Pro- and anti-inflammatory cytokines mediate the progression of severe anemia in malaria-infected children: A prospective study.

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-É£) (p < .001), interleukin (IL)-1ß (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-É£ (p < .001), IL-1ß (p < .001), IL-6 (p < .001), GM-CSF (p < .001), and IL-10 (p < .001), but reduced IL-3 (p < .001) and TGF-ß (p < .001) than those with low parasitemia. Severe malarial anemic children had elevated TNF-α (p < .001), IFN-É£ (p < .001), IL-1ß (p < .001), IL-6 (p < .001), GM-CSF (p < .001), and IL-10 (p < .001), but lower IL-3 (p < .001) and TGF-ß (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-1ß, IFN-É£, and TNF-α, but negatively associated with IL-3 and TGF-ß. 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-ß may offer protection against severe malarial anemia.

Assessment of the impact of cytomegalovirus seropositivity on blood parameters in renal hemodialysis patients.

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.

Infection vs. Reinfection: The Immunomodulation of Erythropoiesis.

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.

Association of the systemic immune-inflammation index with anemia: a population-based study.

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.

Investigation of the correlation between platelet antibodies and peripheral blood cytopenia in patients with hepatocellular carcinoma.

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.

Do Micronutrient and Omega-3 Fatty Acid Supplements Affect Human Maternal Immunity during Pregnancy? A Scoping Review.

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.

Fermented goat's milk modulates immune response during iron deficiency anemia recovery.

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.

Transient Ascaris suum larval migration induces intractable chronic pulmonary disease and anemia in mice.

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.

Macrophages form erythropoietic niches and regulate iron homeostasis to adapt erythropoiesis in response to infections and inflammation.

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.

Epidemiological and Liver Biomarkers Profile of Epstein-Barr Virus Infection and Its Coinfection with Cytomegalovirus in Patients with Hematological Diseases.

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.

Sex Matters: Physiological Abundance of Immuno-Regulatory CD71+ Erythroid Cells Impair Immunity in Females.

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.

Fetal Cytokine Balance, Erythropoietin and Thalassemia but Not Placental Malaria Contribute to Fetal Anemia Risk in Tanzania.

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.

Ovine ß-globin gene: A new qPCR for rapid haplotype identification and association with susceptibility to Haemonchus contortus infection.

Two ß-globin allelic haplotypes (A and B) were identified in domestic sheep, wherein animals which are homozygous for ßB allele (BB haplotype) have a deletion of pre-adult ßC-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 ß-globin haplotype and resistance against this parasite. However, the findings were controversial, pointing out from increased resistance in animals harboring the ßA allele to inexistence of association. Thus, our study aimed to develop a qPCR for ß-globin haplotype identification, and to evaluate the association between ß-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 ß-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.

Cytokine storm in severe COVID-19 pneumonia.

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.

Hyporegenerative anemia in anti-M-associated hemolytic disease of the fetus.

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, r2  = 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.

Blockade of IL-22 signaling reverses erythroid dysfunction in stress-induced anemias.

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 (Riok2f/+Vav1cre) led to reduced erythroid precursor frequency leading to anemia. Proteomic analysis of Riok2f/+Vav1cre erythroid precursors suggested immune system activation, and transcriptomic analysis revealed an increase in p53-dependent interleukin (IL)-22 in Riok2f/+Vav1cre CD4+ T cells (TH22). 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 Riok2f/+Vav1cre 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.

Experimental modulation of Interleukin 1 shows its key role in chronic kidney disease progression and anemia.

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.

Hematological immune related adverse events after treatment with immune checkpoint inhibitors.

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.

The role of inflammatory cytokines in anemia and gastrointestinal mucosal injury induced by foot electric stimulation.

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-1ß, 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.

Autoimmune hematologic complications of umbilical cord blood transplantation.

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.