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1.
Int J Mol Sci ; 23(15)2022 Aug 06.
Article in English | MEDLINE | ID: covidwho-1994086

ABSTRACT

Non-relapse mortality due to GVHD and infections represents a major source of morbidity and mortality in pediatric HSCT recipients. Post-transplant cyclophosphamide (PTCy) has emerged as an effective and safe GVHD prophylaxis strategy, with improved GVHD and relapse-free survival in matched (related and unrelated) and mismatched haploidentical HSCT adult recipients. However, there are no published data in pediatric patients with acute myeloid leukemia who received matched-donor HSCT with PTCy. We demonstrate, in this case series, that the use of PTCy in this population is potentially safe, effective in preventing acute GVHD, does not impair engraftment, is associated with reduced non-relapse mortality, and does not hinder immune reconstitution post HSCT.


Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Adult , Child , Cyclophosphamide/therapeutic use , Graft vs Host Disease/drug therapy , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & control , Humans , Leukemia, Myeloid, Acute/drug therapy , Recurrence , Retrospective Studies , Siblings , Unrelated Donors
2.
PLoS One ; 17(5): e0267556, 2022.
Article in English | MEDLINE | ID: covidwho-1910604

ABSTRACT

BACKGROUND: Anxiety symptoms (AS) are exacerbated in healthcare workers (HCWs) during the COVID-19 pandemic. Spirituality is known to protect against AS in the general population and it is a construct that differs from religion. It can be assessed using structured questionnaires. A validated questionnaire disclosed three spirituality dimensions: peace, meaning, and faith. In HCWs we investigated the predictors of chronic anxiety (pre-COVID-19 and during the pandemic) and acute anxiety (only during the pandemic), including spirituality in the model. Then, we verified which spirituality dimensions predicted chronic and acute anxiety. Lastly, we studied group differences between the mean scores of these spirituality dimensions. MATERIAL AND METHODS: The study was carried out in a Brazilian Hospital. HCWs (n = 118) were assessed for spirituality at a single time-point. They were also asked about AS that had started pre-COVID-19 and persisted during the pandemic (chronic anxiety), and AS that had started only during the pandemic (acute anxiety). The subjects without chronic anxiety were subdivided into two other groups: acute anxiety and without chronic and acute anxiety. Forward stepwise logistic regressions were used to find the significant AS predictors. First, the model considered sex, age, religious affiliation, and spirituality. Then, the analysis were performed considering only the three spirituality dimensions. Group means differences in the spirituality dimensions were compared using univariate ANCOVAS followed by T-tests. RESULTS: Spirituality was the most realible predictor of chronic (OR = 0.818; 95%CI:0.752-0.890; p<0.001) and acute anxiety (OR = 0.727; 95%CI:0.601-0.881; p = 0.001). Peace alone predicted chronic anxiety (OR = 0.619; 95%CI:0.516-0.744; p<0.001) while for acute anxiety both peace (OR:0.517; 95%CI:0.340-0.787; p = 0.002), and faith (OR:0.674; 95%CI:0.509-0.892; p = 0.006) significantly contributed to the model. Faith was significantly higher in subjects without AS. CONCLUSION: Higher spirituality protected against chronic and acute anxiety. Faith and peace spirituality dimensions conferred protection against acute anxiety during the pandemic.


Subject(s)
COVID-19 , Graft vs Host Disease , Anxiety/epidemiology , Brazil/epidemiology , COVID-19/epidemiology , Cross-Sectional Studies , Disease Outbreaks , Health Personnel , Humans , Pandemics , Protective Factors , Spirituality
3.
Nat Med ; 28(7): 1501-1508, 2022 07.
Article in English | MEDLINE | ID: covidwho-1900517

ABSTRACT

In some immunocompromised patients with chronic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, considerable adaptive evolution occurs. Some substitutions found in chronic infections are lineage-defining mutations in variants of concern (VOCs), which has led to the hypothesis that VOCs emerged from chronic infections. In this study, we searched for drivers of VOC-like emergence by consolidating sequencing results from a set of 27 chronic infections. Most substitutions in this set reflected lineage-defining VOC mutations; however, a subset of mutations associated with successful global transmission was absent from chronic infections. We further tested the ability to associate antibody evasion mutations with patient-specific and virus-specific features and found that viral rebound is strongly correlated with the emergence of antibody evasion. We found evidence for dynamic polymorphic viral populations in most patients, suggesting that a compromised immune system selects for antibody evasion in particular niches in a patient's body. We suggest that a tradeoff exists between antibody evasion and transmissibility and that extensive monitoring of chronic infections is necessary to further understanding of VOC emergence.


Subject(s)
COVID-19 , Graft vs Host Disease , Humans , Mutation/genetics , SARS-CoV-2/genetics
6.
Trends Immunol ; 43(6): 459-465, 2022 06.
Article in English | MEDLINE | ID: covidwho-1864570

ABSTRACT

Much has been learned about the genes and pathways that contribute to a diverse array of hematopoietic malignancies and other hematopoietic diseases. However, for many of these diseases, an allogeneic hematopoietic stem cell (HSC) transplant remains the preferred treatment option. This opinion article provides the perspective of a molecular immunologist who became a transplant patient after many years studying basic mechanisms of blood cell development. Among many lessons learned were the magnitude of racial and ethnic disparities in donor registries, the substantial improvement in outcomes over time that were due to the collective impact of numerous advances, the benefits and limitations of genetic and clinical data, and the remarkably intricate balance between promoting graft-versus-disease activity of donor cells while suppressing graft-versus-host disease (GVHD).


Subject(s)
Graft vs Host Disease , Hematologic Neoplasms , Hematopoietic Stem Cell Transplantation , Graft vs Host Disease/genetics , Humans , Transplantation Conditioning , Transplantation, Homologous
7.
Transplant Cell Ther ; 28(7): 366.e1-366.e7, 2022 07.
Article in English | MEDLINE | ID: covidwho-1859949

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are capable of inducing combined humoral and cellular immunity. Which effect is more relevant for their potent protective effects is unclear, but isolated T cell responses without seroconversion in healthy household members of individuals with Coronavirus disease 19 (COVID-19) suggest that T cell responses effectively protect against clinical infection. Oncologic patients have an outsize risk of unfavorable outcomes after SARS-CoV-2 infection and therefore were prioritized when vaccines first became available, although the quality of their immune response to vaccination was expected to be suboptimal, as has been confirmed in subsequent studies. Inherently, patients with anti-CD19 chimeric antigen receptor (CAR) T cell therapy-mediated B cell aplasia would be incapable of generating humoral responses, so that assessment of the vaccine-induced cellular immunity is all the more important to gauge whether the vaccine can induce meaningful protection. A salient difference between T cell and humoral responses is the former's relative impassiveness to mutations of the antigen, which is more relevant than ever since the advent of the omicron variant. The objective of this study was to assess the immune cell composition and spike protein-specific T cell responses before and after the first and second doses of SARS-CoV-2 mRNA vaccine in a cohort of juvenile CD19 CAR T cell therapy recipients with enduring B cell aplasia. The prospective study included all patients age >12 years diagnosed with multiply relapsed B cell precursor acute lymphoblastic leukemia and treated with anti-CD19 CAR T cell (CAR-T19) therapy in our center. The primary endpoint was the detection of cell-mediated and humoral responses to vaccine (flow cytometry and anti-S immunoglobulin G, respectively). Secondary endpoints included the incidence of vaccine-related grade 3 or 4 adverse events, exacerbation of graft-versus-host disease (GVHD), relapse, and the influence of the vaccine on CAR T cells and lymphocyte subsets. Even though one-half of the patients exhibited subnormal lymphocyte counts and marginal CD4/CD8 ratios, after 2 vaccinations all showed brisk T-cell responsiveness to spike protein, predominantly in the CD4 compartment, which quantitatively was well within the range of healthy controls. No severe vaccine-related grade 3 or 4 adverse events, GVHD exacerbation, or relapse was observed in our cohort. We posit that SARS-CoV-2 mRNA vaccines induce meaningful cellular immunity in patients with isolated B cell deficiency due to CAR-T19 therapy.


Subject(s)
COVID-19 Vaccines , COVID-19 , Graft vs Host Disease , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Receptors, Chimeric Antigen , Antigens, CD19 , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Child , Humans , Immunity, Cellular , Immunoglobulin G , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Prospective Studies , Recurrence , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , T-Lymphocytes , Vaccination , Vaccines, Synthetic , mRNA Vaccines
11.
Front Immunol ; 13: 839844, 2022.
Article in English | MEDLINE | ID: covidwho-1775672

ABSTRACT

Mesenchymal stromal cells (MSCs) possess profound immunomodulatory and regenerative properties that are of clinical use in numerous clinical indications with unmet medical need. Common sources of MSCs include among others, bone marrow (BM), fat, umbilical cord, and placenta-derived decidua stromal cells (DSCs). We here summarize our more than 20-years of scientific experience in the clinical use of MSCs and DSCs in different clinical settings. BM-MSCs were first explored to enhance the engraftment of autografts in hematopoietic cell transplantation (HCT) and osteogenesis imperfecta around 30 years ago. In 2004, our group reported the first anti-inflammatory use of BM-MSCs in a child with grade IV acute graft-versus-host disease (GvHD). Subsequent studies have shown that MSCs appear to be more effective in acute than chronic GvHD. Today BM-MSC-therapy is registered for acute GvHD in Japan and for GvHD in children in Canada and New Zeeland. MSCs first home to the lung following intravenous injection and exert strong local and systemic immunomodulatory effects on the host immune system. Thus, they were studied for ameliorating the cytokine storm in acute respiratory distress syndrome (ARDS). Both, MSCs and DSCs were used to treat SARS-CoV-2 coronavirus-induced disease 2019 (COVID-19)-induced ARDS. In addition, they were also used for other novel indications, such as pneumomediastinum, colon perforation, and radiculomyelopathy. MSC and DSCs trigger coagulation and were thus explored to stop hemorrhages. DSCs appear to be more effective for acute GvHD, ARDS, and hemorrhages, but randomized studies are needed to prove superiority. Stromal cell infusion is safe, well tolerated, and only gives rise to a slight fever in a limited number of patients, but no major side effects have been reported in multiple safety studies and metaanalysis. In this review we summarize current evidence from in vitro studies, animal models, and importantly our clinical experience, to support stromal cell therapy in multiple clinical indications. This encloses MSC's effects on the immune system, coagulation, and their safety and efficacy, which are discussed in relation to prominent clinical trials within the field.


Subject(s)
COVID-19 , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Respiratory Distress Syndrome , Animals , COVID-19/therapy , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Hemorrhage/etiology , Humans , Mesenchymal Stem Cell Transplantation/adverse effects , Pregnancy , SARS-CoV-2
12.
J Neurol Sci ; 436: 120231, 2022 05 15.
Article in English | MEDLINE | ID: covidwho-1739963

ABSTRACT

BACKGROUND: Rare autoimmune neurological events have been reported during the ongoing global drive for mass vaccination as a means of controlling the Covid-19 pandemic. Guillain-Barré syndrome, an acute inflammatory neuropathy well recognised as a rare complication of influenza vaccination, has been reported to follow administration of the ChAdOx1 nCoV-19 (AstraZeneca) vaccine. METHODS: We report four patients with inflammatory demyelinating polyneuropathy after vaccination in whom a relapsing or progressive course indicated the development of chronic inflammatory demyelinating polyneuropathy (CIDP). CONCLUSIONS: Awareness of this complication and distinction from Guillain-Barré syndrome enables the timely institution of maintenance immunomodulatory treatment. Our report also highlights the likely relationship between vaccination and the subsequent development of CIDP, but definitive demonstration of a causal link needs larger studies.


Subject(s)
COVID-19 , Graft vs Host Disease , Guillain-Barre Syndrome , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating , Vaccines , COVID-19/prevention & control , ChAdOx1 nCoV-19 , Graft vs Host Disease/complications , Guillain-Barre Syndrome/epidemiology , Guillain-Barre Syndrome/etiology , Humans , Pandemics , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/complications
14.
Bull Exp Biol Med ; 172(2): 250-253, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1544492

ABSTRACT

Mesenchymal stem cells (MSC) are characterized by tolerogenic potential and therefore, are used in the treatment of autoimmune diseases such as graft-versus-host disease (GVHD) reactions after allogeneic hematopoietic cell transplantation to improve the transplant functions, as well as for the therapy and prevention of cytokine storm in COVID-19 patients and some other conditions. However, MSC can exhibit proinflammatory activity, which causes risks for their clinical use. We studied the cytokine profile of bone marrow MSC culture and demonstrate intensive production of IL-6, IL-8, and chemokine MCP-1, which participate in the pathogenesis of cytokine storm and GVHD. At the same time, no anti-inflammatory IL-4 and IL-10 were detected. To reduce the risks of MSC application in the GVHD therapeutic protocols, further studies of the conditions promoting generation of MSC with tolerogenic potential and approved clinical standards of MSC use are required.


Subject(s)
COVID-19/therapy , Cytokine Release Syndrome/prevention & control , Cytokines/analysis , Graft vs Host Disease/prevention & control , Mesenchymal Stem Cell Transplantation/adverse effects , Mesenchymal Stem Cells/immunology , Bone Marrow Cells/immunology , Bone Marrow Cells/metabolism , COVID-19/immunology , Cells, Cultured , Chemokine CCL2/analysis , Graft vs Host Disease/immunology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Immunosuppressive Agents/therapeutic use , Interleukin-6/analysis , Interleukin-8/analysis , Mesenchymal Stem Cells/metabolism , SARS-CoV-2/immunology , Transplantation, Homologous/adverse effects
15.
Expert Opin Pharmacother ; 23(3): 349-360, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1516492

ABSTRACT

INTRODUCTION: Noninvasive mechanical ventilation is the main supportive measure used in patients with pediatric ARDS (PARDS), but adjunctive pharmacological therapies (corticosteroids, inhaled nitric oxide [iNO], surfactant replacement therapy and neuromuscular blocking drugs) are also used, although limited data exists to inform of this practice. AREAS COVERED: The authors review the current challenges in the pharmacological management of PARDS and highlight the few certainties currently available. EXPERT OPINION: Children with PARDS must not be treated as young adults with ARDS, essentially because children's lungs differ substantially from those of adults and PARDS occurs in children differently than ARDS in adults. Pharmacological treatments available for PARDS are relatively few and, since there is great uncertainty about their effectiveness also because of the extreme heterogeneity of this syndrome, it is necessary to conduct large clinical trials using currently available definitions and considering recent pathobiological knowledge. The aim is to identify homogeneous subgroups or phenotypes of children with PARDS that may benefit from the specific pharmaceutical approach examined. It will be then necessary to link endotypes and outcomes to appropriately target therapies in future trials, but this will be possible only after it will be possible to identify the different PARDS endotypes.


Subject(s)
Graft vs Host Disease , Respiratory Distress Syndrome , Adrenal Cortex Hormones , Child , Forecasting , Humans , Respiration, Artificial , Respiratory Distress Syndrome/drug therapy
17.
Signal Transduct Target Ther ; 6(1): 367, 2021 10 20.
Article in English | MEDLINE | ID: covidwho-1475287

ABSTRACT

Cytokine release syndrome (CRS) embodies a mixture of clinical manifestations, including elevated circulating cytokine levels, acute systemic inflammatory symptoms and secondary organ dysfunction, which was first described in the context of acute graft-versus-host disease after allogeneic hematopoietic stem-cell transplantation and was later observed in pandemics of influenza, SARS-CoV and COVID-19, immunotherapy of tumor, after chimeric antigen receptor T (CAR-T) therapy, and in monogenic disorders and autoimmune diseases. Particularly, severe CRS is a very significant and life-threatening complication, which is clinically characterized by persistent high fever, hyperinflammation, and severe organ dysfunction. However, CRS is a double-edged sword, which may be both helpful in controlling tumors/viruses/infections and harmful to the host. Although a high incidence and high levels of cytokines are features of CRS, the detailed kinetics and specific mechanisms of CRS in human diseases and intervention therapy remain unclear. In the present review, we have summarized the most recent advances related to the clinical features and management of CRS as well as cutting-edge technologies to elucidate the mechanisms of CRS. Considering that CRS is the major adverse event in human diseases and intervention therapy, our review delineates the characteristics, kinetics, signaling pathways, and potential mechanisms of CRS, which shows its clinical relevance for achieving both favorable efficacy and low toxicity.


Subject(s)
Cytokine Release Syndrome , Signal Transduction/immunology , Acute Disease , Autoimmune Diseases/complications , Autoimmune Diseases/immunology , Autoimmune Diseases/therapy , COVID-19/complications , COVID-19/immunology , COVID-19/therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/therapy , Graft vs Host Disease/complications , Graft vs Host Disease/immunology , Graft vs Host Disease/therapy , Hematopoietic Stem Cell Transplantation , Humans , Immunotherapy, Adoptive/adverse effects , Influenza, Human/complications , Influenza, Human/immunology , Neoplasms/complications , Neoplasms/immunology , Neoplasms/therapy , SARS Virus/immunology , SARS-CoV-2/immunology , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/therapy
18.
Eur J Haematol ; 108(1): 61-72, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1476174

ABSTRACT

During 2020, the concurrent novel COVID-19 pandemic lead to widespread cryopreservation of allogeneic hematopoietic cell transplant grafts based on National Marrow Donor Program and European Society of Blood and Marrow Transplantation recommendations, in order to secure grafts before the start of conditioning chemotherapy. We sought to examine the impact of this change in practice on patient outcomes. We analyzed the outcomes of 483 patients who received hematopoietic stem cell transplantation (HSCT) between August 2017 and August 2020, at Princess Margaret Cancer Centre, Canada, in the retrospective study, comparing the outcomes between those who received cryopreserved or fresh peripheral blood stem cell grafts. Overall compared with those who received fresh grafts (n = 348), patients who received cryopreserved grafts (n = 135) had reduced survival and GRFS, reduced incidence of chronic graft-versus-host disease (GvHD), delay in neutrophil engraftment, and higher graft failure (GF), with no significant difference in relapse incidence or acute GvHD. However, recipients of cryopreserved matched-related donor HSCT showed significantly worse OS, NRM, GRFS compared with fresh grafts. Multivariable analysis of the entire cohort showed significant impact of cryopreservation on OS, relapse, cGvHD, GF, and GRFS. We conclude that cryopreservation was associated with inferior outcomes post-HSCT, possibly due to the combination of ATG and post-transplant cyclophosphamide impacting differential tolerance to cryopreservation on components of the stem cell graft; further studies are warranted to elucidate mechanisms for this observation.


Subject(s)
Antilymphocyte Serum/therapeutic use , Cryopreservation/methods , Cyclophosphamide/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Hematopoietic Stem Cells/cytology , Leukemia, Myeloid, Acute/therapy , Adolescent , Adult , Aged , COVID-19/epidemiology , Female , Graft vs Host Disease , Humans , Male , Middle Aged , Recurrence , Retrospective Studies , Transplantation Conditioning , Treatment Outcome , Young Adult
20.
Pharmacol Res ; 157: 104866, 2020 07.
Article in English | MEDLINE | ID: covidwho-1318930

ABSTRACT

COVID-19 is a medical emergency, with 20 % of patients presenting with severe clinical manifestations. From the pathogenetic point of view, COVID-19 mimics two other well-known diseases characterized by cytokine storm and hyper-activation of the immune response, with consequent organ damage: acute graft-versus-host disease (aGVHD) and macrophage activation syndrome (MAS). Hematologists are confident with these situations requiring a prompt therapeutic approach for switching off the uncontrolled cytokine release; here, we discuss pros and cons of drugs that are already employed in hematology in the light of their possible application in COVID-19. The most promising drugs might be: Ruxolitinib, a JAK1/2 inhibitor, with a rapid and powerful anti-cytokine effect, tyrosine kinase inhibitors (TKIs), with their good anti-inflammatory properties, and perhaps the anti-Cd26 antibody Begelomab. We also present immunological data from gene expression experiments where TKIs resulted effective anti-inflammatory and pro-immune drugs. A possible combined treatment algorithm for COVID-19 is here proposed.


Subject(s)
Coronavirus Infections/drug therapy , Hematology/methods , Pneumonia, Viral/drug therapy , Betacoronavirus/drug effects , COVID-19 , Graft vs Host Disease/drug therapy , Humans , Macrophage Activation Syndrome/drug therapy , Pandemics , SARS-CoV-2
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