Asunto(s)
COVID-19/complicaciones , Herpes Simple/complicaciones , Herpesvirus Humano 1/aislamiento & purificación , Necrosis Hepática Masiva/complicaciones , Viremia/complicaciones , Aciclovir/uso terapéutico , Antivirales/uso terapéutico , COVID-19/patología , COVID-19/terapia , Manejo de la Enfermedad , Herpes Simple/patología , Herpes Simple/terapia , Herpesvirus Humano 1/efectos de los fármacos , Humanos , Unidades de Cuidados Intensivos , Masculino , Necrosis Hepática Masiva/patología , Necrosis Hepática Masiva/terapia , Persona de Mediana Edad , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/aislamiento & purificación , Índice de Severidad de la Enfermedad , Viremia/patología , Viremia/terapiaAsunto(s)
Anemia Macrocítica , Cromosomas Humanos Par 16/genética , Leucocitosis , Trombocitopenia , Anemia Macrocítica/genética , Anemia Macrocítica/metabolismo , Anemia Macrocítica/patología , Humanos , Leucocitosis/genética , Leucocitosis/metabolismo , Leucocitosis/patología , Masculino , Persona de Mediana Edad , Trombocitopenia/genética , Trombocitopenia/metabolismo , Trombocitopenia/patologíaAsunto(s)
Anemia/complicaciones , Leucemia Mieloide Aguda/patología , Neutropenia/complicaciones , Nucleofosmina/genética , Pancitopenia/complicaciones , Trombocitopenia/complicaciones , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Estudios RetrospectivosRESUMEN
Along with the evolution of immunophenotypic and molecular diagnostics, the assessment of Minimal Residual Disease (MRD) has progressively become a keystone in the clinical management of hematologic malignancies, enabling valuable post-therapy risk stratifications and guiding risk-adapted therapeutic approaches. However, specific prognostic values of MRD in different hematological settings, as well as its appropriate clinical uses (basically, when to measure it and how to deal with different MRD levels), still need further investigations, aiming to improve standardization and harmonization of MRD monitoring protocols and MRD-driven therapeutic strategies. Currently, MRD measurement in hematological neoplasms with bone marrow involvement is based on advanced highly sensitive methods, able to detect either specific genetic abnormalities (by PCR-based techniques and next-generation sequencing) or tumor-associated immunophenotypic profiles (by multiparametric flow cytometry, MFC). In this review, we focus on the growing clinical role for MFC-MRD diagnostics in hematological malignancies-from acute myeloid and lymphoblastic leukemias (AML, B-ALL and T-ALL) to chronic lymphocytic leukemia (CLL) and multiple myeloma (MM)-providing a comparative overview on technical aspects, clinical implications, advantages and pitfalls of MFC-MRD monitoring in different clinical settings.
RESUMEN
The C-terminal aminoacidic sequence from NPM1-mutated protein, absent in normal human tissues, may serve as a leukemia-specific antigen and can be considered an ideal target for NPM1-mutated acute myeloid leukemia (AML) immunotherapy. Different in silico instruments and in vitro/ex vivo immunological platforms have identified the most immunogenic epitopes from NPM1-mutated protein. Spontaneous development of endogenous NPM1-mutated-specific cytotoxic T cells has been observed in patients, potentially contributing to remission maintenance and prolonged survival. Genetically engineered T cells, namely CAR-T or TCR-transduced T cells, directed against NPM1-mutated peptides bound to HLA could prospectively represent a promising therapeutic approach. Although either adoptive or vaccine-based immunotherapies are unlikely to be highly effective in patients with full-blown leukemia, these strategies, potentially in combination with immune-checkpoint inhibitors, could be promising in maintaining remission or preemptively eradicating persistent measurable residual disease, mainly in patients ineligible for allogeneic hematopoietic stem cell transplant (HSCT). Alternatively, neoantigen-specific donor lymphocyte infusion derived from healthy donors and targeting NPM1-mutated protein to selectively elicit graft-versus-leukemia effect may represent an attractive option in subjects experiencing post-HSCT relapse. Future studies are warranted to further investigate dynamics of NPM1-mutated-specific immunity and explore whether novel individualized immunotherapies may have potential clinical utility in NPM1-mutated AML patients.
Asunto(s)
Antígenos de Neoplasias/inmunología , Leucemia Mieloide Aguda/inmunología , Proteínas Nucleares/genética , Linfocitos T/inmunología , Animales , Humanos , Inmunoterapia/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutación , Proteínas Nucleares/inmunología , NucleofosminaRESUMEN
Monocyte Distribution Width (MDW), a new cytometric parameter correlating with cytomorphologic changes occurring upon massive monocyte activation, has recently emerged as promising early biomarker of sepsis. Similar to sepsis, monocyte/macrophage subsets are considered key mediators of the life-threatening hyper-inflammatory disorder characterizing severe COVID-19. In this study, we longitudinally analyzed MDW values in a cohort of 87 COVID-19 patients consecutively admitted to our hospital, showing significant correlations between MDW and common inflammatory markers, namely CRP (p < 0.001), fibrinogen (p < 0.001) and ferritin (p < 0.01). Moreover, high MDW values resulted to be prognostically associated with fatal outcome in COVID-19 patients (AUC = 0.76, 95% CI: 0.66-0.87, sensitivity 0.75, specificity 0.70, MDW threshold 26.4; RR = 4.91, 95% CI: 1.73-13.96; OR = 7.14, 95% CI: 2.06-24.71). This pilot study shows that MDW can be useful in the monitoring of COVID-19 patients, as this innovative hematologic biomarker is: (1) easy to obtain, (2) directly related to the activation state of a fundamental inflammatory cell subset (i.e. monocytes, pivotal in both cytokine storm and sepsis immunopathogenesis), (3) well correlated with clinical severity of COVID-19-associated inflammatory disorder, and, in turn, (4) endowed with relevant prognostic significance. Additional studies are needed to define further the clinical impact of MDW testing in the management of COVID-19 patients.
Asunto(s)
COVID-19/sangre , Tamaño de la Célula , Monocitos/patología , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Proteína C-Reactiva/análisis , COVID-19/epidemiología , COVID-19/virología , Femenino , Ferritinas/sangre , Fibrinógeno/análisis , Humanos , Inflamación/sangre , Italia/epidemiología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Admisión del Paciente , Proyectos Piloto , Pronóstico , Estudios Retrospectivos , Sensibilidad y Especificidad , Adulto JovenRESUMEN
The Philadelphia-negative myeloproliferative neoplasms (MPNs) are malignancies of the hematopoietic stem cell (HSC) arising as a consequence of clonal proliferation driven by somatically acquired driver mutations in discrete genes (JAK2, CALR, MPL). In recent years, along with the advances in molecular characterization, the role of immune dysregulation has been achieving increasing relevance in the pathogenesis and evolution of MPNs. In particular, a growing number of studies have shown that MPNs are often associated with detrimental cytokine milieu, expansion of the monocyte/macrophage compartment and myeloid-derived suppressor cells, as well as altered functions of T cells, dendritic cells and NK cells. Moreover, akin to solid tumors and other hematological malignancies, MPNs are able to evade T cell immune surveillance by engaging the PD-1/PD-L1 axis, whose pharmacological blockade with checkpoint inhibitors can successfully restore effective antitumor responses. A further interesting cue is provided by the recent discovery of the high immunogenic potential of JAK2V617F and CALR exon 9 mutations, that could be harnessed as intriguing targets for innovative adoptive immunotherapies. This review focuses on the recent insights in the immunological dysfunctions contributing to the pathogenesis of MPNs and outlines the potential impact of related immunotherapeutic approaches.
Asunto(s)
Células Madre Hematopoyéticas/inmunología , Inmunoterapia/métodos , Inflamación/inmunología , Trastornos Mieloproliferativos/terapia , Linfocitos T/inmunología , Microambiente Tumoral/inmunología , Calreticulina/genética , Calreticulina/inmunología , Calreticulina/metabolismo , Células Madre Hematopoyéticas/metabolismo , Humanos , Inflamación/genética , Janus Quinasa 2/genética , Janus Quinasa 2/inmunología , Janus Quinasa 2/metabolismo , Mutación/inmunología , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/inmunología , Cromosoma Filadelfia , Linfocitos T/metabolismo , Microambiente Tumoral/genéticaRESUMEN
Coronavirus Disease 2019 (COVID-19) is upsetting the world and innovative therapeutic solutions are needed in an attempt to counter this new pandemic. Great hope lies in vaccines, but drugs to cure the infected patient are just as necessary. In the most severe forms of the disease, a cytokine storm with neuroinflammation occurs, putting the patient's life at serious risk, with sometimes long-lasting sequelae. Palmitoylethanolamide (PEA) is known to possess anti-inflammatory and neuroprotective properties, which make it an ideal candidate to be assumed in the earliest stage of the disease. Here, we provide a mini-review on the topic, pointing out phospholipids consumption in COVID-19, the possible development of an antiphospholipid syndrome secondary to SARS-CoV-2 infection, and reporting our preliminary single-case experience concerning to a 45-year-old COVID-19 female patient recently treated with success by micronized / ultramicronized PEA.
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Amidas/administración & dosificación , Antiinflamatorios/administración & dosificación , Síndrome Antifosfolípido/tratamiento farmacológico , Tratamiento Farmacológico de COVID-19 , Etanolaminas/administración & dosificación , Fármacos Neuroprotectores/administración & dosificación , Ácidos Palmíticos/administración & dosificación , SARS-CoV-2/metabolismo , Síndrome Antifosfolípido/etiología , Síndrome Antifosfolípido/metabolismo , Síndrome Antifosfolípido/patología , COVID-19/complicaciones , COVID-19/metabolismo , COVID-19/patología , Femenino , Humanos , Persona de Mediana EdadAsunto(s)
COVID-19/inmunología , Inmunoglobulina G/análisis , Laringoestenosis/inmunología , Células Plasmáticas/inmunología , SARS-CoV-2 , Células Th2/inmunología , Tráquea/inmunología , Traqueostomía/efectos adversos , Anciano , Cicatriz/etiología , Cicatriz/inmunología , Diagnóstico Diferencial , Fibrosis , Humanos , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Laringoestenosis/etiología , Laringoestenosis/patología , Masculino , Células Plasmáticas/patología , Tráquea/patología , Tráquea/cirugíaRESUMEN
Coronavirus disease 2019 (COVID-19) is a global public health emergency with many clinical facets, and new knowledge about its pathogenetic mechanisms is deemed necessary; among these, there are certainly coagulation disorders. In the history of medicine, autopsies and tissue sampling have played a fundamental role in order to understand the pathogenesis of emerging diseases, including infectious ones; compared to the past, histopathology can be now expanded by innovative techniques and modern technologies. For the first time in worldwide literature, we provide a detailed postmortem and biopsy report on the marked increase, up to 1 order of magnitude, of naked megakaryocyte nuclei in the bone marrow and lungs from serious COVID-19 patients. Most likely related to high interleukin-6 serum levels stimulating megakaryocytopoiesis, this phenomenon concurs to explain well the pulmonary abnormal immunothrombosis in these critically ill patients, all without molecular or electron microscopy signs of megakaryocyte infection.
Asunto(s)
Betacoronavirus/patogenicidad , Médula Ósea/patología , Infecciones por Coronavirus/patología , Síndrome de Liberación de Citoquinas/patología , Coagulación Intravascular Diseminada/patología , Pulmón/patología , Neumonía Viral/patología , Trombosis/patología , Adulto , Anciano , Autopsia , Betacoronavirus/inmunología , Médula Ósea/inmunología , Médula Ósea/virología , COVID-19 , Núcleo Celular/inmunología , Núcleo Celular/patología , Núcleo Celular/virología , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Enfermedad Crítica , Síndrome de Liberación de Citoquinas/complicaciones , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/virología , Coagulación Intravascular Diseminada/complicaciones , Coagulación Intravascular Diseminada/inmunología , Coagulación Intravascular Diseminada/virología , Resultado Fatal , Interacciones Huésped-Patógeno/inmunología , Humanos , Interleucina-6/biosíntesis , Interleucina-6/inmunología , Pulmón/inmunología , Pulmón/virología , Masculino , Megacariocitos/inmunología , Megacariocitos/patología , Megacariocitos/virología , Persona de Mediana Edad , Pandemias , Neumonía Viral/complicaciones , Neumonía Viral/inmunología , Neumonía Viral/virología , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Trombopoyesis/inmunología , Trombosis/complicaciones , Trombosis/inmunología , Trombosis/virologíaRESUMEN
COVID-19 is a major public health issue around the world and new data about its etiological agent, SARS-CoV-2, are urgently necessary, also translating the scientific knowledge acquired on its more similar predecessors, SARS-CoV-1 and MERS-CoV, the coronaviruses responsible for SARS and MERS, respectively. Like SARS-CoV-1, SARS-CoV-2 exploits the ACE2 receptors to enter the host cells; nevertheless, recent bioinformatics insights suggest a potential interaction of SARS-CoV-2 with the «moonlighting protein¼ CD26/DPP4, exactly how MERS-CoV works. CD26/DPP4 is overexpressed on T-helper type 1 (Th1) cells and its expression increases with aging, all factors which could well explain the Th1 immune lockdown, especially in the elderly, during fatal SARS-CoV-2 infections. Facing with this scenario, it is possible that Th1 and T-cytotoxic lymphocytes are the immune cells most affected by SARS-CoV-2, and that the immune system is forced to mount a T-helper type 2 (Th2) response, the only one still mountable, in the attempt to counteract the viral load. However, in this way, the symptomatic patient experiences all the negative effects of the Th2 response, which can seriously aggravate the clinical picture.
Asunto(s)
Infecciones por Coronavirus/inmunología , Dipeptidil Peptidasa 4/inmunología , Neumonía Viral/inmunología , Células TH1/inmunología , Adulto , Anciano , Autopsia , Betacoronavirus , COVID-19 , Biología Computacional , Regulación de la Expresión Génica , Humanos , Sistema Inmunológico , Italia , Masculino , Persona de Mediana Edad , Pandemias , Unión Proteica , SARS-CoV-2 , Linfocitos T Citotóxicos/virología , Células TH1/virologíaRESUMEN
Coronavirus Disease 2019 (COVID-19) is an ongoing public health emergency and new knowledge about its immunopathogenic mechanisms is deemed necessary in the attempt to reduce the death burden, globally. For the first time in worldwide literature, we provide scientific evidence that in COVID-19 vasculitis a life-threatening escalation from type 2 T-helper immune response (humoral immunity) to type 3 hypersensitivity (immune complex disease) takes place. The subsequent deposition of immune complexes inside the vascular walls is supposed to induce a severe inflammatory state and a cytokine release syndrome, whose interleukin-6 is the key myokine, from the smooth muscle cells of blood vessels.