scholarly journals Pathomechanisms of Immunological Disturbances in β-Thalassemia

2021 ◽  
Vol 22 (18) ◽  
pp. 9677
Author(s):  
Anna Gluba-Brzózka ◽  
Beata Franczyk ◽  
Magdalena Rysz-Górzyńska ◽  
Robert Rokicki ◽  
Małgorzata Koziarska-Rościszewska ◽  
...  
Keyword(s):  
Immune Deficiency ◽  
Immune System ◽  
Globin Gene ◽  
Iron Chelation ◽  
Polymorphonuclear Neutrophils ◽  
Clinical Severity ◽  
Multiple Organs ◽  
Increased Risk ◽  
Multiple Blood ◽  
Chain Synthesis

Thalassemia, a chronic disease with chronic anemia, is caused by mutations in the β-globin gene, leading to reduced levels or complete deficiency of β-globin chain synthesis. Patients with β-thalassemia display variable clinical severity which ranges from asymptomatic features to severe transfusion-dependent anemia and complications in multiple organs. They not only are at increased risk of blood-borne infections resulting from multiple transfusions, but they also show enhanced susceptibility to infections as a consequence of coexistent immune deficiency. Enhanced susceptibility to infections in β-thalassemia patients is associated with the interplay of several complex biological processes. β-thalassemia-related abnormalities of the innate immune system include decreased levels of complement, properdin, and lysozyme, reduced absorption and phagocytic ability of polymorphonuclear neutrophils, disturbed chemotaxis, and altered intracellular metabolism processes. According to available literature data, immunological abnormalities observed in patients with thalassemia can be caused by both the disease itself as well as therapies. The most important factors promoting such alterations involve iron overload, phenotypical and functional abnormalities of immune system cells resulting from chronic inflammation oxidative stress, multiple blood transfusion, iron chelation therapy, and splenectomy. Unravelling the mechanisms underlying immune deficiency in β-thalassemia patients may enable the designing of appropriate therapies for this group of patients.

scholarly journals Iron overload in thalassemia: different organs at different rates

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 265-271 ◽  
Author(s):  
Ali T. Taher ◽  
Antoine N. Saliba
Keyword(s):  
Iron Overload ◽  
Imaging Techniques ◽  
Globin Gene ◽  
Iron Chelation ◽  
Response To Therapy ◽  
Clinical Severity ◽  
Iron Loading ◽  
Genetic Determinants ◽  
Transfusion Therapy ◽  
Treatment And Prevention

Abstract Thalassemic disorders lie on a phenotypic spectrum of clinical severity that depends on the severity of the globin gene mutation and coinheritance of other genetic determinants. Iron overload is associated with increased morbidity in both patients with transfusion-dependent thalassemia (TDT) and non–transfusion-dependent thalassemia (NTDT). The predominant mechanisms driving the process of iron loading include increased iron burden secondary to transfusion therapy in TDT and enhanced intestinal absorption secondary to ineffective erythropoiesis and hepcidin suppression in NTDT. Different organs are affected differently by iron overload in TDT and NTDT owing to the underlying iron loading mechanism and rate of iron accumulation. Serum ferritin measurement and noninvasive imaging techniques are available to diagnose iron overload, quantify its extent in different organs, and monitor clinical response to therapy. This chapter discusses the general approach to iron chelation therapy based on organ involvement using the available iron chelators: deferoxamine, deferiprone, and deferasirox. Other novel experimental options for treatment and prevention of complications associated with iron overload in thalassemia are briefly discussed.

Severe Thalassemia Intermedia Resulting From Coinheritance of IVSI-110 G>A Beta Gene Mutation and Duplication of Alpha-Globin Gene Cluster in Homozygosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2011-2011 ◽  
Author(s):  
Chiara Refaldi ◽  
Wilma Barcellini ◽  
Elena Cassinerio ◽  
Giovanna Graziadei ◽  
Maria Domenica Cappellini
Keyword(s):  
Gene Cluster ◽  
Molecular Mechanisms ◽  
Globin Gene ◽  
Clinical Severity ◽  
Globin Genes ◽  
Beta Globin ◽  
Thalassemia Intermedia ◽  
Globin Gene Cluster ◽  
Increased Risk ◽  
Alpha Globin

Abstract Abstract 2011 Poster Board I-1033 Introduction The clinical severity of thalassemia intermedia depends on the degree of a/non-a-chains iimbalance. Among the molecular mechanisms responsible for thalassemia intermedia is the coinheritance of excessive a-globin gene production with a defective beta-globin gene. Materials and Methods: we describe an Italian family where thalassemia intermedia apparently segregates as a dominant form but it tourned out to be due to the coinheritance of a beta-globin mutation and a duplication of the alpha-globin gene cluster. The father (aged 51yrs) showed a well tolerated severe chronic hemolytic anemia (Hb 7.5-8.5 g/dL) not transfusion dependent, jaundice, splenomegaly and leg ulcers:The mother (aged 46yrs) has a completely normal hematological and hemoglobin pattern. Two sons (19 and 14 yrs) showed more severe clinical manifestations than the father. They underwent splenectomy at 12 and 13 years respectively without any benefit and afterwards they become transfusion dependent. Results: The hemoglobin analysis revealed that the father and the sons were heterozygotes for the beta mutation IVSI-110 G>A. MLPA analysis of the alpha-globin gene cluster disclosed a full duplication of the alpha-globin locus, spanning a 175 kb from the telomere to the 3'HVR downstream of the alpha-globin gene and including the upstream regulatory element HS-40. This rearrangement increases the number of the active alpha-globin genes in cis from 2 to 4.Surprisengly it was found in heterozygosis in both parents and in homozygosis in both sons. The hematological and molecular data of the family are reported in the table. In the father the 6 alpha-globin genes led to increased synthesis of alpha-chains; the coinheritance with a beta-thalassemia mutation causes a moderate/severe thalassemia intermedia phenotype. The presence of 8 alpha-globin genes in the sons raises further the degree of globin-chains imbalance and exacerbates the clinical phenotype. It is important to note that splenectomy worsened the clinical course.in the 2 homozygotes for the alpha duplication. Conclusions: Based also on previous experience we suggest that splenectomy in patients with a real excess of alphaa chain production is unconvenient since a large amount of circulating red cells with precipitated alpha chains may be responsible for increased hemolysis as well as increased risk of thrombosis This family moreover raises concerns regarding genetic counselling, suggesting that whenever one of the partner is affected by TI it is advisable a complete molecular screening of the couple in order to exclude any possible alpha gene defects interaction Disclosures: No relevant conflicts of interest to declare.

Clinical-Reported Outcomes Of Deferoxamine Versus Deferasirox In The Treatment Of Homozygous BetaThalassemia

2018 ◽  
Vol 9 (SPL1) ◽  
Author(s):  
Zeina A Munim Al-Thanoon ◽  
Zeina A Munim Al-Thanoon ◽  
Mustafa Basil ◽  
Nasih A Al-Kazzaz
Keyword(s):  
Serum Ferritin ◽  
Iron Chelation ◽  
Iron Chelator ◽  
Beta Thalassemia ◽  
Control Group ◽  
Current Standard ◽  
Cross Sectional ◽  
Significant Difference ◽  
Multiple Blood ◽  
Group 2

Iron chelation therapy with deferoxamine (DFO),the current standard for the treatment of iron overload in patients with betathalassemia,requires regular subcutaneous or intravenous infusions. This can lead to reduced quality of life and poor adherence,resulting in increased morbidity and mortality in iron-overloaded patients with beta-thalassemia. Deferasirox (DFX) is an orally administered iron chelator that has been approved for use in many countries. The requirement of an effective,well tolerated iron chelator with a less demanding mode of administration has led to the development of deferasirox. The present study was aimed to compare the satisfaction and compliance with deferoxamine versus deferasirox (Exjade®),a novel oral iron chelator in patients with transfusion - dependent beta- thalassemia. A cross-sectional,single-center investigation study was carried out in the Thalassemia Center of Ibn-Atheer Teaching Hospital in Nineveh province,Iraq. One hundred and eight thalassemic patients aged between 2- 20 years old having received multiple blood transfusions and a serum ferritin greater than 1500 ng/ml. Patients were randomised into two groups. Group 1 received deferoxamine at a dose of 20-50mg/kg/day and group 2 received deferasirox at the dose of 10-30 mg/kg/day. Another 56 apparently healthy volunteers were used as a control group. The assessment of chelation was done during the period between November 2013 and February 2014 by measurement of serum ferritin. Satisfaction and compliance was assessed by using a special questionnaire prepared by the researcher. Out of the 108 thalassemic patients enrolled there was no discontinuation in treatment with the two drugs under study. The serum ferritin did not change significantly in any of the chelation groups. In comparison with the patients who were treated with DFO,those receiving DFX reported a significantly higher rate of compliance and satisfaction (P < 0.05). However,no significant difference was observed between the two groups regarding their satisfaction (P > 0.05).Compliance with deferasirox (50 %) was more than that with deferoxamine (20 %). Satisfaction with deferoxamine was significantly lower than deferasirox (p= 0.00).

scholarly journals Risk Factors, and Clinical and Etiological Characteristics of Ischemic Strokes in COVID-19-Infected Patients: A Systematic Review of Literature

2021 ◽  
pp. 1-4
Author(s):  
Simone Vidale
Keyword(s):  
Risk Factors ◽  
Systematic Review ◽  
Clinical Features ◽  
Case Reports ◽  
Clinical Severity ◽  
Large Artery ◽  
Causal Association ◽  
Review Of Literature ◽  
Increased Risk ◽  
Long Time

<b><i>Background and Purpose:</i></b> Coronavirus disease 2019 (CO­VID-19) infection is an ongoing pandemic and worldwide health emergency that has caused important changes in healthcare systems. Previous studies reported an increased risk of thromboembolic events, including stroke. This systematic review aims to describe the clinical features and etiological characteristics of ischemic stroke patients with CO­VID-19 infection. <b><i>Method:</i></b> A literature search was performed in principal databases for studies and case reports containing data concerning risk factors, clinical features, and etiological characteristics of patients infected with COVID-19 and suffering from stroke. Descriptive and analytical statistics were applied. <b><i>Results:</i></b> Overall, 14 articles were included for a total of 93 patients. Median age was 65 (IQR: 55–75) years with prevalence in males. Stroke occurred after a median of 6 days from COVID-19 infection diagnosis. Median National of Institute of Health Stroke Scale (NIHSS) score was 19. Cryptogenic (Cry) strokes were more frequent (51.8%), followed by cardioembolic etiology, and they occurred a long time after COVID-19 diagnosis compared with large-artery atherosclerosis strokes (<i>p</i><sub>trend</sub>: 0.03). The clinical severity of stroke was significantly associated with the severity grade of COVID-19 infection (<i>p</i><sub>trend</sub>: 0.03). <b><i>Conclusions:</i></b> Ischemic strokes in COVID-19-infected patients were clinically severe, affecting younger patients mainly with Cry and cardioembolic etiologies. Further multicenter prospective registries are needed to better describe the causal association and the effect of COVID-19 infection on stroke.

The Association Between Immunodeficiency and the Development of Autoimmune Disease

1996 ◽  
Vol 10 (1) ◽  
pp. 57-61 ◽  
Author(s):  
J.W. Sleasman
Keyword(s):  
Immune System ◽  
Autoimmune Disease ◽  
Lupus Erythematosus ◽  
Iga Deficiency ◽  
Selective Iga Deficiency ◽  
Increased Risk ◽  
High Incidence ◽  
Autoimmune Cytopenias ◽  
The Complement System ◽  
Common Variable

There is a paradoxical relationship between immunodeficiency diseases and autoimmunity. While not all individuals with immunodeficiency develop autoimmunity, nor are all individuals with autoimmunity immunodeficient, defects within certain components of the immune system carry a high risk for the development of autoimmune disease. Inherited deficiencies of the complement system have a high incidence of systemic lupus erythematosus (SLE), glomerulonephritis, and vasculitis. Carrier mothers of children with chronic granulomatous disease, an X-linked defect of phagocytosis, often develop discoid lupus. Several antibody deficiencies are associated with autoimmune disease. Autoimmune cytopenias are commonly observed in individuals with selective IgA deficiency and common variable immune deficiency. Polyarticular arthritis can be seen in children with X-linked agammaglobulinemia. Combined cellular and antibody deficiencies, such as Wiskott-Aldrich syndrome, carry an increased risk for juvenile rheumatoid arthritis and autoimmune hemolytic anemia. Several hypothetical mechanisms have been proposed to explain the associations between autoimmunity and immunodeficiency. Immunologic defects may result in a failure to exclude microbial antigens, resulting in chronic immunologic activation and autoimmune symptoms. There may be shared genetic factors, such as common HLA alleles, which predispose an individual to both autoimmunity and immunodeficiency. Defects within one component of the immune system may alter the way a pathogen induces an immune response and lead to an inflammatory response directed at self-antigens. An understanding of the immunologic defects that contribute to the development of autoimmunity will provide an insight into the pathogenesis of the autoimmune process.

scholarly journals Human papillomavirus-driven immune deviation: challenge and novel opportunity for immunotherapy

2017 ◽  
Vol 5 (3) ◽  
pp. 69-82 ◽  
Author(s):  
Sigrun Smola ◽  
Connie Trimble ◽  
Peter L. Stern
Keyword(s):  
Human Papillomavirus ◽  
Immune System ◽  
Immune Escape ◽  
Hpv Vaccination ◽  
Suppressor Cells ◽  
Clinical Problem ◽  
Hpv Infection ◽  
Treatment Protocols ◽  
Increased Risk ◽  
Risk Of Cancer

It is now recognized that the immune system can be a key component of restraint and control during the neoplastic process. Human papillomavirus (HPV)-associated cancers of the anogenital tract and oropharynx represent a significant clinical problem but there is a clear opportunity for immune targeting of the viral oncogene expression that drives cancer development. However, high-risk HPV infection of the target epithelium and the expression of the E6/E7 oncogenes can lead to early compromise of the innate immune system (loss of antigen-presenting cells) facilitating viral persistence and increased risk of cancer. In these circumstances, a succession of interacting and self-reinforcing events mediated through modulation of different immune receptors, chemokine and cytokine responses (CCL20; CCL2; CCR2; IL-6; CCR7; IL-12) further promote the generation of an immune suppressive microenvironment [increased levels of Tregs, Th17, myeloid-derived suppressor cells (MDSCs) and PD-L1]. The overexpression of E6/E7 expression also compromises the ability to repair cellular DNA, leading to genomic instability, with the acquisition of genetic changes providing for the selection of advantaged cancer cells including additional strategies for immune escape. Therapeutic vaccines targeting the HPV oncogenes have shown some encouraging success in some recent early-phase clinical trials tested in patients with HPV-associated high-grade anogenital lesions. A significant hurdle to success in more advanced disease will be the local and systemic immune suppressive factors. Interventions targeting the different immunosuppressive components can provide opportunity to release existing or generate new and effective antitumour immunity. Treatments that alter the protumour inflammatory environment including toll-like receptor stimulation, inhibition of IL-6-related pathways, immune-checkpoint inhibition, direct modulation of MDSCs, Tregs and macrophages could all be useful in combination with therapeutic HPV vaccination. Future progress in delivering successful immunotherapy will depend on the configuration of treatment protocols in an insightful and timely combination.

scholarly journals Osteoporosis and periodontitis: a bidirectional relationship

2017 ◽  
Vol 20 (2) ◽  
pp. 19
Author(s):  
Paramjit Kaur Khinda
Keyword(s):  
Immune System ◽  
Osteoclast Differentiation ◽  
Osteoporotic Bone ◽  
Molecular Evidence ◽  
Hormonal Changes ◽  
Inflammatory Conditions ◽  
Current Perspective ◽  
Increased Risk ◽  
Bidirectional Relationship ◽  
Bone Changes

<p>Osteoporosis is a condition of compromised bone strength that predisposes an individual to increased risk of fracture and is a major cause of morbidity in older susceptible individuals. Osteoporosis is related to various endocrinal abnormalities, metabolic and nutritional factors, postmenopausal hormonal changes and consumption of certain drugs such as cortisone. Emerging clinical and molecular evidence suggests that inflammation also exerts significant influence on osteoporotic bone changes. Numerous pro-inflammatory cytokines have been shown to be associated with regulation of osteoblast and osteoclast differentiation. Chronic inflammatory conditions causing immune system remodeling may serve as pathological risk factors for osteoporosis. The present article reviews the current perspective on the interaction between bone morphology and immune system in the inflammatory condition (periodontitis), unleashing the link between two chronic conditions.</p><p><strong>Keywords</strong></p><p>Osteoporosis; Periodontitis; Inflammation; Bone remodelling.</p>

scholarly journals A delta-globin gene derived from patients with homozygous delta zero- thalassemia functions normally on transient expression in heterologous cells

Blood ◽  
1987 ◽  
Vol 70 (3) ◽  
pp. 809-813
Author(s):  
T Nakamura ◽  
Y Takihara ◽  
Y Ohta ◽  
S Fujita ◽  
Y Takagi ◽  
...  
Keyword(s):  
Globin Gene ◽  
Molecular Genetic ◽  
Regulation Of Gene Expression ◽  
Molecular Genetic Analysis ◽  
Nucleotide Sequence Analysis ◽  
Complete Suppression ◽  
Erythroid Cells ◽  
Base Pairs ◽  
Chain Synthesis ◽  
A Chain

Three Japanese individuals with homozygous delta zero-thalassemia from different families were the subjects of molecular genetic analysis. They were homozygous for seven polymorphic sites in the beta-globin gene cluster. Nucleotide sequence analysis of the delta-globin gene cloned from each patient revealed a single nucleotide substitution (T- C) 77 base pairs 5′ to the cap site, just upstream of the CCAAC box of the delta-globin gene. When introduced into COS cells, the gene was expressed at normal levels with proper processing of RNA. These results suggest that the complete suppression of delta-globin chain synthesis in these patients is not due to a defective promoter, a defective RNA processing or a chain terminator mutation, but rather to impaired regulation of gene expression specific to erythroid cells. The region around the CCAAC box may have a significant role in expression of the delta-globin gene in erythroid cells.

scholarly journals Multiple Myeloma and SARS-CoV-2 Infection: Clinical Characteristics and Prognostic Factors of Inpatient Mortality

2020 ◽  
Author(s):  
Joaquín Martínez-López ◽  
María-Victoria Mateos ◽  
Cristina Encinas ◽  
Anna Sureda ◽  
José Ángel Hernández-Rivas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Factors ◽  
Renal Disease ◽  
Cancer Patients ◽  
Case Series ◽  
Clinical Severity ◽  
Collaborative Group ◽  
List Type ◽  
Inpatient Mortality ◽  
Increased Risk

ABSTRACTThere is limited information on the characteristics, pre-admission prognostic factors, and outcomes of patients with multiple myeloma (MM) hospitalized with coronavirus disease 2019 (COVID-19). This retrospective case series investigated characteristics and outcomes of 167 MM patients hospitalized with COVID-19 reported from 73 hospitals within the Spanish Myeloma Collaborative Group network in Spain between March 1 and April 30, 2020. Outcomes were compared with a randomly selected contemporary cohort of 167 age-/sex-matched non-cancer patients with COVID-19 admitted at 6 participating hospitals. Common demographic, clinical, laboratory, treatment, and outcome variables were collected; specific disease status and treatment data were collected for MM patients. Among the MM and non-cancer patients, median age was 71 years and 57% of patients were male in each series, and 75% and 77% of patients, respectively, had at least one comorbidity. COVID-19 clinical severity was moderate-severe in 77% and 89% of patients and critical in 8% and 4%, respectively. Supplemental oxygen was required by 47% and 55% of MM and non-cancer patients, respectively, and 21%/9% vs 8%/6% required non-invasive/invasive ventilation. Inpatient mortality was 34% and 23% in MM and non-cancer patients, respectively. Among MM patients, inpatient mortality was 41% in males, 42% in patients aged >65 years, 49% in patients with active/progressive MM at hospitalization, and 59% in patients with comorbid renal disease at hospitalization, which were independent prognostic factors of inpatient mortality on adjusted multivariate analysis. This case series demonstrates the increased risk and identifies predictors of inpatient mortality among MM patients hospitalized with COVID-19.Key PointsThere is an increased risk of inpatient mortality (34% vs 23%) in MM vs age-/sex-matched non-cancer patients hospitalized with COVID-19.Adverse prognostic factors at admission for inpatient mortality in MM patients include age >65 y, male sex, renal disease, and active MM.

scholarly journals Post-COVID-19 pulmonary fibrosis and its predictive factors: a prospective study

2021 ◽  
Vol 52 (1) ◽  
Author(s):  
Mehrdad Nabahati ◽  
Soheil Ebrahimpour ◽  
Reza Khaleghnejad Tabari ◽  
Rahele Mehraeen
Keyword(s):  
Pulmonary Fibrosis ◽  
Ct Scan ◽  
Predictive Factors ◽  
Lung Fibrosis ◽  
Chest Ct ◽  
Clinical Severity ◽  
Secondary Outcome ◽  
Increased Risk ◽  
Chest Ct Scan

Abstract Background We aimed to prospectively assess the lung fibrotic-like changes, as well as to explore their predictive factors, in the patients who survived Coronavirus Disease 2019 (COVID-19) infection. In this prospective cross-sectional study, we recruited patients who had been treated for moderate or severe COVID-19 pneumonia as inpatients and discharged from Rohani hospital in Babol, northern Iran, during March 2020. The clinical severity of COVID-19 pneumonia was classified as per the definition by World Health Organization. We also calculated the CT severity score (CSS) for all patients at admission. Within the 3 months of follow-up, the next chest CT scan was performed. As the secondary outcome, the patients with fibrotic abnormalities in their second CT scan were followed up in the next 3 months. Results Totally, 173 COVID-19 patients were finally included in the study, of whom 57 (32.9%) were male and others were female. The mean age was 53.62 ± 13.67 years old. At 3-month CT follow-up, evidence of pulmonary fibrosis was observed in 90 patients (52.0%). Consolidation (odds ratio [OR] = 2.84), severe disease (OR 2.40), and a higher CSS (OR 1.10) at admission were associated with increased risk of fibrotic abnormalities found at 3-month CT follow-up. Of 62 patients who underwent chest CT scan again at 6 months of follow-up, 41 patients (66.1%) showed no considerable changes in the fibrotic findings, while the rest of 21 patients (33.9%) showed relatively diminished lung fibrosis. Conclusion Post-COVID-19 lung fibrosis was observed in about half of the survivors. Also, patients with severe COVID-19 pneumonia were at a higher risk of pulmonary fibrosis. Moreover, consolidation, as well as a higher CSS, in the initial chest CT scan, was associated with increased risk of post-COVID-19 lung fibrosis. In addition, some patients experienced diminished fibrotic abnormalities in their chest CT on 6-month follow-up, while some others did not.

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