This retrospective cross-sectional survey was conducted using data from the 2005-2018 National Health and Nutrition Examination Survey (NHANES) population. In total, 19851 American adults aged ≥18 years were included. SII was calculated as the platelet count×neutrophil count/lymphocyte count. Anemia was defined as hemoglobin (Hgb) levels of < 13 g/dL in males and < 12 g/dL in females. Logistic regression analyses, subgroup analyses and sensitivity analyses were performed to investigate the relationship between SII and anemia., Results: Our study included a total of 19851 patients, of which 1501 (7.6%) had anemia. After adjusting for all covariates, the multivariate logistic regression analysis showed that a higher SII (In-transform) level was associated with increased likelihood of anemia (OR=1.51, 95% CI: 1.36-1.68, P<0.001). The association between SII and anemia exhibited a nonlinear manner. The positive correlation between SII and anemia was related to the severity of anemia. Subgroup analysis showed that there was no significant dependence on age, family income, body mass index, hypertension, kidney disease and cancer except gender on this positive association. Furthermore, sensitivity analyses confirmed the robustness of our results., Conclusion: Our study demonstrated that SII was positively associated with anemia especially among female participants. And this positive correlation was related to the severity of anemia. Further large-scale prospective studies are still needed to analyze the role of SII in anemia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Xiao, Cai, Lu, Liu, Dong, Zheng, Song, Sun, Wang and Xiao.)

The primary triggers that stimulate the body to generate platelet antibodies via immune mechanisms encompass events such as pregnancy, transplantation, and blood transfusion. Interestingly, our findings revealed that a subset of male patients with hepatocellular carcinoma (HCC), despite having no history of transplantation or blood transfusion, has shown positive results in platelet antibody screenings. This hints at the possibility that certain factors, potentially related to the tumor itself or its treatment, may affect antibody production. To delve the causes we initiated this study. We employed a case-control study approach to analyze potential influential factors leading to the positive results via univariate and multivariate regression analysis. We utilized Kendall's tau-b correlation to examine the relationship between the strength of platelet antibodies and peripheral blood cytopenia. Antitumor medication emerged as an independent risk factor for positive results in HCC patients, and the strength of platelet antibodies positively correlated with the severity of anemia and thrombocytopenia. Without history of blood transfusion, transplantation, pregnancy, those HCC patients underwent recent tumor medication therapy are experiencing peripheral erythrocytopenia or thrombocytopenia, for them platelet antibody screenings holds potential clinical value for prevention and treatment of complications like drug-immune-related anemia and/or bleeding., (© 2024. The Author(s).)

Background: Iron deficiency and iron overload can affect the normal functioning of the innate and adaptive immune responses. Fermented milk products may enhance immune functions, but little is known about the effect of fermented milks on modulation of the immune response during iron deficiency anemia and recovery with normal or high dietary iron intake. Eighty male Wistar rats were randomly assigned to a control group fed a standard diet or to an anemic group fed a diet deficit in iron. Control and anemic groups were fed for 30 days with diets based on a fermented goat's or cow's milk product, with normal iron content or iron overload., Results: In general, during anemia recovery lectin and alternative complement pathway activity and lactoferrin decreased, because it improves iron homeostasis, which is critically important in immune system functions. Fermented goat's milk diet enhanced immune function during iron deficiency recovery, suppressed oxidant-induced eotaxin and fractalkine expression due to the concurrent reduction of free radical production and pro-inflammatory cytokines, and decreased monocyte chemoattractant protein-1 and monocyte migration and adhesion. The increase in interferon-γ can confer immunological colonization of gut microbiota and downregulate inflammation., Conclusion: Fermented goat's milk consumption enhances immune function, modifying complement pathway activity and decreasing pro-inflammatory cytokines as well as lactoferrin concentration, due to the improvement of iron homeostasis, which is critically important in the normal function of the immune system. © 2021 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry., (© 2021 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.)

Maternal dietary micronutrients and omega-3 fatty acids support development of the fetal and neonatal immune system. Whether supplementation is similarly beneficial for the mother during gestation has received limited attention. A scoping review of human trials was conducted looking for evidence of biochemical, genomic, and clinical effects of supplementation on the maternal immune system. The authors explored the literature on PubMed, Cochrane Library, and Web of Science databases from 2010 to the present day using PRISMA-ScR methodology. Full-length human trials in English were searched for using general terms and vitamin A, B12, C, D, and E; choline; iodine; iron; selenium; zinc; and docosahexaenoic/eicosapentaenoic acid. Of 1391 unique articles, 36 were eligible for inclusion. Diverse biochemical and epigenomic effects of supplementation were identified that may influence innate and adaptive immunity. Possible clinical benefits were encountered in malaria, HIV infections, anemia, Type 1 diabetes mellitus, and preventing preterm delivery. Only limited publications were identified that directly explored maternal immunity in pregnancy and the effects of micronutrients. None provided a holistic perspective. It is concluded that supplementation may influence biochemical aspects of the maternal immune response and some clinical outcomes, but the evidence from this review is not sufficient to justify changes to current guidelines.

Ascariasis is one of the most common infections in the world and associated with significant global morbidity. Ascaris larval migration through the host's lungs is essential for larval development but leads to an exaggerated type-2 host immune response manifesting clinically as acute allergic airway disease. However, whether Ascaris larval migration can subsequently lead to chronic lung diseases remains unknown. Here, we demonstrate that a single episode of Ascaris larval migration through the host lungs induces a chronic pulmonary syndrome of type-2 inflammatory pathology and emphysema accompanied by pulmonary hemorrhage and chronic anemia in a mouse model. Our results reveal that a single episode of Ascaris larval migration through the host lungs leads to permanent lung damage with systemic effects. Remote episodes of ascariasis may drive non-communicable lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), and chronic anemia in parasite endemic regions., Competing Interests: The authors have declared that no competing interests exist.

It has recently emerged that tissue-resident macrophages are key regulators of several stem cell niches orchestrating tissue formation during development, as well as postnatally, when they also organize the repair and regeneration of many tissues including the hemopoietic tissue. The fact that macrophages are also master regulators and effectors of innate immunity and inflammation allows them to coordinate hematopoietic response to infections, injuries, and inflammation. After recently reviewing the roles of phagocytes and macrophages in regulating normal and pathologic hematopoietic stem cell niches, we now focus on the key roles of macrophages in regulating erythropoiesis and iron homeostasis. We review herein the recent advances in understanding how macrophages at the center of erythroblastic islands form an erythropoietic niche that controls the terminal differentiation and maturation of erythroblasts into reticulocytes; how red pulp macrophages in the spleen control iron recycling and homeostasis; how these macrophages coordinate emergency erythropoiesis in response to blood loss, infections, and inflammation; and how persistent infections or inflammation can lead to anemia of inflammation via macrophages. Finally, we discuss the technical challenges associated with the molecular characterization of erythroid island macrophages and red pulp macrophages., Competing Interests: Conflict of interest disclosure The authors declare no competing financial interests., (Copyright © 2021 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

In this study, laboratorial parameters of hospitalized novel coronavirus (COVID-19) patients, who were complicated with severe pneumonia, were compared with the findings of cytokine storm developing in macrophage activation syndrome (MAS)/secondary hemophagocytic lymphohistiocytosis (sHLH). Severe pneumonia occurred as a result of cytokine storm in some patients who needed intensive care unit (ICU), and it is aimed to determine the precursive parameters in this situation. Also in this study, the aim is to identify laboratory criteria that predict worsening disease and ICU intensification, as well as the development of cytokine storm. This article comprises a retrospective cohort study of patients admitted to a single institution with COVID-19 pneumonia. This study includes 150 confirmed COVID-19 patients with severe pneumonia. When they were considered as severe pneumonia patients, the clinic and laboratory parameters of this group are compared with H-score criteria. Patients are divided into two subgroups; patients with worsened symptoms who were transferred into tertiary ICU, and patients with stable symptoms followed in the clinic. For the patients with confirmed COVID-19 infection, after they become complicated with severe pneumonia, lymphocytopenia (55.3%), anemia (12.0%), thrombocytopenia (19.3%), hyperferritinemia (72.5%), hyperfibrinogenemia (63.7%) and elevated lactate dehydrogenase (LDH) (90.8%), aspartate aminotransaminase (AST) (31.3%), alanine aminotransaminase (ALT) (20.7%) are detected. There were no significant changes in other parameters. Blood parameters between the pre-ICU period and the ICU period (in which their situation had been worsened and acute respiratory distress syndrome [ARDS] was developed) were also compared. In the latter group lymphocyte levels were found significantly reduced (p = 0.01), and LDH, highly sensitive troponin (hs-troponin), procalcitonin, and triglyceride levels were significantly increased (p < 0.05). In addition, there was no change in hemoglobin, leukocyte, platelet, ferritin, and liver function test levels, including patients who developed ARDS, similar to the cytokine storm developed in MAS/sHLH. COVID-19 pneumonia has similar findings as hyperinflammatory syndromes but does not seem to have typical features as in cytokine storm developed in MAS/sHLH. In the severe patient group who has started to develop ARDS signs, a decrease in lymphocyte level in addition to the elevated LDH, hs-troponin, procalcitonin, and triglyceride levels can be a predictor in progression to ICU admission and could help in the planning of anti-cytokine therapy., (© 2021 Wiley Periodicals LLC.)

Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are viruses globally distributed that have been associated with the development and prognosis of many pathologies, including hematological diseases. This study aimed to characterize the epidemiological profile of EBV infection and the infection-correlated hepatic manifestations in patients with hematological diseases of the northern Brazilian state of Amazonas . A total of 228 patients were serologically tested for the presence of anti-EBV and anti-CMV IgG antibodies through an enzyme-linked immunosorbent assay. The coinfection with CMV, sociodemographic and laboratory records of all patients were also assessed. The overall prevalence observed among the study population for EBV infection and EBV/CMV coinfection was 85.09% (95% CI: 0.80-0.90) and 78.51% (95% CI: 0.73-0.84), respectively. The age group 31-40 years old were more susceptible to EBV/CMV coinfection (95% CI: 1.59-93.41, p = 0.011), while young people aged 1-10 years old were less affected for both EBV infection (CI 95%; 0.66-0.91, p = 0.001) and EBV/CMV coinfection (95% CI: 0.52-0.81, p < 0.0001). High serum levels of the liver biomarker ferritin were associated with EBV infection (95% CI: 1.03-1.54, p = 0.031) and EBV/CMV coinfection (95% CI: 1.02-1.70, p = 0.038). Our findings indicated that the elevated prevalence of EBV infection is not associated with the hematological diseases or transfusion rates, but with the socioeconomic status of the study population. Also, this study suggests that the EBV infection and its coinfection with CMV are related to the increase of serum ferritin levels.

Mature erythrocytes are the major metabolic regulators by transporting oxygen throughout the body. However, their precursors and progenitors defined as CD71+ Erythroid Cells (CECs) exhibit a wide range of immunomodulatory properties. Here, we uncover pronounced sexual dimorphism in CECs. We found female but not male mice, both BALB/c and C57BL/6, and human females were enriched with CECs. CECs, mainly their progenitors defined as CD45+CECs expressed higher levels of reactive oxygen species (ROS), PDL-1, VISTA, Arginase II and Arginase I compared to their CD45- counterparts. Consequently, CECs by the depletion of L-arginine suppress T cell activation and proliferation. Expansion of CECs in anemic mice and also post-menstrual cycle in women can result in L-arginine depletion in different microenvironments in vivo (e.g. spleen) resulting in T cell suppression. As proof of concept, we found that anemic female mice and mice adoptively transferred with CECs from anemic mice became more susceptible to Bordetella pertussis infection. These observations highlight the role of sex and anemia-mediated immune suppression in females. Notably, enriched CD45+CECs may explain their higher immunosuppressive properties in female BALB/c mice. Finally, we observed significantly more splenic central macrophages in female mice, which can explain greater extramedullary erythropoiesis and subsequently abundance of CECs in the periphery. Thus, sex-specific differences frequency in the frequency of CECs might be imprinted by differential erythropoiesis niches and hormone-dependent manner., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mashhouri, Koleva, Huynh, Okoye, Shahbaz and Elahi.)

Two β-globin allelic haplotypes (A and B) were identified in domestic sheep, wherein animals which are homozygous for β B allele (BB haplotype) have a deletion of pre-adult β C -globin and consequently are less tolerant to anemia and hypoxia. Since Haemonchus contortus infection, is associated with severe anemia, studies performed from 1960s to 1990s investigated the association between β-globin haplotype and resistance against this parasite. However, the findings were controversial, pointing out from increased resistance in animals harboring the β A allele to inexistence of association. Thus, our study aimed to develop a qPCR for β-globin haplotype identification, and to evaluate the association between β-globin haplotype and resistance against H. contortus in a group of sheep submitted to artificial infection with this parasite. A total of 286 lambs of Morada Nova breed were experimentally challenged with 4000 H. contortus L3 and monitored for 112 days from weaning. Significantly improved (p < 0.05) phenotypic profiles (lower fecal egg counts, higher packed cell volume and birthweight) were observed for AA haplotype animals, especially when compared to BB animals, while AB animals were similar to BB. This is the first report of a qPCR assay for ovine β-globin haplotype identification. In view of significant differences of phenotypic profiles between haplotype groups, the developed qPCR may constitute an important tool for sheep producers to improve genetic selection of parasite resistant animals., (Copyright © 2021 Elsevier B.V. All rights reserved.)

While umbilical cord blood is increasingly utilized as a stem cell source, immune complications associated with the procedure have been recognized. These complications result from significant immune system dysregulation and defective reconstitution following transplant causing an imbalance between T-cell subsets, aberrant B cells, and abnormal antibody production. This may occur up to 12 months after transplant coinciding with thymic regeneration in adults. The aim of our review is to describe the incidence, pathophysiology, clinical features, and prognosis of autoimmune cytopenias following umbilical cord blood transplant. Furthermore, we review the treatment strategies reported in the existing literature, describe the authors' experience with the complication, and highlight novel treatment options being studied. The knowledge of the occurrence and timing of autoimmune complications of umbilical cord blood transplantation is essential for detection and treatment of the disease. Emerging therapeutic options include interleukin-2 (IL-2), which is also being studied for the treatment of acute and chronic graft-versus-host disease. IL-2 has favorable effects on growth, differentiation, and function of regulatory T cells. Monoclonal antibody treatments, such as daratumumab, are also on the forefront and more experience with them will guide further treatment strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.)

This study investigated the frequency of and predictive factors for autoimmune lymphoproliferative syndrome (ALPS) in children with lymphoma, chronic immune cytopenia, and nonmalignant organomegaly. Thirty-four children with suspected ALPS (n=13, lymphoma; n=12, immune cytopenia; n=9, nonmalignant organomegaly) were included. Double-negative T-cells, lymphocyte apoptosis, and genetic findings were analyzed. Patients were stratified into two groups as proven/probable ALPS and clinically suspected patients according to the ALPS diagnostic criteria. Of the 34 patients, 18 (53%) were diagnosed with proven/probable ALPS. One patient had a mutation (c.652-2A>C) in the FAS gene. The remaining 16 (47%) patients were defined as clinically suspected patients. Predictive factors for ALPS were anemia and thrombocytopenia in patients with lymphoma, splenomegaly and lymphadenopathy in patients with immune cytopenia, and young age in patients with nonmalignant organomegaly. ALPS may not be rare in certain risk groups. Our study indicates that screening for ALPS may be useful in children having lymphoma with cytopenia at diagnosis, in those having nonmalignant organomegaly with immune cytopenia, and in those having chronic immune thrombocytopenic purpura or autoimmune hemolytic anemia with organomegaly developing during follow-up.

Background: The anti-M antibody can lead to hemolytic disease of the fetus and newborn (HDFN) and adverse fetal outcomes, especially in the Asian population. However, fetal erythropoiesis resulting from M alloimmunization needs further investigation., Study Design and Methods: We analyzed erythropoiesis in eight fetuses with M alloimmunization and compared them with the fetuses affected by anti-D. They were matched as pairs according to the gestational age of diagnosis and the hematocrit before treatment. Paired t-tests or paired Wilcoxon rank-sum tests were conducted to compare the difference in the cord blood indexes. Pearson correlation analysis was used to evaluate the correlativity between hematocrit and the reticulocyte percentage in the two groups., Results: The fetuses in the MN group had lower reticulocyte count and percentage than those in the RhD group (p < .05). All of the fetal reticulocyte production indexes (RPIs) in the MN group were less than 2, indicating an inadequate hemopoietic response to anemia, while the majority of the RPIs in the RhD group (85.7%) were significantly higher (p = .003), with 6 cases greater than 2.5. Hematocrit was negatively correlated with reticulocyte percentage (y = 54.7-171.7x, r 2  = 0.825, p = .005) in the RhD group, while no significant correlation was found in the MN group. No difference in the number of IUT, interval, or the fetal outcome was found between the two groups., Conclusion: Fetal reticulocytopenia provided direct evidence of an inadequate hemopoietic response in HDFN due to anti-M, leading to hyporegenerative anemia. Once the IgG component of anti-M is detected, close monitoring should be considered., (© 2021 AABB.)

Fetal anemia is common in malaria-endemic areas and a risk factor for anemia as well as mortality during infancy. Placental malaria (PM) and red cell abnormalities have been proposed as possible etiologies, but the relationship between PM and fetal anemia has varied in earlier studies, and the role of red cell abnormalities has not been studied in malaria-endemic areas. In a Tanzanian birth cohort study designed to elucidate the pathogenesis of severe malaria in young infants, we performed a cross-sectional analysis of risk factors for fetal anemia. We determined PM status, newborn red cell abnormalities, and maternal and cord blood levels of iron regulatory proteins, erythropoietin (EPO), cytokines and cytokine receptors. We examined the relationship between these factors and fetal anemia. Fetal anemia was present in 46.2% of the neonates but was not related to PM. Maternal iron deficiency was common (81.6%), most frequent in multigravidae, and interacted with parity to modify risk of fetal anemia, but it was not directly related to risk. Among offspring of iron-deficient women, the odds of fetal anemia increased with fetal α + -thalassemia, as well as these patterns of cord blood cytokines: increased cord IL-6, decreased TNF-RI, and decreased sTfR. The EPO response to fetal anemia was low or absent and EPO levels were significantly decreased in newborns with the most severe anemia. This study from an area of high malaria transmission provides evidence that 1) fetal α + -thalassemia and cytokine balance, but not PM at delivery, are related to fetal anemia; 2) maternal iron deficiency increases the risk that other factors may cause fetal anemia; and 3) fetal anemia has a multifactorial etiology that may require a variety of interventions, although measures that reduce maternal iron deficiency may be generally beneficial., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kabyemela, Fried, Kurtis, Moses, Gorres, Muehlenbachs and Duffy.)

Introduction: With the increasing use of checkpoint inhibitors, rare immune-related adverse events (irAE) are being identified. Haematological irAE (hem-irAE) are difficult to treat and have shown high mortality rates. In order to improve side-effect management for these potentially life-threatening events, we analysed frequency, severity and outcomes., Patients and Methods: Patients who developed hem-irAE while being treated with immune checkpoint inhibitors (ICI) therapy were retrospectively identified from 18 international cancer centres., Results: In total, more than 7626 patients treated with ICI were screened, and 50 patients with hem-irAE identified. The calculated incidence amounts to 0.6% and median onset was 6 weeks after the ICI initiation (range 1-128 weeks). Thrombocytopenia and leucopaenia were the most frequent hem-irAE with 34% (17/50) and 34% (17/50), respectively, followed by anaemia 28% (14/50), hemophagocytic lymphohistiocytosis (4% (2/50)), aplastic anaemia (2% (1/50)), acquired haemophilia A (2% (1/50)) and coagulation deficiency (2% (1/50)). Simultaneous thrombocytopenia and neutropenia occurred in two patients, concurrent anaemia and thrombocytopenia in one patient. Other than cessation of ICI (in 60%) and corticosteroids (in 78%), treatment included second-line immunosuppression in 24% of cases. Events resolved in 78% (39/50), while 18% (9/50) had persistent changes, and 2% (1/50) had fatal outcomes (agranulocytosis)., Conclusion: Hem-irAE can affect all haematopoietic blood cell lineages and may persist or even be fatal. Management may require immunosuppression beyond corticosteroids. Although these irAE are rare, treating physicians should be aware, monitor blood counts regularly and promptly act upon detection., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Rafaela Kramer: NoneZaremba Anne: Received travel support from Novartis, Genzyme and Bristol-Myers Squibb. Alvaro Moreira: Speaker's honoraria from AbbVie, Novartis, Bristol-Myers Squibb, Pfizer and Roche; consultant's honoraria from Almirall. Selma Ugurel: Selma Ugurel declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp and Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, and Merck Sharp and Dohme. Douglas Johnson: Advisory boards for Array Biopharma, BMS, Catalyst, Iovance, Jansen, Merck, Novartis, and research funding from BMS and Incyte. Jessica C. Hassel: honoraria from BMS, MSD, Roche, Novartis, Pfizer, Sanofi; consultant's honoraria from Pierre Faber, MSD, Sunpharma; science grant from BMS. Martin Salzmann: honoraria and travel grants from Abbvie, Bristol-Myers Squibb (BMS), Merck, Merck Sharp & Dohme (MSD), Novartis and Pfizer. Anja Gesierich: speaker's honoraria from Bristol-Myers Squibb, MSD Sharp and Dohme and Roche; Consultant's honoraria from Amgen, Bristol-Myers Squibb, Novartis, MSD Sharp and Dohme, Pierre Fabre Pharmaceuticals, Pfizer, Roche and Sanofi Genzyme; travel support from Bristol-Myers Squibb, MSD Sharp and Dohme, Novartis, Pierre Fabre Pharmaceuticals and Roche. Clinical studies: Amgen, Array, Bristol-Myers Squibb, GSK, Novartis, Merck, MSD Sharp and Dohme, Pfizer and Roche. Alisonn Weppler: none. Lavinia Spain: Honoraria from Bristol-Myers Squibb for Advisory Boards Carmen Loquai: Advisory board, speakers fee, travel reimbursement: Roche, Pierre Fabre, Novartis, BMS, Merck, MSD, Biontech, Almiral Hermal, Kyowa Kirin, Sun Pharma, Sanofi Milena Dudda: none. Claudia Pföhler: Consultancy, speaker fees, travel grants: BMS, MSD, Merck, Roche, Amgen, GSK, Novartis, Sanofi Genzyme, Pierre Fabre, LEO. Clinical studies: Novartis, BMS. Adriana Hepner: AH is employee of AstraZeneca with stock options in the company, has received honoraria from Novartis and travel expenses from Roche. Georgina V. Long: consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Highlight Therapeutics S.L., Merck Sharpe and Dohme, Novartis Pharma AG, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDX B.V. Alexander Menzies: advisory board BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics Matteo S. Carlino: MSC has served on advisory boards for Bristol-Myers Squibb, MSD, Amgen, Novartis, Pierre Fabre, Roche, Sanofi, Merck, Ideaya, Regeneron, Nektar, Eisai and honoraria from Bristol-Myers Squibb, MSD, Novartis Michael M. Sachse: Speaker fees: Roche, MSD, Novartis Céleste Lebbé: Consultancy, speaker fees, travel grants or research funding: BMS, MSD, Merck, Roche, Amgen, Novartis, Sanofi, Pierre Fabre. Clinical studies: BMS, MSD, Merck, Sanofi, Incyrte, Roche, Amgen, GSK, Curevac, Genentech and Novartis Barouyr Baroudjian: Consultancy, speaker fees, travel grants: BMS, MSD, Novartis, Pierre Fabre Tomohiro Enokida: none. Makoto Tahara: reports grants and personal fees from Ono Pharmaceutical, grants and personal fees from MSD, grants and personal fees from BMS, during the conduct of the study; grants and personal fees from Bayer, grants and personal fees from Eisai, grants and personal fees from Merck serono, personal fees from LOXO, grants and personal fees from Pfizer, grants and personal fees from Rakuten Medical, personal fees from Celgene, personal fees from Amgen, grants and personal fees from Novartis, outside the submitted work. Max Schlaak: Consultancy, speaker fees or travel grants: BMS, MSD, Roche, Kyowa Kirin, Novartis, Sanofi Genzyme, Pierre Fabre, Sun Pharma Kinan Hayani: none. Paul Bröckelmann: PJB declares honoraria and non-financial support by Bristol-Myers Squibb and research funding by Bristol-Myers Squibb and MSD Sharp and Dohme. Friedegund Meier: F.M. has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche. Lydia Reinhardt: none. Philip Friedlander: none. Thomas Eigentler: received fees for advisory boards from Roche, Novartis, MSD, BMS, Sanofi and Philogen Katharina C. Kähler: serves as consultant to Roche, BMS, MSD, Pierre Fabre and received travel grants and speaker fees from Roche, BMS, MSD, Amgen, Pierre Fabre and Philogen. Lisa Zimmer: LZ has received honoraria from Roche, Bristol-Myers Squibb, Merck Sharp and Dohme, Novartis, Pierre Fabre, research funding from Novartis and has served on advisory boards for Bristol-Myers Squibb, Novartis, Pierre Fabre, Sunpharma, Sanofi, Merck Sharp and Dohme; travel support: Bristol-Myers Squibb, Pierre Fabre, Sanofi, Amgen, Novartis, Sunpharma Lucie Heinzerling: Consultancy, speaker fees, travel grants or research funding: BMS, MSD, Merck, Roche, Amgen, Curevac, Novartis, Sanofi, Pierre Fabre. Clinical studies: BMS, MSD, Merck, Roche, Amgen, GSK, Curevac and Novartis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Patients with myelodysplastic syndromes (MDSs) display severe anemia but the mechanisms underlying this phenotype are incompletely understood. Right open-reading-frame kinase 2 (RIOK2) encodes a protein kinase located at 5q15, a region frequently lost in patients with MDS del(5q). Here we show that hematopoietic cell-specific haploinsufficient deletion of Riok2 (Riok2 f/+ Vav1 cre ) led to reduced erythroid precursor frequency leading to anemia. Proteomic analysis of Riok2 f/+ Vav1 cre erythroid precursors suggested immune system activation, and transcriptomic analysis revealed an increase in p53-dependent interleukin (IL)-22 in Riok2 f/+ Vav1 cre CD4 + T cells (T H 22). Further, we discovered that the IL-22 receptor, IL-22RA1, was unexpectedly present on erythroid precursors. Blockade of IL-22 signaling alleviated anemia not only in Riok2 f/+ Vav1 cre mice but also in wild-type mice. Serum concentrations of IL-22 were increased in the subset of patients with del(5q) MDS as well as patients with anemia secondary to chronic kidney disease. This work reveals a possible therapeutic opportunity for reversing many stress-induced anemias by targeting IL-22 signaling.

Inflammation in chronic kidney disease (CKD) is mostly due to activation of the innate immune system, in which Interleukin-1 (IL-1) is a key player. Anemia of CKD may also be due to erythropoietin (EPO) resistance, clinically associated with inflammation. IL-1 receptor antagonist knockout (RaKO) mice show arthritis and excessive inflammation. Inhibition of IL-1 was shown to be beneficial in many inflammatory conditions, but its role in CKD and anemia is unknown. Here, we report that enhanced inflammation in RaKO mice with CKD provoked both higher degrees of renal insufficiency and anemia in comparison to wild-type CKD, in association with a downregulation of renal hypoxia inducible factor-2 (HIF2) as well as decreased bone marrow EPO-receptor (EPOR) and transferrin receptor (TFR). In contrast, administration of P2D7KK, an anti-IL1b monoclonal antibody, to CKD mice results in a lower grade of systemic inflammation, better renal function and blunted anemia. The latter was associated with upregulation of renal HIF-2α, bone marrow EPO-R and TFR. Altogether, this supports the key role of inflammation, and IL-1 particularly, in CKD progression and anemia. Novel treatments to reduce inflammation through this and other pathways, may improve renal function, attenuate the anemic state or increase the response to exogenous EPO.

Foot electrical stimulation (FES) has been considered as a classic stressor that can disturb homeostasis. Acute anemia was observed in the model induced by FES. The aim of this study was to explore the role of inflammatory cytokines underlying the acute anemia and gastrointestinal (GI) mucosal injury in the FES. Twenty-four male Kunming mice (20 ± 2 g) were randomly divided into control group and experimental group. The mice were placed in a footshock chamber that can generate 0.5 mA electrical impulse periodically for 0.5 h. After the process, red blood cell count, hemoglobin concentration and hematocrit, the levels of corticotropin releasing hormone (CRH) in serum and hypothalamus, and adrenocorticotropic hormone (ACTH) in serum and pituitary were detected separately. In addition, we investigated the expressions of inflammatory cytokines (IL-1, IL-6, TNF-α, iNOS, and IL-10) in the hypothalamus and duodenum by Polymerase Chain Reaction (PCR). Results showed that this FES model induced anemia, increased CRH and ACTH activity in the serum after the FES. Moreover, the expressions of IL-1β, IL-6, TNF-α, and iNOS were significantly increased following the process, while IL-10 was not activated. These findings suggest that anemia, the inflammatory cytokines in the hypothalamus and duodenum of the mice in the model induced by FES is closely related to GI mucosal injury/bleeding. Taken together, these results underscore the importance of anemia, GI mucosal injury/bleeding and stress, future studies would be needed to translate these findings into the benefit of affected patients.

Pregnancy-associated malaria (PAM) caused by Plasmodium falciparum can result in detrimental outcomes for both mother and infant, including low infant birth weight, preterm birth, maternal anemia, spontaneous abortion, and maternal and/or infant mortality. Maternal anemia is a particularly complex outcome, as the body must both maintain erythropoiesis and tolerance of the growing fetus, while directing a Th1 response against the parasite. Underlying the pathogenesis of PAM is the expression of variant surface antigens (VSA PAM ) on the surface of infected red blood cells (iRBC) that mediate sequestration of the iRBC in the placenta. Naturally acquired antibodies to VSA PAM can block sequestration and activate opsonic phagocytosis, both associated with improved pregnancy outcomes. In this review, we ask whether VSA PAM antibodies can also protect mothers against malarial anemia. Studies were identified where VSA PAM antibody titres and/or function were associated with higher maternal hemoglobin levels, thus supporting additional protective mechanisms for these antibodies against PAM. Yet these associations were not widely observed, and many studies reported no association between protection from maternal anemia and VSA PAM antibodies. We discuss the epidemiological, biological and technical factors that may explain some of the variability among these studies. We appraise the current evidence of these complex interactions between PAM-specific immunity and maternal anemia, propose potential mechanisms, and discuss knowledge gaps., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with one of the authors, SY., (Copyright © 2020 Wiebe and Yanow.)

Infection from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), though mainly a respiratory disease, can impair many systems, including causing hematological complications. Lymphopenia and hypercoagulability have been reported in adults with coronavirus disease 2019 (COVID-19) and are considered markers of poor prognosis. This review summarizes the hematological findings in children with SARS-CoV-2 infection. The majority of infected children had a normal leukocyte count, while the most common white blood cell abnormality was leukopenia. Lymphopenia, which may be a marker of severe disease, was rarer in children than in adults, possibly due to their immature immune system or due to the less severe manifestation of COVID-19 in this age group. Age may have an impact, and in neonates and infants the most common abnormality was lymphocytosis. Abnormalities of red blood cells and platelets were uncommon. Anemia and hypercoagulability were reported mainly in children presenting the novel multisystem inflammatory syndrome (MIS) associated with SARS-CoV-2., (© 2020 Wiley Periodicals LLC.)

Anemia of inflammation (AI) is the second most prevalent anemia after iron deficiency anemia and results in persistent low blood erythrocytes and hemoglobin, fatigue, weakness, and early death. Anemia of inflammation is common in people with chronic inflammation, chronic infections, or sepsis. Although several studies have reported the effect of inflammation on stress erythropoiesis and iron homeostasis, the mechanisms by which inflammation suppresses erythropoiesis in the bone marrow (BM), where differentiation and maturation of erythroid cells from hematopoietic stem cells (HSCs) occurs, have not been extensively studied. Here we show that in a mouse model of acute sepsis, bacterial lipopolysaccharides (LPS) suppress medullary erythroblastic islands (EBIs) and erythropoiesis in a TLR-4- and MyD88-dependent manner with concomitant mobilization of HSCs. LPS suppressive effect on erythropoiesis is indirect as erythroid progenitors and erythroblasts do not express TLR-4 whereas EBI macrophages do. Using cytokine receptor gene knock-out mice LPS-induced mobilization of HSCs is G-CSF-dependent whereas LPS-induced suppression of medullary erythropoiesis does not require G- CSF-, IL- 1-, or TNF-mediated signaling. Therefore suppression of medullary erythropoiesis and mobilization of HSCs in response to LPS are mechanistically distinct. Our findings also suggest that EBI macrophages in the BM may sense innate immune stimuli in response to acute inflammation or infections to rapidly convert to a pro-inflammatory function at the expense of their erythropoietic function., (Copyright © 2020 Bisht, Tay, Wellburn, McGirr, Fleming, Nowlan, Barbier, Winkler and Levesque.)

Anemia in women of reproductive age is highly prevalent globally and remains a public health problem. In Ethiopia, despite efforts to minimize the burden of anemia, it is still a moderate public health problem. Anemia has various etiologies including nutritional deficiency, parasitic infection, and inflammation. The aim of this study was to examine contributing factors to anemia in lactating women. Following ethical approval, and six months after delivery, all lactating women (n = 150) were recruited to participate in this study from eight randomly selected rural villages. Anthropometric and socio-economic factors were assessed. From each, a blood sample was collected for measuring hemoglobin, iron biomarkers, zinc, selenium, and inflammation markers. The median (IQR) hemoglobin (Hb) was 132 (123, 139) g/L. Of the women, 19% were anemic and 7% had iron deficiency anemia; 31% were iron deficient and 2% had iron overload. Also, 8% had functional iron deficit, 6% had acute inflammation, 13% had chronic inflammation, and 16% had tissue iron deficiency. The majority (78%) of the women had low plasma zinc out of which more than 16% were anemic. Hb was positively associated with plasma iron and plasma zinc and negatively associated with transferrin receptor (TfR) and α-1-acid glycoprotein (AGP). Plasma iron, AGP, TfR, hepcidin and plasma zinc were significant predictors of maternal anemia. Additionally MUAC and level of education were associated positively with maternal hemoglobin. This study showed that maternal anemia was associated with multiple factors including nutritional deficiencies, inflammation and limited education., Competing Interests: The authors have declared that no competing interests exist.

Autoantibodies play an important role in the destruction of non-infected red blood cells (nRBCs) during malaria. However, the relationship between this clearance and ABO blood groups is yet to be fully enlightened, especially for Plasmodium vivax infections. Here we show that anti-RBC IgG and IgM are increased in anemic patients with acute vivax malaria. Furthermore, both antibodies are able to decrease the deformability of nRBCs, but only IgG can induce in vitro erythrophagocytosis. Such effects are enhanced in type O erythrocytes, suggesting that individuals from this blood group infected with P. vivax malaria may be more susceptible to develop anemia., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests., (Copyright © 2020 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

Malaria during pregnancy is a major cause of maternal morbidity as well as fetal and neonatal mortality. Previous studies, including our own, suggested that placental and peripheral cytokine and chemokine levels measured at delivery can be used as biomarkers for pregnancy outcomes. However, the timing of malaria infection during pregnancy matters, and these studies do not address the effect of different cytokines in peripheral blood plasma samples taken at early and midpregnancy and at delivery. Here, we aimed to investigate whether peripheral plasma cytokine levels were associated with pregnancy outcomes in a cohort of 400 Beninese pregnant women. Using a high-sensitivity cytometry-based method, we quantified the levels of interleukin-4 (IL-4), IL-5, IL-10, IL-12p70, and gamma interferon (IFN-γ) in peripheral plasma samples taken at two time points during pregnancy and at delivery in various groups of pregnant women identified with Plasmodium falciparum infection, with anemia, with preterm births, or giving birth to babies who are small for their gestational age. We found that, consistently at all time points, elevated levels of IL-10 were strongly and significantly associated with P. falciparum infection, while the levels of IFN-γ at inclusion and delivery were weakly but also significantly associated. Low levels of IL-5 at delivery were associated with a greater risk of both preterm births and small-for-gestational-age babies. The immunosuppressive effects of IL-10 likely affect the overall cytokine equilibrium during pregnancy in women harboring P. falciparum infections. Our findings highlight the peripheral signature of pregnancy outcomes and strengthen the idea of using cytokines as diagnostic or prognostic markers., (Copyright © 2020 American Society for Microbiology.)

Malaria caused by Plasmodium vivax is a highly prevalent infection world-wide, that was previously considered mild, but complications such as anemia have been highly reported in the past years. In mice models of malaria, anti-phosphatidylserine (anti-PS) autoantibodies, produced by atypical B-cells, bind to uninfected erythrocytes and contribute to anemia. In human patients with P. falciparum malaria, the levels of anti-PS, atypical B-cells and anemia are strongly correlated to each other. In this study, we focused on assessing the relationship between autoantibodies, different B-cell populations and hemoglobin levels in two different cohorts of P. vivax patients from Colombia, South America. In a first longitudinal cohort, our results show a strong inverse correlation between different IgG autoantibodies tested (anti-PS, anti-DNA and anti-erythrocyte) and atypical memory B-cells (atMBCs) with hemoglobin in both P. vivax and P. falciparum patients over time. In a second cross-sectional cohort, we observed a stronger relation between hemoglobin levels, atMBCs and autoantibodies in complicated P. vivax patients compared to uncomplicated ones. Altogether, these data constitute the first evidence of autoimmunity associating with anemia and complicated P. vivax infections, suggesting a role for its etiology through the expansion of autoantibody-secreting atMBCs., Competing Interests: The authors have declared that no competing interests exist.

Background: Tislelizumab is an investigational, humanized, IgG4 monoclonal antibody with high affinity and binding specificity for programmed cell death-1 (PD-1) that was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy., Methods: The purpose of this phase 1/2, open-label, non-comparative study was to examine the safety, tolerability, and antitumor activity of tislelizumab in adult (≥18 years) Chinese patients with histologically or cytologically confirmed advanced solid tumors with measurable disease. The phase 1 portion of the study consisted of a dose-verification study and a pharmacokinetic (PK) substudy; phase 2 was an indication-expansion study including 11 solid tumor cohorts. Patients previously treated with therapies targeting PD-1 or its ligand, programmed cell death ligand-1 were excluded. During dose-verification, dose-limiting toxicities (DLTs) were monitored; safety and tolerability were examined and the previously determined recommended phase 2 dose (RP2D) was verified. The primary endpoint of phase 2 was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors V.1.1., Results: As of December 1, 2018, 300 patients were treated with tislelizumab 200 mg intravenously once every 3 weeks (Q3W). Median duration of follow-up was 8.1 months (range 0.2-21.9). No DLTs were reported during the phase 1 dose-verification study and the RP2D was confirmed to be 200 mg intravenously Q3W. Most treatment-related adverse events (62%) were grade 1 or 2, with the most common being anemia (n=70; 23%) and increased aspartate aminotransferase (n=67; 22%). Of the 251 efficacy evaluable patients, 45 (18%) achieved a confirmed clinical response, including one patient from the PK substudy who achieved a complete response. Median duration of response was not reached for all except the nasopharyngeal carcinoma cohort (8.3 months). Antitumor responses were observed in multiple tumor types., Conclusions: Tislelizumab was generally well tolerated among Chinese patients. Antitumor activity was observed in patients with multiple solid tumors., Trial Registration Number: CTR20160872., Competing Interests: Competing interests: LS, JG, QZ, HP, YY, YB, TL, QZ, JZ, YS, XH, SW, JW, AZ, DY, TS, and Y-LW have nothing to declare. YG, SY, ZW, and JL are employees of BeiGene., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Autoimmune hemolytic anemia (AIHA) is a rare comorbidity in colorectal cancer (CRC) and has an unknown etiology. Previously, we described an AIHA case secondary to CRC with ectopic band 3 expression. Herein, we investigated ectopic band 3 expression and erythrocyte membrane-bound IgG in a CRC cohort. Between September 2016 and August 2018, 50 patients with CRC and 26 healthy controls were enrolled in the present study. The expression of band 3 and SLC4A1 mRNA was observed in 97% of CRC surgical specimens. Although clinical AIHA was not observed in any patient with CRC, a direct antiglobulin test was positive in 10 of the patients in the CRC group (p = 0.01). Flow cytometry revealed significantly increased erythrocyte membrane-bound IgG among patients with CRC compared to healthy controls (mean ± standard deviation; 38.8 ± 4.7 vs. 29.9 ± 15.6, p = 0.012). Normocytic anemia was observed, including in cases negative for fecal occult blood, suggesting a shortened erythrocyte life-span due to increased membrane-bound IgG. Immunoprecipitation revealed increased anti-band 3 autoantibodies in patients' sera. Mouse experiments recapitulated this phenomenon. We also confirmed that band 3 expression is controlled by 5'AMP-activated protein kinase under hypoxic conditions. These findings increase our understanding of the etiology of cancer-related anemia.

Background: Inflammatory cytokines, such as interleukin (IL)-1β, alter iron homeostasis and erythropoiesis, resulting in anemia, but whether inhibition of IL-1β can reverse these effects is unclear., Objective: To determine whether IL-1β inhibition with canakinumab reduces incident anemia and improves hemoglobin levels among those with prevalent anemia., Design: Exploratory analysis of a randomized controlled trial. (ClinicalTrials.gov: NCT01327846)., Setting: Many clinical sites in 39 countries., Participants: 8683 CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) participants without anemia at trial entry and 1303 with prevalent anemia at trial entry., Intervention: Random assignment to receive placebo or canakinumab (50, 150, or 300 mg) subcutaneously once every 3 months., Measurements: Primary outcome was incident anemia (hemoglobin level <130 g/L in men or <120 g/L in women)., Results: Anemia incidence increased with rising baseline levels of high-sensitivity C-reactive protein (hsCRP), and both hsCRP and IL-6 decreased among participants receiving canakinumab compared with the placebo group. During a median follow-up of 3.7 years, participants without baseline anemia who received canakinumab at any dosage had significantly less incident anemia than those who received placebo (hazard ratio, 0.84 [95% CI, 0.77 to 0.93]; P < 0.001). Compared with placebo, the greatest benefits of IL-1β inhibition on incident anemia were observed among participants with the most robust anti-inflammatory response, an effect corroborated in formal mediation analyses. Among those with baseline anemia, canakinumab increased mean hemoglobin levels by 11.3 g/L (P < 0.001) compared with placebo after 2 years of treatment. Canakinumab increased the risk for infection and was associated with mild cases of thrombocytopenia and neutropenia, none of which was grade 3 or higher., Limitation: CANTOS was not designed to assess the cause of anemia in individual trial participants., Conclusion: These exploratory analyses of randomized trial data provide proof of principle that inflammation inhibition, at least through the IL-1β/IL-6 signaling pathway, reduces the incidence of anemia and improves hemoglobin levels in patients with anemia., Primary Funding Source: Novartis Pharmaceuticals.

Anemia is associated with impairment in oxygen transport, affecting an individual's physical and mental wellbeing, and work performance. The aim of this study was to examine the prevalence of anemia and its possible association with serum antibody titers to Hsp27 (as an indicator of cellular stress), cognitive function, measures of emotion, and sleep patterns in adolescent girls. A total of 940 adolescent girls were assessed to evaluate neuropsychological function with validated questionnaires. A complete blood count was determined as part of the assessment of hematological parameters. Serum anti-Hsp27 was measured for each subject. Among the total of 940 participants, 99 girls (10.5%) were anemic [hemoglobin <12(g/dL)]. Serum anti-HSP27 was significantly higher in anemic compared to healthy girls ( p  < 0.05). There was no significant differences in depression, aggression, insomnia, daytime sleepiness and sleep apnea score between two groups. However, the total cognitive abilities score was significantly lower in the anemic girls (76.8 ± 2.1 vs. 85.7 ± 2.5, p  = 0.002). Logistic regression analysis showed that anemic girls were 1.73 times more likely than nonanemic girls to have cognitive impairment (95% confidence interval [CI] = 1.07-2.78; P  = 0.025). Anemia was associated with elevated levels of anti-HSP27 and supports the hypothesis that cellular stress may be associated with anemia. Anemia was adversely associated with an assessment of cognitive abilities and was an independent risk factor for cognitive impairment in this group.

Background: The accurate estimation of zinc deficiency at the population level is important, as it guides the design, targeting, and evaluation of nutrition interventions. Plasma or serum zinc concentration (PZC) is recommended to estimate zinc nutritional status; however, concentrations may decrease in the presence of inflammation., Objectives: We aimed to assess the relation between PZC and inflammation in preschool children (PSC; 6-59 mo) and nonpregnant women of reproductive age (WRA; 15-49 y), and to compare different inflammation adjustment approaches, if adjustment is warranted., Methods: Cross-sectional data from 13 nationally representative surveys (18,859 PSC, 22,695 WRA) from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project were analyzed. Correlation and decile analyses were conducted, and the following 3 adjustment methods were compared if a consistent negative association between PZC and C-reactive protein (CRP) or α-1-acid glycoprotein (AGP) was observed: 1) exclude individuals with CRP > 5 mg/L or AGP > 1 g/L; 2) apply arithmetic correction factors; and 3) use the BRINDA regression correction (RC) approach., Results: In 6 of 12 PSC surveys, the estimated prevalence of zinc deficiency increased with increasing CRP deciles, and to a lesser extent, with increasing AGP deciles. In WRA, the association of PZC with CRP and AGP was weak and inconsistent. In the 6 PSC surveys in which adjustment methods were compared, application of RC reduced the estimated prevalence of zinc deficiency by a median of 11 (range: 4-18) percentage points, compared with the unadjusted prevalence., Conclusions: Relations between PZC and inflammatory markers were inconsistent, suggesting that correlation and decile analyses should be conducted before applying any inflammation adjustments. In populations of PSC that exhibit a significant negative association between PZC and CRP or AGP, application of the RC approach is supported. At this time, there is insufficient evidence to warrant inflammation adjustment in WRA., (Copyright © The Author(s) 2020.)

Background: There are conflicting data regarding angiotensin receptor blockers (ARBs) induced anemia and its beneficial anti-inflammatory effect in rheumatoid arthritis. The aim of the present study was to investigate the effect of telmisartan administration either alone or in combination with etanercept on anemia of chronic inflammatory diseases in a model of rheumatoid arthritis in rats., Methods: Rheumatoid arthritis (RA) was induced by Freund's Complete Adjuvant (FCA; 1 mg/0.1 ml paraffin oil), injected subcutaneously on days 0, 30 and 40. Rats with RA received dimethyl sulfoxide (DMSO), etanercept (0.3 mg/kg 3 times/week; sc), telmisartan (1.5 mg/kg/day; orally) or combination of etanercept and telmisartan. Arthritis parameters (footpad circumference change and paw volume change), erythrocyte indices (hemoglobin, mean corpuscular volume and mean corpuscular hemoglobin level changes), iron profile (serum iron and serum ferritin), serum levels of erythropoietin (EPO), hepcidin, tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 were evaluated, along with measuring serum urea and creatinine levels., Results: All treated groups showed improvement of the measured parameters in comparison to RA-control subgroup. Telmisartan either alone or in combination with etanercept significantly improved arthritis and erythrocyte indices. Telmisartan showed significant increase in EPO and decrease in hepcidin compared to etanercept. Combination group showed significant improvement in serum iron, ferritin, EPO, hepcidin, TNF-α, IL-6, urea and creatinine, compared to etanercept. Telmisartan either alone or in combination, but not etanercept alone, significantly decreased creatinine level., Conclusion: Telmisartan improved anemia and arthritis parameters and showed anti-inflammatory and reno-protective effects, in a rat model of rheumatoid arthritis.

Background: Vitamin B-12 and folate deficiencies in women and children have important public health implications. However, the evidence is conflicting and limited on whether the influence of inflammation on biomarker concentrations may be sufficiently and consistently influenced by inflammation to require adjustment for interpreting concentrations or estimating population prevalence of deficiencies., Objective: We examined correlations between concentrations of the inflammation biomarkers C-reactive protein (CRP) and α1-acid glycoprotein (AGP) and serum vitamin B-12 and serum and RBC folate among nonpregnant women of reproductive age (WRA; 15-49 yr) and preschool children (PSC; 6-59 mo)., Methods: We analyzed cross-sectional data from 16 nationally representative nutrition surveys conducted in WRA (n = 32,588) and PSC (n = 8,256) from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia project. Spearman correlations between CRP or AGP and vitamin B-12 or folate concentrations were examined, taking into account complex survey design effects., Results: Correlations between inflammation and vitamin B-12 or folate were weak, with no clear pattern of association in either WRA or PSC. Correlation coefficients between CRP and vitamin B-12 for WRA and PSC ranged from -0.25 to 0.16, and correlations between AGP and vitamin B-12 ranged between -0.07 and 0.14. Similarly, correlations between CRP and serum folate ranged from -0.13 to 0.08, and correlations between AGP and serum folate between -0.21 and 0.02. Only 3 surveys measured RBC folate, and among them, correlations for WRA ranged from -0.07 to 0.08 for CRP and -0.04 for AGP (1 country)., Conclusions: Based on the weak and inconsistent correlations between CRP or AGP and vitamin B-12 or folate biomarkers, there is no rationale to adjust for inflammation when estimating population prevalence of vitamin B-12 or folate deficiencies in WRA or PSC., (Copyright © The Author(s) 2020.)

Background: Parvovirus B19 (B19) has tropism for cells of the erythroid lineage, which may lead to transient inhibition of erythropoiesis. Several studies and case reports suggested that B19 infection may contribute significantly to severe chronic anemia in HIV infected persons., Objective: To detect parvovirus B19 DNA in treatment-naïve HIV patients., Methods: This was a case control retrospective study. One hundred nineteen anemic and 81 non-anemic treatment-naïve HIV infected patients participated in the study at the Lagos University Teaching Hospital, Lagos, Nigeria. Polymerase chain reaction was used to detect B19 DNA., Results: Out of 200 patients analysed, 13(6.5%) had parvovirus B19 DNA. Eight HIV patients with anemia had B19 DNA while five non-anemic HIV patients had B19 DNA. This suggests that the presence of B19 DNA in the blood of HIV positive individuals may contribute to anemia because the majority (61.5%) who were positive for B19 DNA had anemia as compared to the non-anemic control group (38.5%)., Conclusion: This study shows that the presence of B19 DNA in anemic HIV infected patients is not associated with chronic anaemia in HIV infection because no significant association exist., (© 2020 Ashaka OS et al.)

Severe anemia is a major cause of death by malaria. The loss of uninfected erythrocytes is an important contributor to malarial anemia; however, the mechanisms underlying this pathology are not well understood. Malaria-induced anemia is related to autoimmune antibodies against the membrane lipid phosphatidylserine (PS). In mice, these antibodies induce the clearance of uninfected erythrocytes after binding to PS exposed in their membrane. In human malaria patients there is a strong correlation between anemia and anti-PS antibodies. During malaria, anti-PS antibodies are produced by atypical B cells, whose levels correlate with the development of anemia in patients. Autoimmune responses, which are documented frequently in different infections, contribute to the pathogenesis of malaria by inducing the clearance of uninfected erythrocytes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: A decreased response to erythropoiesis-stimulating agents (ESAs) leads to refractory anemia and worse prognosis in patients with chronic kidney disease. We examined the association between autoantibodies to the erythropoietin receptor (EPOR) and responsiveness to ESAs in patients on maintenance hemodialysis., Methods: A total of 108 Japanese patients on maintenance hemodialysis at three institutions were enrolled. Sera from these patients were screened for anti-EPOR antibodies using an enzyme-linked immunosorbent assay. An ESA resistance index (ERI) was calculated, and patients in the highest ERI quartile were defined as ESA hyporesponsive., Results: Anti-EPOR antibodies were detected in 11 patients (10%). Body mass index and hemoglobin, platelet, magnesium, and ferritin levels decreased with higher ERI levels. On the other hand, C-reactive protein (CRP) levels and the prevalence of anti-EPOR antibodies increased with higher ERI levels. In multivariate analysis, the presence of anti-EPOR antibodies together with CRP was a significant risk factor for ESA hyporesponsiveness., Conclusions: Anti-EPOR antibodies were detected in patients on maintenance hemodialysis, and these autoantibodies were independent factors for hyporesponsiveness to ESAs in these patients.

Nanoparticles are becoming an increasingly popular tool for biomedical imaging and drug delivery. While the prevalence of nanoparticle drug-delivery systems reported in the literature increases yearly, relatively little translation from the bench to the bedside has occurred. It is crucial for the scientific community to recognize this shortcoming and re-evaluate standard practices in the field, to increase clinical translatability. Currently, nanoparticle drug-delivery systems are designed to increase circulation, target disease states, enhance retention in diseased tissues, and provide targeted payload release. To manage these demands, the surface of the particle is often modified with a variety of chemical and biological moieties, including PEG, tumor targeting peptides, and environmentally responsive linkers. Regardless of the surface modifications, the nano-bio interface, which is mediated by opsonization and the protein corona, often remains problematic. While fabrication and assessment techniques for nanoparticles have seen continued advances, a thorough evaluation of the particle's interaction with the immune system has lagged behind, seemingly taking a backseat to particle characterization. This review explores current limitations in the evaluation of surface-modified nanoparticle biocompatibility and in vivo model selection, suggesting a promising standardized pathway to clinical translation., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Monocytes are plastic heterogeneous immune cells involved in host-parasite interactions critical for malaria pathogenesis. Human monocytes have been subdivided into three populations based on surface expression of CD14 and CD16. We hypothesised that proportions and phenotypes of circulating monocyte subsets can be markers of severity or fatality in children with malaria. To address this question, we compared monocytes sampled in children with uncomplicated malaria, severe malarial anaemia, or cerebral malaria. Flow cytometry was used to distinguish and phenotype monocyte subsets through CD14, CD16, CD36 and TLR2 expression. Data were first analysed by univariate analysis to evaluate their link to severity and death. Second, multinomial logistic regression was used to measure the specific effect of monocyte proportions and phenotypes on severity and death, after adjustments for other variables unrelated to monocytes. Multivariate analysis demonstrated that decreased percentages of non-classical monocytes were associated with death, suggesting that this monocyte subset has a role in resolving malaria. Using univariate analysis, we also showed that the role of non-classical monocytes involves a mostly anti-inflammatory profile and the expression of CD16. Further studies are needed to decipher the functions of this sub-population during severe malaria episodes, and understand the underlying mechanisms.

Anemia is one of the most common complications in patients with inflammatory bowel disease (IBD). Hepcidin as a key regulator of iron metabolism is pivotal in mediating the occurrence of anemia of chronic disease. Herein, we analyzed the levels of hepcidin in sera from IBD patients by enzyme-linked immunosorbent assay and investigated its potential role in regulating the anemia in IBD. We observed that the levels of serum hepcidin were increased in active IBD patients compared with those in remitted IBD patients and healthy controls and that serum hepcidin was associated with disease activity, CRP, and ESR, respectively. Importantly, we found that the increased levels of serum hepcidin were positively correlated with the severity of anemia and the imbalance of iron metabolism in anemic UC and CD patients. Proinflammatory factors (e.g., IL-6, IL-17, and TNF- α ) were positively correlated with the concentrations of serum hepcidin in IBD patients. Interestingly, hepcidin was found to be decreased in patients with Crohn's disease after successful therapy with anti-TNF- α mAb (i.e., infliximab), indicating the underlying association between TNF- α and hepcidin expression. To investigate the specific mechanisms involved, we cultured LO2 and HepG2 cell lines in vitro under stimulation with TNF- α and observed that the levels of hepcidin mRNA were markedly upregulated in caspase-3/8- and NF- κ B-dependent manners. Therefore, our data suggest that TNF- α stimulates the expression of hepcidin in IBD patients, resulting in aggravated anemia and that blockage of TNF- α or the caspase-3/8 and NF- κ B pathways could downregulate hepcidin expression. This study provides inspiration for the therapy and management of anemia in IBD., Competing Interests: The authors declare no competing financial interests., (Copyright © 2019 Weigang Shu et al.)

Anemia is a common complication of malaria that is characterized by the loss of infected and uninfected erythrocytes. In mouse malaria models, clearance of uninfected erythrocytes is promoted by autoimmune anti-phosphatidylserine (PS) antibodies produced by T-bet + B-cells, which bind to exposed PS in erythrocytes, but the mechanism in patients is still unclear. In Plasmodium falciparum patients with anemia, we show that atypical memory FcRL5 + T-bet + B-cells are expanded and associate both with higher levels of anti-PS antibodies in plasma and with the development of anemia in these patients. No association of anti-PS antibodies or anemia with other B-cell subsets and no association of other antibody specificities with FcRL5 + T-bet + B-cells is observed, revealing high specificity in this response. We also identify FcRL5 + T-bet + B-cells as producers of anti-PS antibodies in ex vivo cultures of naïve human peripheral blood mononuclear cells (PBMC) stimulated with P.-falciparum -infected erythrocyte lysates. These data define a crucial role for atypical memory B-cells and anti-PS autoantibodies in human malarial anemia., Competing Interests: JR, MM, TJ, JS, TR, AR No competing interests declared, (© 2019, Rivera-Correa et al.)

Myelodysplastic syndromes (MDS) are biologically and clinically heterogenous groups of clonal haematopoietic stem cell diseases characterized by ineffective haematopoiesis and peripheral blood cytopenia, with a variable tendency to transform within acute leukaemia (AL). DNA hypermethylation and hypo-methylation are associated with cancer. Thus, the hypermethylation of DNA is essential for the molecular pathophysiology of MDS by inactivating genes involved in cell growth, differentiation and apoptosis. It was documented that the 5-methylcytosine (5mc) immunostaining score of BM haematopoietic mononuclear cells is higher in MDS patients than in a normal control group, and that the prognosis of the disease significantly correlated with global DNA methylation, age and IPSS score. In our study, we analysed the immunocytochemical expression of 5mc in bone marrow (BM) mononuclear cells from 13 MDS patients and a control group consisting of 13 patients with anaemia of chronic disease. The immunopositivity of 5mc BM mononuclear cells was statistically significantly higher in our MDS patients than in patients with anaemia of chronic disease. In most MDS patients (11 out of 13), a higher 5mc immunopositivity of BM mono-nuclear cells (above 10%) was found. Our results are in concordance with data from literature observing that a higher percentage of 5mc immunopositive BM mononuclear cells is documented in MDS patients., (© 2019 by the Association of Clinical Scientists, Inc.)

Autoantibodies targeting host antigens contribute to autoimmune disorders, frequently occur during and after infections and have been proposed to contribute to malaria-induced anemia. We measured anti-phosphatidylserine (PS) and anti-DNA antibody levels in 382 Ugandan children prospectively recruited in a study of severe malaria (SM). High antibody levels were defined as antibody levels greater than the mean plus 3 standard deviations of community children (CC). We observed increases in median levels of anti-PS and anti-DNA antibodies in children with SM compared to CC (p < 0.0001 for both). Children with severe malarial anemia were more likely to have high anti-PS antibodies than children with cerebral malaria (16.4% vs. 7.4%), p = 0.02. Increases in anti-PS and anti-DNA antibodies were associated with decreased hemoglobin (p < 0.05). A one-unit increase in anti-DNA antibodies was associated with a 2.99 (95% CI, 1.68, 5.31) increase odds of acute kidney injury (AKI) (p < 0.0001). Elevated anti-PS and anti-DNA antibodies were associated with post-discharge mortality (p = 0.031 and p = 0.042, respectively). Children with high anti-PS antibodies were more likely to have multiple hospital readmissions compared to children with normal anti-PS antibody levels (p < 0.05). SM is associated with increased autoantibodies against PS and DNA. Autoantibodies were associated with anemia, AKI, post-discharge mortality, and hospital readmission.

Background: The aims of this study were to determine the prevalence of the different anti-erythrocytic alloantibodies, to describe pregnancy outcomes according to a low-risk and high-risk classification for fetal anemia and to determine the factors that influence adverse perinatal outcomes., Methods: This retrospective observational study included women referred to our center following the identification of maternal anti-erythrocytic alloantibodies between 2002 and 2017. Pregnancies were classified as high risk for fetal anemia in cases with clinically significant antibodies, no fetal-maternal compatibility and titers ≥1:16 or any titration in cases of Kell system incompatibility. In high-risk pregnancies, maternal antibody titration and the fetal middle cerebral artery peak systolic velocity (MCA-PSV) were monitored. Low-risk pregnancies underwent routine pregnancy follow-up., Results: Maternal antibodies were found in 337 pregnancies, and 259 (76.9%) of these antibodies were clinically significant. The most frequent antibodies were anti-D (53%) and anti-K (19%). One hundred forty-three pregnancies were classified as low risk for fetal anemia, 65 (25%) cases were classified as no fetal-maternal incompatibility, 78 had clinically nonsignificant antibodies, 4 (2.8%) resulted in first-trimester pregnancy loss, and 139 (97.2%) resulted in livebirths. Of the 194 high-risk pregnancies, 38 had titers < 1:16 (resulting in 38 livebirths), and 156 had titers ≥1:16 or anti-K antibodies. In the last group, 6 cases miscarried before 18 weeks, 93 had a MCA-PSV < 1.5 multiples of the median (MoM), resulting in 3 perinatal deaths that were unrelated to fetal anemia, one termination and 89 livebirths; and 57 had a MCA-PSV > 1.5 MoM, resulting in 3 intrauterine deaths, 6 terminations and 48 livebirths. Ninety-two intrauterine transfusions were performed in 45 fetuses (87% anti-D). Adverse outcomes were related to a MCA-PSV > 1.5 MoM (p < 0.001), hydrops (p < 0.001) and early gestational age at first transfusion (p = 0.029) CONCLUSION: Anti-D remains the most common antibody in fetuses requiring intrauterine transfusion. A low or high-risk classification for fetal anemia based on the type of antibody, paternal phenotype and fetal antigen allows follow-up of the pregnancy accordingly, with good perinatal outcomes in the low-risk group. In the high-risk group, adverse perinatal outcomes are related to high MCA-PSV, hydrops and early gestational age at first transfusion.

The spleen is an important secondary lymph organ. Splenomegaly induced by anemia could affect the function of spleen in immune responses. We observe that anemia induced in mice with reduced peripheral T cell trafficking to the spleen T cell zones as well as CCL21 and CCL19 expression. In accordance with previous research, we found that the production of EPO in the mice kidney was sharply increased post anemia. In addition, mice were injected with different doses of EPO. Our results show that with the increased dosage of EPO, the chemokine expression in the spleen is lowered with a decrease in peripheral T cell homing to the spleen T cell zones. At last, our results show that the anemia mice model administrated with anti-EPO antibody had a higher expression of spleen CCL19 and CCL21 and an increased count of periphery T cells trafficking to spleen T cell zones at day 3 post induction. These data indicate that anemia could disturb T cell movement in the spleen, which might further affect T cell immune response, with partial involvement of EPO., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Chronic inflammatory diseases are associated with altered hematopoiesis that could result in neutrophilia and anemia. Here we report that genetic or chemical manipulation of different inflammasome components altered the differentiation of hematopoietic stem and progenitor cells (HSPC) in zebrafish. Although the inflammasome was dispensable for the emergence of HSPC, it was intrinsically required for their myeloid differentiation. In addition, Gata1 transcript and protein amounts increased in inflammasome-deficient larvae, enforcing erythropoiesis and inhibiting myelopoiesis. This mechanism is evolutionarily conserved, since pharmacological inhibition of the inflammasome altered erythroid differentiation of human erythroleukemic K562 cells. In addition, caspase-1 inhibition rapidly upregulated GATA1 protein in mouse HSPC promoting their erythroid differentiation. Importantly, pharmacological inhibition of the inflammasome rescued zebrafish disease models of neutrophilic inflammation and anemia. These results indicate that the inflammasome plays a major role in the pathogenesis of neutrophilia and anemia of chronic diseases and reveal druggable targets for therapeutic interventions., (Copyright © 2019 Elsevier Inc. All rights reserved.)